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"abstract": "Plasmablastic lymphoma (PBL) and plasmablastic plasma cell myeloma (PCM) have many overlapping characteristics. Clinical correlation can help make the distinction between the two entities. Human immunodeficiency virus- (HIV-) negative PBL is a rare disease, making the diagnosis more challenging. While there is no standard of care for PBL, current recommendations include dose-adjusted EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone), with or without bortezomib. We report an aggressive case of HIV-negative plasmablastic lymphoma and discuss the challenge in establishing a diagnosis. We review the literature regarding this disease and current recommendations for treatment.",
"affiliations": "Department of Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA.;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.",
"authors": "Kessler|Alaina J|AJ|0000-0001-9058-5118;Marcellino|Bridget K|BK|0000-0001-8590-6175;Niglio|Scot A|SA|;Petersen|Bruce E|BE|0000-0002-4329-7460;Malone|Adriana K|AK|0000-0003-1581-3445",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2019/2907317",
"fulltext": "\n==== Front\nCase Rep HematolCase Rep HematolCRIHEMCase Reports in Hematology2090-65602090-6579Hindawi 10.1155/2019/2907317Case ReportA Rare Presentation of HIV-Negative Plasmablastic Lymphoma: A Diagnostic Dilemma http://orcid.org/0000-0001-9058-5118Kessler Alaina J. alaina.kessler@mountsinai.org\n1\nhttp://orcid.org/0000-0001-8590-6175Marcellino Bridget K. \n2\nNiglio Scot A. \n2\nhttp://orcid.org/0000-0002-4329-7460Petersen Bruce E. \n3\nhttp://orcid.org/0000-0003-1581-3445Malone Adriana K. \n2\n\n1Department of Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA\n2Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA\n3Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USAAcademic Editor: Marie-Christine Kyrtsonis\n\n2019 13 2 2019 2019 29073178 10 2018 17 12 2018 1 1 2019 Copyright © 2019 Alaina J. Kessler 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.Plasmablastic lymphoma (PBL) and plasmablastic plasma cell myeloma (PCM) have many overlapping characteristics. Clinical correlation can help make the distinction between the two entities. Human immunodeficiency virus- (HIV-) negative PBL is a rare disease, making the diagnosis more challenging. While there is no standard of care for PBL, current recommendations include dose-adjusted EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone), with or without bortezomib. We report an aggressive case of HIV-negative plasmablastic lymphoma and discuss the challenge in establishing a diagnosis. We review the literature regarding this disease and current recommendations for treatment.\n==== Body\n1. Introduction\nPlasmablastic lymphoma (PBL), a variant of diffuse large B-cell lymphoma (DLBCL), and plasmablastic plasma cell myeloma (PCM) have many overlapping features, often relying on clinical factors to make the distinction between the two entities. While the majority of cases of PBL are described in patients with human immunodeficiency virus (HIV), HIV-negative PBL is a rare disease associated with poor outcomes, making the diagnosis even more challenging [1]. The distinction between PBL and PCM is important to guide treatment. Although there is no current standard of care for PBL, the most recent literature recommends dose-adjusted EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone), with or without bortezomib, as first-line therapy [2]. Stem cell transplant (SCT) should be considered for chemosensitive patients [2]. This case highlights an aggressive presentation of a rare entity, HIV-negative PBL, and the challenges of diagnosis and treatment.\n\n2. Case Presentation\nAn 81-year-old male with a history of heart failure with reduced ejection fraction, coronary artery disease with a history of coronary artery bypass grafting, atrial fibrillation (on warfarin), chronic obstructive lung disease, and diabetes mellitus presented to the emergency department with worsening shortness of breath. Two weeks prior to presentation, he had experienced sharp left-sided abdominal pain, which resolved without intervention. Approximately one week prior to presentation, he reported increased dyspnea and orthopnea, which remained present on admission. Additionally, he reported numerous episodes of spontaneous epistaxis for the past week.\n\nOn presentation to the emergency department, he was afebrile but tachycardic, tachypneic, and hypoxic to 83% on room air. No neurologic deficits were noted. Initial laboratory examination showed a white blood cell count of 21,500 cells/mm3 (reference range 4,500–11,000 cells/mm3) with 5% atypical lymphocytes, 22% band cells, 5% metamyelocytes, 2% myelocytes, a hemoglobin of 12.1 g/dL (reference range 13.9–16.3 g/dL), and a platelet count of 42,000/μL (reference range 150,000–450,000/μL). The INR was 4.4, PT was 40.9 seconds (reference range 12.3–14.0 seconds), and APTT was 46.3 seconds (reference range 25.4–34.9 seconds). Chemistries were notable for a creatinine of 3.4 mg/dL (baseline 1.5 mg/dL), total protein 6.5 g/dL (reference range 6.0–8.3 g/dL), albumin 3.2 g/dL (reference range 3.5–4.9 g/dL), AST 310 U/L (reference range 1–35 U/L), ALT 22 U/L (reference range 1–45 U/L), uric acid > 30 mg/dL (reference range 4.0–9.0 mg/dL), and lactate dehydrogenase (LDH) 12,851 U/L (reference range 100–220 U/L). Calcium was within normal limits. Serum free light chain analysis demonstrated elevated free kappa 13,889 mg/L (reference range 3.3–19.4 mg/L) with a kappa/lambda ratio of 491.5 (reference range 0.26–1.65). M-spike was 0.00 g/dL. Testing for HIV was negative. Epstein–Barr virus (EBV) testing was consistent with prior exposure, with EBV IgM negative and IgG positive. Computerized tomography (CT) of the chest, abdomen, and pelvis without contrast showed extensive mediastinal and hilar lymphadenopathy (measuring up to 2 cm), which had increased in size and extent since imaging six months prior which was obtained as routine follow-up for a left lung nodule; no lytic lesions of the bone were identified. He was initiated on dialysis in the setting of worsening renal failure and subsequently intubated for hypoxemic respiratory failure. Bronchoscopy revealed diffuse alveolar hemorrhage.\n\nPeripheral blood flow cytometry showed an aberrant kappa-restricted monotypic plasmacytoid population comprising 7-8% of total (CD138+, CD38 bright+, cytoplasmic kappa+, CD19−, CD56 dim+, CD45+, CD20−, and CD22−). Bone marrow biopsy (Figure 1) showed a hypercellular marrow (60–70%), with an infiltrate of markedly pleomorphic kappa-restricted monotypic plasmacytoid cells, many with immature features, comprising approximately 50% of overall cellularity (CD138+, kappa+, lambda−, CD117 focal+, CD56−, CD20−, and TdT−, by immunohistochemistry). In situ hybridization study for EBV-encoded RNA (EBER) was negative; however, sensitivity may have been limited due to decalcification. Flow cytometry showed an immunophenotype similar to that of the peripheral blood specimen.\n\nCytogenetic analysis demonstrated 100% of cells with a complex karyotype consisting of a jumping 1q translocation between t(1;3), t(1;11), and t(1;12) resulting in gains of 1q; a balanced translocation between the long arm of chromosomes 8 and 14, associated with MYC-IGH fusion; interstitial deletions of chromosomes 4p and 4q; gains/partial gains of chromosomes 7 and 12, and a derivative chromosome 21 as a result of an unbalanced translocation t(13;21) resulting in three copies of 13q. FISH analysis showed 43% of cells with MYC-IGH [t(8;14)] fusion.\n\nThe differential diagnosis included plasmablastic lymphoma (PBL) and plasmablastic plasma cell myeloma (PCM). The favored diagnosis of PBL was largely based on clinical factors, including the highly aggressive presentation, lymphadenopathy both above and below the diaphragm, and absence of lytic lesions.\n\nDue to advanced age, comorbidities, and impaired renal function, the decision was made to treat with dose-adjusted V-EPOCH (bortezomib, etoposide, dexamethasone, vincristine, cyclophosphamide, and doxorubicin) with the plan for 50% dose reduction of etoposide, doxorubicin, and vincristine and 25% dose reduction of cyclophosphamide on account of the patient being in acute renal failure. The patient received bortezomib (1.3 mg/m2 on day 1), doxorubicin (5 mg/m2 on days 1 and 2), etoposide (25 mg/m2 on days 1 and 2), and vincristine (0.2 mg/m2 on days 1 and 2). After two days of chemotherapy, he was noted to have unequal pupillary size. Magnetic resonance imaging (MRI) of the brain revealed watershed temporal lobe infarctions, and further chemotherapy was held. Based on his family's wishes, the patient was transitioned to comfort care measures and transferred to the palliative care unit. He was palliatively extubated and died 12 hours later.\n\n3. Discussion\nThe case presented here exemplifies the difficulty of distinguishing between PBL, a variant of diffuse large B-cell lymphoma (DLBCL), and PCM with extramedullary involvement. Distinguishing between the two can be difficult as the two entities have many overlapping characteristics. It is imperative however to make this diagnostic distinction because the two entities are treated differently.\n\nPBL and PCM have similar morphological and immunophenotypic features but subtle histological differences have been noted by Vega et al. [3]. PBL typically demonstrates a proliferation of plasmablasts and immunoblasts with rare cells showing mature plasmacytic differentiation. In contrast, cells with plasmacytic differentiation are typically more numerous in PCM. The two entities also have similar immunophenotypic profiles with both expressing plasma cell markers, such as CD38, CD138, and MUM1, without classic B-cell markers, such as CD19, CD20, and PAX-5 [3]. Monotypic light chain expression has been demonstrated in both PBL and PCM [3]. Complex karyotypes have also been shown to be associated with both entities [4]. Rearrangements in MYC, an oncogene originally described in Burkitt lymphoma, have been associated with both tumor progression in multiple myeloma as well as plasmablastic lymphoma [1, 4]. Despite these similar features, genomic profiling suggests PBL may be more closely related to DLBCL based on segmental gains such as 16p13.3 frequently seen in both diseases. [5].\n\nDue to the overlapping pathologic features of PBL and PCM, clinical correlation is nearly always required to make the distinction between these two entities. PBL is highly associated with viral reactive lymphadenopathies such as HIV and EBV [3, 6, 7]. EBV positivity is detected more frequently in HIV-positive patients (75%) and posttransplant PBL (67%) compared to PBL in immunocompetent patients (50%) [1]. This patient was HIV-negative, and presence or absence of EBV could not be firmly established. While some criteria for multiple myeloma were present including anemia, renal insufficiency, and elevated free light-chain ratio, the patient lacked the presence of lytic lesions and hypercalcemia that would have favored a diagnosis of multiple myeloma [8]. Ultimately, the diagnosis of PBL was favored over PCM due to the aggressive presentation associated with diffuse lymphadenopathy, elevated LDH, and hyperuricemia.\n\nAlthough the actual incidence of HIV-negative PBL is unknown, the limited numbers of published cases suggest it is a rare entity. The largest case review from 1997 to 2014 revealed only 164 cases of HIV-negative PBL [2]. HIV-negative PBL is a male-predominant malignancy with a median age of 55 years [2]. The majority (75%) of patients with HIV-negative PBL are immunocompetent although PBL has been associated with lymphoproliferative and autoimmune disorders [9]. PBL has also been identified after solid organ transplantation [9]. A review of 76 patients with HIV-negative PBL showed the majority (89%) of patients presented with extranodal involvement, including disease in the oral cavity (21%), gastrointestinal tract (20%), soft tissue (17%), and bone marrow (15%) [9]. Poor prognostic factors include immunosuppression, Ann Arbor stage IV, EBV negativity, disease refractory to treatment, and C-MYC aberrations [1, 10]. Median overall survival of immunocompetent patients with PBL ranged from 11 to 19 months [1, 10].\n\nWhile plasmablastic plasma cell myeloma is initially treated with VRd (bortezomib, lenalidomide, and dexamethasone), there is no standard of care for PBL [2, 11]. Given the poor outcomes and lack of response to commonly used chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and CHOP-like regimens, the National Comprehensive Cancer Network (NCCN) guidelines state that standard CHOP is not adequate treatment [12]. The NCCN recommends dose-adjusted EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone), CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide, and cytarabine), or Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine).\n\nRecent studies have focused on new therapeutic approaches, specifically the use of bortezomib, a proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma. There are limited case reports using bortezomib in patients with HIV-negative PBL. A recent review of the literature through March 2017 by Guerrero-Garcia et al. [13] identified 21 patients, ten of which (48%) were HIV-negative PBL. All had extranodal involvement. Of these ten patients, three (30%) patients achieved complete response and seven (70%) patients had partial response. Also of note in the frontline setting, the three patients (60%) who achieved complete response had received bortezomib as part of CYBORD (cyclophosphamide, bortezomib, and dexamethasone) or in combination with EPOCH. A recently published case report of PBL involving the right parotid gland in a HIV-negative patient showed continuous complete remission at 12 months using bortezomib plus lenalidomide upon relapse after CHOP [14]. Another case report of HIV-negative PBL utilizing a lenalidomide-based regimen with complete remission at 24 months suggests its usage as an alternative therapy for patients unable to tolerate intensive chemotherapy [8].\n\nStem cell transplant (SCT) should be considered for chemosensitive patients. A small case series of nine patients with HIV-negative PBL in which all were treated with CHOP or hyper-CVAD showed that seven patients achieved complete response and one patient achieved a partial response. [15] Three of the seven patients who achieved complete response and one patient who achieved partial response underwent consolidation with high-dose chemotherapy and autologous hematopoietic SCT. Of these four patients, two had no evidence of disease at 24 months. Although a small case series, these findings suggest that SCT can obtain durable and prolonged responses. The suggested treatment by Castillo et al. [2] is six cycles of infusional dose-adjusted EPOCH, with or without bortezomib, accompanied by intrathecal prophylaxis with each cycle of EPOCH as first-line therapy. For appropriate candidates, those authors also recommend consolidative high-dose chemotherapy followed by autologous SCT for patients in first remission. In patients who are chemorefractory in whom autologous SCT is not feasible, there is a single case report of an allogeneic SCT with cord blood transplantation achieving durable remission [16]. Recent data show SLAMF2 (CD319/CS1), targetable by elotuzumab, is expressed in PBL and has been proposed as a potential therapeutic target [17].\n\nIn conclusion, this case highlights an aggressive presentation of a rare entity, HIV-negative PBL, and discusses the clinical dilemma arriving at the diagnosis. As with this case, clinical correlation is frequently required to make the diagnosis. The distinction between these two entities is important for guiding treatment.\n\nConflicts of Interest\nDr. Niglio discloses his other significant works for STEMCELL Technologies.\n\nFigure 1 (a, b) Bone marrow biopsy with extensive infiltration by atypical plasmacytoid cells (original magnifications: ×100; ×400). (c) The cells are positive for CD138 by immunohistochemistry, indicative of plasma cell differentiation (original magnification: ×400). (d) Atypical plasmacytoid cells, including forms with plasmablastic morphology, as visualized on bone marrow aspirate smear (original magnification: ×1000).\n==== Refs\n1 Morscio J. Dierickx D. Nijs J. Clinicopathologic comparison of plasmablastic lymphoma in HIV-positive, immunocompetent, and posttransplant patients The American Journal of Surgical Pathology 2014 38 7 875 886 10.1097/pas.0000000000000234 2-s2.0-84902550662 24832164 \n2 Castillo J. J. Bibas M. Miranda R. N. The biology and treatment of plasmablastic lymphoma Blood 2015 125 15 2323 2330 10.1182/blood-2014-10-567479 2-s2.0-84927547047 25636338 \n3 Vega F. Chang C.-C. Medeiros L. J. Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles Modern Pathology 2004 18 6 806 815 10.1038/modpathol.3800355 2-s2.0-20344381814 \n4 Taddesse-Heath L. Meloni-Ehrig A. Scheerle J. Kelly J. C. Jaffe E. S. Plasmablastic lymphoma with MYC translocation: evidence for a common pathway in the generation of plasmablastic features Modern Pathology 2010 23 7 991 999 10.1038/modpathol.2010.72 2-s2.0-77954244220 20348882 \n5 Chang C.-C. Zhou X. Taylor J. J. Genomic profiling of plasmablastic lymphoma using array comparative genomic hybridization (aCGH): revealing significant overlapping genomic lesions with diffuse large B-cell lymphoma Journal of Hematology and Oncology 2009 2 1 p. 47 10.1186/1756-8722-2-47 2-s2.0-72849134550 \n6 Carbone A. Cesarman E. Spina M. Gloghini A. Schulz T. F. HIV-associated lymphomas and gamma-herpesviruses Blood 2009 113 6 1213 1224 10.1182/blood-2008-09-180315 2-s2.0-60849090778 18955561 \n7 Montes-Moreno S. Montalbán C. Piris M. A. Large B-cell lymphomas with plasmablastic differentiation: a biological and therapeutic challenge Leukemia & Lymphoma 2011 53 2 185 194 10.3109/10428194.2011.608447 2-s2.0-84856095900 21812534 \n8 Schmit J. M. DeLaune J. Norkin M. Grosbach A. A case of plasmablastic lymphoma achieving complete response and durable remission after lenalidomide-based therapy Oncology Research and Treatment 2017 40 1-2 46 48 10.1159/000455146 2-s2.0-85009971733 28095384 \n9 Castillo J. J. Winer E. S. Stachurski D. HIV-negative plasmablastic lymphoma: not in the mouth Clinical Lymphoma Myeloma and Leukemia 2011 11 2 185 189 10.1016/j.clml.2011.03.008 2-s2.0-79955011995 \n10 Liu M. Liu B. Liu B. Human immunodeficiency virus-negative plasmablastic lymphoma: a comprehensive analysis of 114 cases Oncology Reports 2015 33 4 1615 1620 10.3892/or.2015.3808 2-s2.0-84924898324 25695332 \n11 Yadav S. Kumar R. Jaiyesimi I. A. Aggressive plasmablastic multiple myeloma in a 42-year-old: is inflammatory bowel disease or infliximab treatment to be blamed? BMJ Case Reports December 2018 10.1136/bcr-2013-200607 \n12 National Comprehensive Cancer Network Non- Hodgkin’s lymphomas (version 4.2014). NCCN guidelines website November 2017 https://www.nccn.org/about/nhl.pdf \n13 Guerrero-Garcia T. A. Mogollon R. J. Castillo J. J. Bortezomib in plasmablastic lymphoma: a glimpse of hope for a hard-to-treat disease Leukemia Research 2017 62 12 16 10.1016/j.leukres.2017.09.020 2-s2.0-85030114518 28963907 \n14 Marrero W. D. Cruz-Chacón A. Castillo C. Cabanillas F. Successful use of bortezomib-lenalidomide combination as treatment for a patient with plasmablastic lymphoma Clinical Lymphoma Myeloma and Leukemia 2018 18 7 e275 e277 10.1016/j.clml.2018.04.011 2-s2.0-85046629830 \n15 Liu J. J. Zhang L. Ayala E. Human immunodeficiency virus (HIV)-negative plasmablastic lymphoma: a single institutional experience and literature review Leukemia Research 2011 35 12 1571 1577 10.1016/j.leukres.2011.06.023 2-s2.0-80055119570 21752466 \n16 Nishi K. Mitani S. Hatanaka K. Imada K. Successful cord blood transplantation for an HIV-negative patient with refractory plasmablastic lymphoma Annals of Hematology 2017 96 6 1057 1058 10.1007/s00277-017-2977-y 2-s2.0-85015205458 28293711 \n17 Shi J. Bodo J. Zhao X. SLAMF7 (CD319/CS1) is expressed in plasmablastic lymphoma and is a potential diagnostic marker and therapeutic target British Journal of Haematology 2018 10.1111/bjh.15393\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6579",
"issue": "2019()",
"journal": "Case reports in hematology",
"keywords": null,
"medline_ta": "Case Rep Hematol",
"mesh_terms": null,
"nlm_unique_id": "101576456",
"other_id": null,
"pages": "2907317",
"pmc": null,
"pmid": "30906602",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "15578069;18955561;19909553;20348882;21575922;21752466;21812534;24169869;24832164;25636338;25695332;28095384;28293711;28963907;29753690;29785767",
"title": "A Rare Presentation of HIV-Negative Plasmablastic Lymphoma: A Diagnostic Dilemma.",
"title_normalized": "a rare presentation of hiv negative plasmablastic lymphoma a diagnostic dilemma"
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"companynumb": "US-ACCORD-118447",
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"abstract": "BACKGROUND\nCardiotoxicity associated with 5-Fluorouracil (5FU) administration has been infrequently reported in literature, albeit various series of acute coronary syndromes have recorded a low but definite incidence of the above toxicity. In the present study, patients undergoing 5FU-based and oral capecitabine (Xeloda-based chemotherapy were tested for the potential development of cardiac-related symptoms during their administration.\n\n\nMETHODS\nSix hundred and forty-four patients entered the study. Those experiencing any cardiac-related symptoms during 5FU infusion or oral capecitabine were subjected to ECG and serum cardiac enzymes determination. If cardiotoxicity was confirmed, 5FU infusion or oral capecitabine were interrupted, sublingual nitrates administered and cardiac monitoring initiated, while patients with >two-fold enzyme elevation were followed in a coronary care unit for at least 72 h. Cases with acute myocardial infarction were excluded from further 5FU or oral capecitabine treatment.\n\n\nRESULTS\nOverall 26 patients (4.03%) developed symptoms and/or ECG abnormalities due to 5FU and capecitabine. Patients with continuous 5FU infusion presented a higher incidence of cardiotoxicity [14/209; 6.7%, 95% confidence interval (CI) = 3.3-10.1%] than the remaining (7/317; 2.3%, 95% CI = 0.8-3.3%) (P < 0.012). Specifically, an increased incidence of cardiac-related events was encountered in patients with continuous 24-h 5FU + LV infusion for 5 days (12.5%, 95% CI = 2.3-22.7%) rather than in patients with the same schedule without LV (5.3%, 95% CI = 1.95-8.67%) (P < 0.027), as well as in patients with short 5FU + LV administration (2.4%, 95% CI = 0.9-3.9%) (P < 0.019). Overall, 3/54 patients (5.5%, 95% CI = -0.6-11.1%) on oral capecitabine developed cardiac-related events. Seven out of the 20 patients suffered an acute myocardial infarction, 6 developed ischemia only, while 4 more patients had ECG consistent with coronary vasospasm and 3 with conduction disturbances, of which one subsequently died. Patients administered oral capecitabine had a similar incidence of cardiac-related events; 1/22 (4.5%) patients with advanced breast cancer and 2/32 (6.2%) with colorectal cancer.\n\n\nCONCLUSIONS\nThe present study supports the toxic effect of 5-FU on the myocardium, which is largely schedule-dependent, whereas a low but finite risk of such toxicity has been observed with oral capecitabine. A high level of alertness is required when using fluoropyrimidines (i.v. 5FU or oral capecitabine), while their toxic effect on the coronary endothelium and myocardium merits further investigation.",
"affiliations": "Department of Medicine, 2nd Division of Medical Oncology, \"Metaxa\" Cancer Hospital, Piraues, 21 Apolloniou Street, 16341 Athens, Greece. ckosm1@ath.forthnet.gr",
"authors": "Kosmas|Christos|C|;Kallistratos|Manolis S|MS|;Kopterides|Petros|P|;Syrios|John|J|;Skopelitis|Helias|H|;Mylonakis|Nicolaos|N|;Karabelis|Athanasios|A|;Tsavaris|Nicolas|N|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil",
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"issue": "134(1)",
"journal": "Journal of cancer research and clinical oncology",
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"medline_ta": "J Cancer Res Clin Oncol",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D001943:Breast Neoplasms; D000069287:Capecitabine; D015179:Colorectal Neoplasms; D003841:Deoxycytidine; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005260:Female; D005472:Fluorouracil; D006258:Head and Neck Neoplasms; D006321:Heart; D006331:Heart Diseases; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies",
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"pmid": "17636329",
"pubdate": "2008-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "647321;5804822;9687887;9813641;2466960;12075751;11996484;8391384;835599;4662004;386594;70620;1222391;8714749;8905032;630214;9250550;1671927;7168016;9296228;3275485;1403060;8233284;7241861;16418875;8374883;7954023;4590654",
"title": "Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study.",
"title_normalized": "cardiotoxicity of fluoropyrimidines in different schedules of administration a prospective study"
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"companynumb": "GR-ALKEM LABORATORIES LIMITED-GR-ALKEM-2018-02383",
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"abstract": "Permanent junctional reciprocating tachycardia (PJRT) is a rare supraventricular tachycardia (SVT), typically involving a single decremental posteroseptal accessory pathway (AP).\n\n\n\nFour patients with long RP SVT underwent electrophysiology (EP) study and ablation. The cases were reviewed.\n\n\n\nCase 1 recurred despite 3 prior ablations at the site of earliest retrograde atrial activation during orthodromic reciprocating tachycardia (ORT). Mapping during a repeat EP study demonstrated a prepotential in the coronary sinus (CS). Ablation over the earliest atrial activation in the CS resulted in dissociation of the potential from the atrium during sinus rhythm. The potential was traced back to the CS os and ablated. Case 2 underwent successful ablation at 6 o'clock on the mitral annulus (MA). ORT recurred and successful ablation was performed at 1 o'clock on the MA. Case 3 had tachycardia with variation in both V-A and A-H intervals which precluded the use of usual maneuvers so we used simultaneous atrial and ventricular pacing and introduced a premature atrial contraction with a closely coupled premature ventricular contraction. Case 4 had had two prior atrial fibrillation ablations with continued SVT over a decremental atrioventricular bypass tract that was successfully ablated at 5 o'clock on the tricuspid annulus. A second SVT consistent with a concealed nodoventricular pathway was successfully ablated at the right inferior extension of the AV nodal slow pathway.\n\n\n\nWe describe challenging cases of PJRT by virtue of complex anatomy, diagnostic features, and multiple arrhythmia mechanisms.",
"affiliations": "Division of Cardiovascular Medicine, Department of Medicine, University of California Davis, Sacramento, California, USA.;Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.;Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.;Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.;Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.;Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.;Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.;Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.;Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.;Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.",
"authors": "Oesterle|Adam|A|0000-0003-1847-8662;Lee|Adam C|AC|;Voskoboinik|Aleksandr|A|;Moss|Joshua D|JD|0000-0002-0769-8072;Vedantham|Vasanth|V|;Walters|Tomos E|TE|;Lee|Byron K|BK|;Tseng|Zian H|ZH|;Gerstenfeld|Edward P|EP|0000-0002-7200-3521;Scheinman|Melvin M|MM|",
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"issue": "31(12)",
"journal": "Journal of cardiovascular electrophysiology",
"keywords": "ablation; accessory pathway; permanent junctional reciprocating tachycardia; supraventricular tachycardia",
"medline_ta": "J Cardiovasc Electrophysiol",
"mesh_terms": "D001283:Atrioventricular Node; D017115:Catheter Ablation; D004562:Electrocardiography; D006801:Humans; D054139:Tachycardia, Reciprocating; D013617:Tachycardia, Supraventricular",
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"pages": "3232-3242",
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"pmid": "33107135",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
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"title": "Electrophysiologic approach to diagnosis and ablation of patients with permanent junctional reciprocating tachycardia associated with complex anatomy and/or physiology.",
"title_normalized": "electrophysiologic approach to diagnosis and ablation of patients with permanent junctional reciprocating tachycardia associated with complex anatomy and or physiology"
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"abstract": "Promyelocytic blast crisis arising from chronic myeloid leukemia (CML) is rare. We present a 40-year-old male who developed promyelocytic blast crisis 17 months after CML diagnosis, confirmed by the presence of the t(15;17) and t(9;22) translocations in the leukemic cells. Preserved nucleic acids from routine BCR-ABL1 testing provided a unique opportunity to evaluate clonal progression over time. Retrospective analysis demonstrated PML-RARA fusion transcripts were first detectable 8 months prior to blast crisis presentation. A review of 21 cases of promyelocytic blasts crisis published in the literature reveals a male predominance with earlier age at onset as compared to females. Interestingly, TKI therapy during chronic phase did not impact the time interval between diagnosis and promyelocytic blast crisis. Treatment with standard acute promyelocytic leukemia regimens provides more favorable outcomes with complete molecular remission. Although rare, it is important to consider a promyelocytic blast crisis when evaluating for transformation of CML due to its effective treatment with specific therapies.",
"affiliations": "Wake Forest Baptist Medical Center, Department of Pathology, Winston-Salem, NC, USA.;Molecular Pathology Laboratory Network, Maryville, TN, USA.;Wake Forest Baptist Medical Center, Department of Pathology, Winston-Salem, NC, USA.;Wake Forest Baptist Medical Center, Department of Pathology, Winston-Salem, NC, USA.;Wake Forest Baptist Medical Center, Department of Pathology, Winston-Salem, NC, USA.;Wake Forest Baptist Comprehensive Cancer Center, Section on Hematology and Oncology, Winston-Salem, NC, USA.;Wake Forest Baptist Medical Center, Department of Pathology, Winston-Salem, NC, USA.",
"authors": "Wolanin|Stephanie|S|;McCall|Robert K|RK|;Pettenati|Mark J|MJ|;Beaty|Michael W|MW|;Insuasti-Beltran|Giovanni|G|;Powell|Bayard L|BL|;O'Neill|Stacey S|SS|https://orcid.org/0000-0002-7006-9615",
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"doi": "10.1155/2020/8830595",
"fulltext": "\n==== Front\nCase Rep Hematol\nCase Rep Hematol\nCRIHEM\nCase Reports in Hematology\n2090-6560 2090-6579 Hindawi \n\n10.1155/2020/8830595\nCase Report\n\nPML-RARA Fusion Transcripts Detectable 8 Months prior to Promyelocytic Blast Crisis in Chronic Myeloid Leukemia\nWolanin Stephanie \n1\n McCall Robert K. \n2\n Pettenati Mark J. \n1\n Beaty Michael W. \n1\n Insuasti-Beltran Giovanni \n1\n Powell Bayard L. \n3\n https://orcid.org/0000-0002-7006-9615O'Neill Stacey S. soneill@wakehealth.edu\n1\n \n1Wake Forest Baptist Medical Center, Department of Pathology, Winston-Salem, NC, USA\n\n2Molecular Pathology Laboratory Network, Maryville, TN, USA\n\n3Wake Forest Baptist Comprehensive Cancer Center, Section on Hematology and Oncology, Winston-Salem, NC, USA\nAcademic Editor: Sudhir Tauro\n\n\n2020 \n1 9 2020 \n2020 883059524 5 2020 11 8 2020 18 8 2020 Copyright © 2020 Stephanie Wolanin et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Promyelocytic blast crisis arising from chronic myeloid leukemia (CML) is rare. We present a 40-year-old male who developed promyelocytic blast crisis 17 months after CML diagnosis, confirmed by the presence of the t(15;17) and t(9;22) translocations in the leukemic cells. Preserved nucleic acids from routine BCR-ABL1 testing provided a unique opportunity to evaluate clonal progression over time. Retrospective analysis demonstrated PML-RARA fusion transcripts were first detectable 8 months prior to blast crisis presentation. A review of 21 cases of promyelocytic blasts crisis published in the literature reveals a male predominance with earlier age at onset as compared to females. Interestingly, TKI therapy during chronic phase did not impact the time interval between diagnosis and promyelocytic blast crisis. Treatment with standard acute promyelocytic leukemia regimens provides more favorable outcomes with complete molecular remission. Although rare, it is important to consider a promyelocytic blast crisis when evaluating for transformation of CML due to its effective treatment with specific therapies.\n==== Body\n1. Introduction\nChronic myeloid leukemia (CML) is a myeloproliferative neoplasm defined by the presence of a translocation between chromosomes 9 and 22 leading to the BCR-ABL1 gene fusion product. The aberrant fusion protein leads to abnormal activation of multiple cellular signaling pathways including JAK/STAT, PI3K/AKT, and Ras/MEK that promote cell growth and survival [1, 2]. Without therapy, progression from chronic phase to accelerated and blast phase is typical. Small molecule tyrosine kinase inhibitors (TKIs) that selectively inhibit the BCR-ABL1 fusion protein have dramatically prolonged survival of CML patients from an average of 3 years to greater than 8 years and decreased the annual rate of progression to blast crisis from 20% to less than 1% per year [1, 3–5]. While fewer patients continue on to develop blast crisis, the prognosis in blast crisis remains poor, with death generally 3-4 months after diagnosis in pre-TKI era and 7–11 months with TKI therapy [4, 6].\n\nBlast crisis in CML derives from the myeloid lineage in 70% of cases, with the majority of the remaining cases having a lymphoid origin [4]. Rare forms of blast crisis have been described including megakaryocytic, erythroid, monoblastic, eosinophilic, basophilic, and biphenotypic [4]. Promyelocytic blast crisis is a rare variant with <25 cases reported in the literature. Herein, we present a case of CML with promyelocytic blast crisis and review of the literature.\n\n2. Case Presentation\nThe patient is a 40-year-old male with a past medical history significant for classic Hodgkin lymphoma treated with 4 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and adjuvant radiation therapy. Approximately seven years after achieving a complete remission, the patient was noted to have asymptomatic leukocytosis (white blood count 44 × 103/μL) during routine follow-up (Table 1). A differential count revealed prominent neutrophilia with maturational left shift and basophilia. No circulating blasts were identified. Hemoglobin and platelets were within normal ranges.\n\nA bone marrow biopsy performed at that time revealed a hypercellular marrow (greater than 95%) with a marked myeloid hyperplasia with maturational left shift and increased myeloid to erythroid ratio. There was no increase in blasts or myelofibrosis. Routine cytogenetics demonstrated presence of the t(9;22)(q34;q11.2) translocation in all cells; no other chromosomal abnormalities were detected (Table 1). Fluorescent in situ hybridization (FISH) was positive for BCR-ABL1 fusion events in 96% of interphase nuclei. Quantitative real-time polymerase chain reaction (RT-PCR) performed on the peripheral blood was positive for p210 BCR-ABL1 fusion transcripts, with an international scale percent ratio (IS%) of 93.869% (Table 2). Together, the findings supported the diagnosis of chronic myeloid leukemia, BCR-ABL1-positive, in chronic phase. The patient was initially treated with imatinib 400 mg daily for 5 months and then reduced for low neutrophils to 300 mg daily for seven months. However, a major molecular response defined as IS% ≤0.1% [7] was not achieved, and therapy was changed to dasatinib 100 mg daily approximately a year after diagnosis secondary to increasing BCR-ABL1 transcripts by RT-PCR testing. His dose of dasatinib was reduced to 60 mg daily for cytopenias just prior to his diagnosis of blast crisis.\n\nSeventeen months after the initial CML diagnosis, routine laboratory evaluation revealed pancytopenia with circulating immature myeloid cells (Table 1). Clinically, the patient was asymptomatic without splenomegaly or evidence of bleeding. Peripheral blood smear review demonstrated 44% immature cells with rare Auer rods, concerning promyelocytic blast crisis. Coagulation studies showed no definitive evidence of disseminated intravascular coagulation.\n\nFlow cytometric analysis of peripheral blood demonstrated an immature myeloid population comprising 42% of all cells with expression of CD13, CD33, CD64, CD4, CD117 (dim), CD38, CD45, and cytoplasmic MPO and without expression of CD34, HLA-DR, or CD11c. The bone marrow revealed a mildly hypercellular marrow largely replaced by promyelocytes (67% by manual aspirate differential count; Figure 1). Morphologically, the promyelocytes had a classic appearance with “sliding-plate” nuclei, course cytoplasmic granules, occasional nucleoli, and Auer rods.\n\nRoutine cytogenetic analysis demonstrated an abnormal cell line containing t(9;22)(q34;q11.2) with a simultaneous t(15;17)(q22;q21) translocation involving 18 of 20 metaphases examined (Figure 2); the two remaining cells showed a normal male karyotype. FISH was positive for the BCR-ABL1 and PML-RARA fusions in 41% and 47% of interphase nuclei, respectively. Quantitative RT-PCR performed on peripheral blood revealed a p210 BCR-ABL1 IS% of 49.667% (Table 2). Quantitative RT-PCR for the common breakpoints associated with the PML-RARA fusion including bcr1 (long form) and bcr3 (short form) was positive for bcr3 (short form) with a fusion to control ratio of 0.2029 in peripheral blood and 0.2909 in bone marrow; bcr1 was negative in both.\n\nWith the aggregate evaluation, a diagnosis of chronic myeloid leukemia in promyelocytic blast phase was rendered. Induction treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) was initiated using the regimen developed by Lo-Coco et al. with arsenic trioxide 0.15 mg/kg intravenously daily and all-trans retinoic acid 45 mg per square meter divided into twice daily oral doses [8]; treatment was continued until blood count recovery (42 days). Dasatinib was restarted on day 4 of induction therapy after tolerance, and a stable QTc was confirmed. Dasatinib was held on days 14–16 for pulmonary edema but restarted with aggressive fluid management; it was discontinued prior to discharge on day 42 when repeat imaging showed pulmonary edema, bilateral pleural effusions, and a moderate pericardial effusion. Two weeks after discharge, he was started on nilotinib 300 mg daily, followed in another two weeks by initiation of outpatient consolidation therapy with ATRA 14 days on and 14 days off for seven cycles plus ATO 5 days per week for 4 weeks on and 4 weeks off for four cycles (same doses as induction [8]). The ATRA dose was decreased to 50% beginning with cycle 2 for headaches. Nilotinib was increased to 300 mg twice daily after completion of ATRA and ATO consolidation but was reduced two weeks later after the patient developed rash and dizziness. He is currently on a dose of 150 mg in the morning and 300 mg in the evening. The side effects observed are commonly noted with the individual agents and do not suggest increased toxicities with the combination of a TKI with ATRA and ATO. Fluid retention including pleural and pericardial effusions is well described with dasatinib, and headaches are a common toxicity of ATRA, frequently requiring dose reduction and even discontinuation. His QTc remained stable throughout induction and consolidation therapy.\n\nThe patient had a complete morphologic and molecular remission of the promyelocytic blast crisis in less than three months, and RT-PCR for PML-RARA transcripts remains undetectable 26 months after diagnosis. With respect to the p210 BCR-ABL1 transcripts, the patient reached a major molecular response 7 months after diagnosis of blast crisis but has not achieved a complete molecular response to date.\n\nSince we had been following the patient over time for the p210 BCR-ABL1 fusion transcript by PCR, we had the unique opportunity to retrospectively evaluate the nucleic acids from peripheral blood samples for the PML-RARA fusion product. Analysis of multiple samples demonstrated that the PML-RARA bcr3 fusion product was first detectable 8 months prior to the onset of promyelocytic blast crisis (Table 2; Figure 3). The PML-RARA transcript level remained at a relatively stable low level for several months leading up to blast crisis diagnosis. Of note, the p210 BCR-ABL1 transcript trend paralleled the PML-RARA transcripts in the progression to blast phase.\n\n3. Discussion\nTherapies that target the BCR-ABL1 fusion tyrosine kinase have dramatically improved survival in CML; however, transformation to blast crisis remains a significant cause of mortality. Though fewer patients now develop blast crisis, the prognosis after blast transformation is still poor, with death generally 7–11 months after diagnosis with TKI therapy as compared to 3-4 months in the pre-TKI era [4, 6]. Herein, we describe an unusual variant of blast crisis in which the PML-RARA fusion characteristic of acute promyelocytic leukemia (APL) is acquired during progression of the disease and summarize a review of 21 cases of promyelocytic blast crisis of CML in the literature [9–28].\n\nPromyelocytic blast crisis is molecularly analogous to de novo APL, which requires demonstration of the PML-RARA fusion by routine cytogenetics, fluorescence in situ hybridization, and/or molecular testing [29]. In our review of the literature, evidence of the t(15;17) translocation or PML-RARA fusion was provided in 16 of the 21 cases of promyelocytic blast crisis (Table 3). Two additional cases had aberrations in chromosome 17 including an iso(17q) and +17, with a normal chromosome 15 [22, 28]; FISH testing was not performed in either of these cases. Reports of cryptic translocations have been seen in APL cases with iso(17q) [30], raising the possibility that an undetected cryptic translocation may have been present in the case with iso(17q). Additionally, rare APL cryptic translocations have been documented that are negative by karyotype and FISH. In such cases, evidence of the PML-RARA fusion is only detectable by PCR and sequence analysis [31]. Other variant translocations including RARβ are difficult to detect by routine karyotype [32]. Although uncommon, APL cases without t(15;17) may have complex translocations involving chromosomes 15 and 17 and a nontraditional chromosome partner, resulting in a submicroscopic insertion of RARA into PML [30]. In 3 of the reviewed cases, the promyelocytic blast crisis diagnosis was based on morphologic, immunophenotypic, and/or flow cytometric findings alone; no disease-defining cytogenetic or molecular results were reported [20, 21, 24]. For the purpose of this review, all cases were considered promyelocytic blast crisis of CML, even in the absence of defining reported cytogenetic/molecular evidence.\n\nReview of the 21 promyelocytic blast crisis cases documented in the literature reveals a male predominance, with a male-to-female ratio of 3.2 : 1. This finding is keeping with male predominance in CML [29]. In addition, men developed blast crisis at an earlier average age (38 years ± 17) as compared to women (64 years ± 22 years) (two-tailed p value of 0.0127). The interval of time between initial CML diagnosis and promyelocytic blast crisis was less than 1 year in 33% of cases, including two patients who presented with promyelocytic blast crisis at CML diagnosis, 1–5 years in 52% of cases, and greater than 5 years in 14% of cases (average 30 months). This interval of time to promyelocytic blast crisis is similar to the reported time of development of nonpromyelocytic blast crisis (3 years) [4].\n\nMany of the CML promyelocytic blast crisis reports in the literature were published prior to the discovery of TKIs, and accordingly, only 5 of the 19 patients who carried a diagnosis of CML at the time of blast phase were receiving TKI therapy and only one patient was on second-generation TKI therapy. Interestingly, there was no significant difference in time from initial CML diagnosis to promyelocytic blast crisis in patients with and without TKI therapy in this cohort, and the interval ranged from 4 months to 7 years for patients receiving TKI therapy as compared to 10 months to 8 years for patients who were not on TKI therapy (two-tailed p value of 0.4964). The data in this cohort suggest that TKI therapy does not prolong the time before progression to promyelocytic blast crisis.\n\nSurvival data and/or response to treatment were provided in 16 of the 21 cases. Nine patients died during or within 3 months of the promyelocytic blast crisis diagnosis. Death in these nine patients was primarily due to infection or bleeding events. Survival of patients with promyelocytic blast crisis overall was poor, with only 4 cases resulting in full remission. Such poor outcomes are in contrast to de novo APL in which 90% of patients with the traditional t(15;17) are alive and disease-free after 5 years [33]. In our literature review, the treatment regimen was provided for 7 of the 9 patients with survival ≤3 months, and only one patient received APL-specific therapy (e.g., ATRA and ATO). In contrast, 3 of 4 of the patients with complete remission were treated with ATRA; the remaining patient had no documentation of the characteristic t(15;17) or PML-RARA transcripts [24]. Overall, the data suggest that APL-specific treatment is most successful in achieving remission of promyelocytic blast crisis with documented characteristic cytogenetic/molecular changes.\n\nHerein, we present a unique evaluation of the clonal development of promyelocytic blast crisis in a patient with CML on TKI therapy. At 9 months after initial diagnosis of chronic phase CML, the appearance of low-level PML-RARA transcripts was identified by RT-PCR. PML-RARA transcripts remained at a stable low level for several months before showing a dramatic increase 8 months after initial detection. In conjunction with this elevation in transcript levels, a marked increase in promyelocytes was appreciated by peripheral blood and bone marrow morphologic evaluation. These findings were consistent with overt promyelocytic blast crisis occurring 17 months after the initial CML diagnosis. With standard APL treatment and continued TKI therapy, the patient has achieved complete molecular remission of the promyelocytic blast crisis. To our knowledge, this is the first report demonstrating the time course of molecular acquisition of PML-RARA during chronic phase CML and progression to blast crisis.\n\nAlso, of note, is our patient's history of treated classic Hodgkin lymphoma approximately 7 years prior to the diagnosis of CML. This raises the possibility that the CML may be a therapy-related myeloid neoplasm. Although there is an unusual manifestation of a therapy-related myeloid neoplasm, documented cases are present in the literature [34–36]. No additional cytogenetic changes were present at the time of CML chronic phase diagnosis or blast phase to give additional insight into this possibility.\n\nAlthough therapy-related CML is rare, therapy-related APL (t-APL) is well documented and is most commonly associated with DNA topoisomerase II inhibitor administration [37, 38]. In vitro studies have elucidated the mechanism as chemotherapeutic drug-induced DNA topoisomerase II cleavage of double-stranded DNA at the PML and RARA breakpoint hotspots seen in APL [39]. In our patient, the history of doxorubicin administration for classic Hodgkin lymphoma raises the possibility of a therapy-related PML-RARA translocation. In a systemic review, the peak incidence of t-APL following completion of DNA topoisomerase II inhibitor treatment was 2 years, with 95% of cases occurring within 8 years [37]. Our patient presented with promyelocytic blast crisis approximately 8.6 years after completion of ABVD therapy for classic Hodgkin lymphoma. Although this is a long interval, a therapy-related process cannot be excluded. Interestingly, more than one-third of cases in this systematic review were incidentally found on laboratory testing during routine clinical follow-up [37], analogous to our patient. Treatment and outcomes in t-APL are similar to de novo APL [37, 40].\n\nIn summary, promyelocytic blast crisis in CML is rare, occurring more commonly in younger males with relatively few cases documented in the literature. Analogous to de novo APL, the t(15;17) translocation leads to the aberrant PML-RARA fusion protein, and treatment with standard APL regimens provides better outcome in these patients. While the power of this study is limited due to the relatively few published cases available, no previous comprehensive reviews have been published on this subject. Additional studies on these rare cases to further investigate the pathophysiologic mechanisms behind the development of promyelocytic clones, as well as the nidus for the evolution of blast crisis, are warranted. Quantitative RT-PCR has become a routine, highly sensitive tool used not only in the initial diagnosis of APL and CML but also in monitoring patients for treatment response. Since many of these patients are followed by routine BCR-ABL1 PCR studies for months or years before progression to promyelocytic blast crisis, preserved extracted nucleic acids leading up to the blast crisis are often available, providing a unique opportunity to evaluate clonal development and progression.\n\nData Availability\nThe data used to support this study are provided in tables, figures, and references within the manuscript.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Bone marrow at diagnosis of promyelocytic blast crisis. Promyelocytes with multiple Auer rods (a) and sliding plate nuclear morphology (b) in bone marrow aspirate smears. The bone marrow clot section demonstrates a mildly hypercellular bone marrow with increased promyelocytes (c).\n\nFigure 2 Cytogenetic findings at the time of promyelocytic blast crisis. (a) Conventional karyotype demonstrating t(15;17) (black arrows) and t(9;22) (red arrows) translocations. (b) FISH probes positive for the PML-RARA fusion. (c) FISH probes positive for the BCR-ABL1 fusion (dual-color, dual-fusion probes).\n\nFigure 3 \nBCR-ABL1 and PML-RARA fusion products over time. CML, chronic myeloid leukemia; F/C, fusion to control ratio.\n\nTable 1 Peripheral blood, bone marrow, and conventional cytogenetic findings over time.\n\nTime relative to CML diagnosis\tPeripheral blood\tBone marrow\tConventional cytogenetics\t\nWBC (×103/μL)\tHemoglobin (g/dL)\tPlatelets (×103/μL)\tPromyelocytes (%)\tCellularity\tPromyelocytes (%)\t\n−7 years\t7.2\t14.9\t200\t0\tNormocellular\t<1\t46, XY [20]\t\n0\t44\t14.8\t225\t0\t>95%\t1\t46, XY, t(9;22)(q34;q11.2) [20]\t\n10 months\t3\t13.2\t106\t0\tN/A∗\t1\t46, XY, t(9;22)(q34;q11.2) [1]/46, XY [19]\t\n17 months\t2\t12.8\t56\t44\t70%\t67\t46, XY, t(9;22)(q34;q11.2), t(15;17)(q22;q21) [18]/46, XY [2]\t\n\n∗The trephine biopsy was suboptimal and unable to be accessed for cellularity. Reference ranges: WBC 4.8–10.8 × 103/μL, hemoglobin 14.0–18.0 g/dL, platelets 160–360 × 103/μL. CML, chronic myeloid leukemia; WBC, white blood count; N/A, not applicable.\n\nTable 2 Quantitative RT-PCR analysis of fusion transcripts in peripheral blood over time.\n\nMonths after CML diagnosis\tp210 BCR-ABL1 (IS%)\t\nPML-RARA (bcr3 F/C ratio)\tWBC (×103/μL)\t\n0\t93.869\t0\t44\t\n1\t49.315\tND\t3.7\t\n2\t15.427\tND\t2.6\t\n3\t1.085\tND\t1.9\t\n5\t2.678\tND\t2.3\t\n6\t1.594\tND\t2.6\t\n8\t0.691\t0\t3.7\t\n9\t0.567\t0.0003\t3.2\t\n12\t0.879\t0.0057\t2.3\t\n14\t1.174\t0.0031\t2.7\t\n17∗\t45.328\t0.2029\t1.7\t\n19\t0.107\t0\t2.5\t\n21\t0.138\t0\t3.8\t\n24\t0.070\t0\t2.9\t\n27\t0.074\t0\t3.5\t\n30\t0.104\t0\t4.1\t\n33\t0.045\t0\t4.2\t\n36\t0.081\t0\t4.8\t\n\n∗Blast crisis diagnosis. CML, chronic myeloid leukemia; IS%, international scale percent ratio; F/C, fusion to control; WBC, white blood count; ND, not done.\n\nTable 3 Summary of 21 reported cases of promyelocytic blast crisis in CML.\n\nSex\tAge (years)\tTreatment during CML chronic phase\tInterval between CML diagnosis and blast crisis\tTreatment during promyelocytic blast phase\tConventional cytogenetic results\tSurvival (after blast crisis onset)/outcome\tReference\t\nF\t82\tImatinib\t2 years\tND\tND‡\tND\t[9]\t\n\n\n\t\nM\t22\tN/A\tConcurrent\tATRA, chemotherapy, allogeneic SCT\t46, XY, t(9;22)(q34;q11) [5], 47, XY, t(9;22), +8, t(15;17)(q22;q11-21) [4]‡\t118 days after allogeneic SCT\t[10]\t\n\n\n\t\nM\t31\tCytosine arabinoside, 6-thioguanine#\t27 months\tND\t46, XY, t(9;22) [40%], 46, XY, t(9;22), t(15;17)(q15;q21) [60%]\t3 months\t[11]\t\n\n\n\t\nF\t69\tImatinib\t13 months\tATRA, idarubicin, Ara-C, imatinib, ATO\t46, XX, t(9;22)(q34;q11.2), t(15;17)(q22;q12) [19], 46, XX [1]§‡\tComplete molecular response\t[12]\t\n\n\n\t\nF\t85\tNone#\t10 months\tNone\t46, XX, t(9;22), t(15;17)(q22;q21) [100%]\t2 days\t[13]\t\n\n\n\t\nM\t78\tImatinib, dasatinib\t7 years\tATRA, ATO\t46, XY, t(9;22)(q34;q11.2), t(15;17)(q24;q21) [100%]§‡\t2 months\t[14]\t\n\n\n\t\nM\t32\tImatinib\t6 months\tATRA, imatinib\t46, XY, t(9;22)(q34;q11), t(15;?;17)(q22;?;q21) [100%]§‡\tComplete remission\t[15]\t\n\n\n\t\nM\t37\tMisulban#\t10 months\tDaunorubicin, cytosine arabinoside\t46,(9;22), t(15;17) [26], 46, t(9;22) [5]∗\tND\t[16]\t\n\n\n\t\nF\t52\tHydroxyurea#\t3 years\tMitoxantrone, etoposide\t\nt(9;22)(q34;q11.2), t(15;17)(q24;q11.2–12) [9]∗\t6 weeks\t[17]\t\n\n\n\t\nM\t55\tHydroxyurea#\t2 years\tATRA, mitoxantrone, cytosine arabinoside, etoposide\t\nt(9;22)(q34;q11.2), t(15;17)(q22;q11.2–12) [2]∗\tND\t[17]\t\n\n\n\t\nM\t60\tND#\t3 years\tCytarabine, mitoxantrone, etoposide, idarubicine, 6-thioguanine\t46, XY, t(9;22)(q34;q11)[40%], 46, XY, t(9;22)(q34;q11), t(15;17)(q22;q21) [60%]§\t3 weeks\t[18]\t\n\n\n\t\nM\t50\tND#\t3 years\tND\t46, XY, t(9;12;22)(q34;q22;q11) [43.8%], 46, XY, t(9;12;22)(q34;q22;q11), t(15;17)(q22;q12–21) [56.2%]\tND\t[19]\t\n\n\n\t\nM\t30\tBusulfan#\t10 months\t\nN\n4-Behenoyl-1-β-D-arabinofuranosyl-cytosine, daunorubicin, 6-mercaptopurine, prednisone\t46, XY, t(9;22)(q34;q11) [25%], 46, XY, t(9;22)(q34;q11), t(3;21)(q12;q22) [75%]◊\t5 months\t[20]\t\n\n\n\t\nF\t32\tBusulfan#\t8 years\tDoxorubicin\t74, XX, t(9;22), t(9;22)(3n±)◊\t1 month\t[21]\t\n\n\n\t\nM\t3\tBusulfan, alpha-2a interferon, hydroxyurea, cytarabine#\t3.5 years\t“Chemotherapy”\tHypodiploidy, t(9;22), iso(17q)∗◊\t2 months\t[22]\t\n\n\n\t\nM\t38\tND#\t25 months\tAziridinyl-benzoquinone\t46, XY, t(9;22)(q34;q11) [4], 46, XY, t(15;17), t(9;22) [4], 45, X, -Y, t(15;17), t(9;22) [2]\t1 month\t[23]\t\n\n\n\t\nM\t26\tN/A\tConcurrent\tCytarabine, arabinoside, daunorubicin, dasatinib, allogeneic SCT\t\nt(9;22)∗†\tComplete molecular remission\t[24]\t\n\n\n\t\nM\t31\tHydroxy-carbamide, imatinib\t4 months\tATRA, ATO, dasatinib, idarubicin, cytarabine, allogeneic SCT\tND§‡\tComplete molecular remission\t[25]\t\n\n\n\t\nM\t27\tNatural interferon-α\t4 years\tND\t51, XY, +der(1)t(1;17)(p11;q11), +7, +8, +8, t(9;22)(q34;q11), 22q-‡\tND\t[26]\t\n\n\n\t\nM\t38\tAllopurinol, busulfan\t25 months\tND\t46, XY, t(9;22)(q34:q11) [4], 46, XY, t(15;17)(q22;q12?), t(9;22) (q34;q11) [6]\t47 days\t[27]\t\n\n\n\t\nM\t48\tND#\t6 years\tATRA\t46, XY [6]/48, XY, +17, +der(1)t(1;?)(p13;?), t(9;22)(q34;q11) [14]◊\t>87 days\t[28]\t\n\n∗Full karyotype information not provided. #Publication date prior to 2001. †FISH studies negative for PML-RARA fusion. §FISH studies positive for PML-RARA fusion. ◊FISH and RT-PCR testing not performed. ‡RT-PCR positive for PML/RARA fusion. ND, no data provided; N/A, not applicable; ATRA, all-trans retinoic acid; ATO, arsenic trioxide; SCT, stem-cell transplantation.\n==== Refs\n1 Chereda B. Melo J. V. Natural course and biology of CML Annals of Hematology 2015 94 2 S107 S121 10.1007/s00277-015-2325-z 2-s2.0-84964222417 25814077 \n2 Perrotti D. Silvestri G. Stramucci L. Yu J. Trotta R. Cellular and molecular networks in chronic myeloid leukemia: the leukemic stem, progenitor and stromal cell interplay Current Drug Targets 2017 18 4 377 388 10.2174/1389450117666160615074120 2-s2.0-85010654158 27307150 \n3 Gorkin L. Kantarjian H. Generic imatinib—impact on frontline and salvage therapy for CML Nature Reviews Clinical Oncology 2016 13 5 270 272 10.1038/nrclinonc.2016.59 2-s2.0-84966318901 \n4 Shi Y. Rand A. J. Crow J. H. Moore J. O. Lagoo A. S. Blast phase in chronic myelogenous leukemia is skewed toward unusual blast types in patients treated with tyrosine kinase inhibitors American Journal of Clinical Pathology 2015 143 1 105 119 10.1309/ajcpwex5yy4phscn 2-s2.0-84923568687 25511149 \n5 Hochhaus A. Saglio G. Hughes T. P. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial Leukemia 2016 30 5 1044 1054 10.1038/leu.2016.5 2-s2.0-84959482245 26837842 \n6 Jain P. Kantarjian H. M. Ghorab A. Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: cohort study of 477 patients Cancer 2017 123 22 4391 4402 10.1002/cncr.30864 2-s2.0-85026356485 28743165 \n7 Hochhaus A. Baccarani M. Silver R. T. European leukemianet 2020 recommendations for treating chronic myeloid leukemia Leukemia 2020 34 4 966 984 10.1038/s41375-020-0776-2 32127639 \n8 Lo-Coco F. Avvisati G. Vignetti M. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia New England Journal of Medicine 2013 369 2 111 121 23841729 \n9 Angriman F. Acevedo M. N. G. Rossi M. S. Promyelocytic blastic crisis in chronic myeloid leukemia during imatinib treatment Turkish Journal of Hematology 2015 32 2 193 194 10.4274/tjh.2014.0211 2-s2.0-84930691219 26316496 \n10 Matsue K. Yamada K. Takeuchi M. Tabayashi T. Rapid improvement of disseminated intravascular coagulation by donor leukocyte infusions in a patient with promyelocytic crisis of chronic myelogenous leukemia after reduced-intensity stem cell transplantation from an HLA 2-antigen-mismatched mother International Journal of Hematology 2003 77 4 408 411 10.1007/bf02982653 2-s2.0-0141569502 12774933 \n11 Louwagie A. C. Mecucci C. Criel A. Van Hoof A. Van Den Berghe H. Variant translocation t (15q; 17q) accompanying a promyelocytic accelerated phase of Ph-positive chronic myeloid leukemia Cancer Genetics and Cytogenetics 1987 28 2 349 352 10.1016/0165-4608(87)90222-6 2-s2.0-0023500781 3476191 \n12 Kashimura M. Ohyashiki K. Successful imatinib and arsenic trioxide combination therapy for sudden onset promyelocytic crisis with t (15; 17) in chronic myeloid leukemia Leukemia Research 2010 34 8 e213 e214 10.1016/j.leukres.2010.02.030 2-s2.0-77953620758 20299093 \n13 Laï J.-L. Fenaux P. Zandecki M. Promyelocytic blast crisis of Philadelphia-positive thrombocythemia with translocations (9; 22) and (15; 17) Cancer Genetics and Cytogenetics 1987 29 2 311 314 10.1016/0165-4608(87)90241-x 2-s2.0-0023514418 3479236 \n14 Colvin T. A. Vachhani P. Sait S. Neppalli V. Wang E. S. All-trans-retinoic-acid and arsenic trioxide induced remission in promyelocytic blast crisis Leukemia Research Reports 2018 10 16 19 10.1016/j.lrr.2018.07.002 2-s2.0-85050375676 30090695 \n15 Chung H. J. Chi H. S. Cho Y. U. Promyelocytic blast crisis of chronic myeloid leukemia during imatinib treatment Annals of Clinical and Laboratory Science 2008 38 3 283 286 18715859 \n16 Berger R. Bernheim A. Daniel M.-T. Flandrin G. \nt (15; 17) in a promyelocytic form of chronic myeloid leukemia blastic crisis Cancer Genetics and Cytogenetics 1983 8 2 149 152 10.1016/0165-4608(83)90046-8 2-s2.0-0020578215 6572090 \n17 Rosenthal N. S. Knapp D. Farhi D. C. Promyelocytic blast crisis of chronic myelogenous leukemia: a rare subtype Associated with disseminated intravascular coagulation American Journal of Clinical Pathology 1995 103 2 185 188 10.1093/ajcp/103.2.185 7856560 \n18 Scolnik M. P. Palacios M. F. Acevedo S. H. Promyelocytic blast crisis of chronic myelogenous leukaemia with translocations (9; 22) and (15; 17) Leukemia & Lymphoma 1998 31 1-2 231 236 10.3109/10428199809057603 9720733 \n19 Kadam P. R. Merchant A. A. Advani S. H. Cytogenetic findings in patients with acute promyelocytic leukemia and a case of CML blast crisis with promyelocytic proliferation Cancer Genetics and Cytogenetics 1990 50 1 109 117 10.1016/0165-4608(90)90244-5 2-s2.0-0025641267 2253178 \n20 Abe R. Shichishima T. Kawaguchi M. Uchida T. Kariyone S. Promyelocytic crisis of chronic myelogenous leukemia without t (15; 17) Cancer Genetics and Cytogenetics 1986 21 2 175 179 10.1016/0165-4608(86)90044-0 2-s2.0-0022578698 3456258 \n21 Mijovic A. Rolovic Z. Novak A. Biljanovic-Paunovic L. Tomin D. Chronic myeloid leukemia associated with pure red cell aplasia and terminating in promyelocytic transformation American Journal of Hematology 1989 31 2 128 130 10.1002/ajh.2830310211 2-s2.0-0024368933 2500017 \n22 Ören H. Düzovalı Ö. Yüksel E. Sakızlı M. I·rken G. Development of acute promyelocytic leukemia with isochromosome 17q after BCR/ABL positive chronic myeloid leukemia Cancer Genetics and Cytogenetics 1999 109 2 141 143 10.1016/s0165-4608(98)00158-7 2-s2.0-0344267743 10087949 \n23 Misawa S. Lee E. Schiffer C. Liu Z. Testa J. Association of the translocation (15; 17) with malignant proliferation of promyelocytes in acute leukemia and chronic myelogenous leukemia at blastic crisis Blood 1986 67 2 270 274 10.1182/blood.v67.2.270.bloodjournal672270 3455826 \n24 Bobba R. K. Doll D. C. Promyelocytic blast crisis of chronic myelogenous leukemia Blood 2012 120 19 p. 3873 10.1182/blood-2012-07-433136 2-s2.0-84868603642 \n25 Cai B. Yang W. Zhao Y. Successful management with an effective induction regimen followed by allogeneic hematopoietic stem cell transplantation for promyelocytic blast crisis of chronic myelogenous leukemia Annals of Hematology 2012 91 4 621 623 10.1007/s00277-011-1269-1 2-s2.0-84860801475 21643679 \n26 Amano M. Togawa A. Tsurugano S. Rearrangement of retinoic acid receptor alpha and PML in promyelocytic blast crisis of Ph1 chromosome positive chronic myelocytic leukemia with normal copies of chromosome 15 Blood 1993 81 9 2469 2470 10.1182/blood.v81.9.2469.2469 8386953 \n27 Hogge D. E. Misawa S. Schiffer C. A. Testa J. R. Promyelocytic blast crisis in chronic granulocytic leukemia with 15; 17 translocation Leukemia Research 1984 8 6 1019 1023 10.1016/0145-2126(84)90056-0 2-s2.0-0021707160 6595476 \n28 Wiernik P. Dutcher J. Paietta E. Treatment of promyelocytic blast crisis of chronic myelogenous leukemia with all trans-retinois acid Leukemia 1991 5 6 504 509 2056773 \n29 Swerdlow S. H. Campo E. Harris N. L. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 2017 Lyon, France IARC \n30 Tang Y. Wang Y. Hu L. Acute promyelocytic leukemia with cryptic t (15; 17) on isochromosome 17: a case report and review of literature International Journal of Clinical and Experimental Pathology 2015 8 11 15294 15300 26823883 \n31 Kim M. J. Cho S. Y. Kim M.-H. FISH-negative cryptic PML-RARA rearrangement detected by long-distance polymerase chain reaction and sequencing analyses: a case study and review of the literature Cancer Genetics and Cytogenetics 2010 203 2 278 283 10.1016/j.cancergencyto.2010.08.026 2-s2.0-78650018082 21156244 \n32 Osumi T. Tsujimoto S.-I. Tamura M. Recurrent RARB translocations in acute promyelocytic leukemia lacking RARA translocation Cancer Research 2018 78 16 4452 4458 10.1158/0008-5472.can-18-0840 2-s2.0-85051523339 29921692 \n33 Adams J. Nassiri M. Acute promyelocytic leukemia: a review and discussion of variant translocations Archives of Pathology & Laboratory Medicine 2015 139 10 1308 1313 10.5858/arpa.2013-0345-rs 2-s2.0-84942883955 26414475 \n34 Aguiar R. C. Therapy-related chronic myeloid leukemia: an epidemiological, clinical and pathogenetic appraisal Leukemia & Lymphoma 1998 29 1-2 17 26 10.3109/10428199809058378 2-s2.0-0031806721 9638972 \n35 Iriyama N. Tokuhira M. Takaku T. Incidences and outcomes of therapy-related chronic myeloid leukemia in the era of tyrosine kinase inhibitors: surveillance of the CML cooperative study group Leukemia Research 2017 54 55 58 10.1016/j.leukres.2017.01.003 2-s2.0-85009904468 28109974 \n36 Bauduer F. Jensen L. D. Dastugue N. Marolleau J.-P. Chronic myeloid leukemia as a secondary neoplasm after anti-cancer radiotherapy: a report of three cases and a brief review of the literature Leukemia & Lymphoma 2002 43 5 1057 1060 10.1080/10428190290021533 2-s2.0-0036237414 12148886 \n37 Rashidi A. Fisher S. I. Therapy-related acute promyelocytic leukemia: a systematic review Medical Oncology 2013 30 625 634 10.1007/s12032-013-0625-5 2-s2.0-84878815434 23771799 \n38 Lo-Coco F. Hasan S. K. Montesinos P. Sanz M. A. Biology and management of therapy-related acute promyelocytic leukemia Current Opinion in Oncology 2013 25 6 695 700 10.1097/cco.0000000000000013 2-s2.0-84885420409 24076582 \n39 Mistry A. R. Felix C. A. Whitmarsh R. J. DNA topoisomerase II in therapy-related acute promyelocytic leukemia New England Journal of Medicine 2005 352 15 1529 1538 10.1056/nejmoa042715 2-s2.0-20144388623 15829534 \n40 Kayser S. Krzykalla J. Elliott M. A. Characteristics and outcome of patients with therapy-related acute promyelocytic leukemia front-line treated with or without arsenic trioxide Leukemia 2017 31 11 2347 2354 10.1038/leu.2017.92 2-s2.0-85017498433 28322237\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6579",
"issue": "2020()",
"journal": "Case reports in hematology",
"keywords": null,
"medline_ta": "Case Rep Hematol",
"mesh_terms": null,
"nlm_unique_id": "101576456",
"other_id": null,
"pages": "8830595",
"pmc": null,
"pmid": "32953185",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "7856560;12148886;28743165;2500017;29921692;28109974;21156244;9720733;21643679;6572090;27098218;12774933;3456258;26837842;3476191;23289111;15829534;26823883;32127639;2056773;23771799;25814077;3479236;9638972;23841729;24076582;10087949;25511149;26316496;8386953;3455826;28322237;30090695;20299093;2253178;26414475;6595476;27307150;18715859",
"title": "PML-RARA Fusion Transcripts Detectable 8 Months prior to Promyelocytic Blast Crisis in Chronic Myeloid Leukemia.",
"title_normalized": "pml rara fusion transcripts detectable 8 months prior to promyelocytic blast crisis in chronic myeloid leukemia"
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"activesubstancename": "BLEOMYCIN SULFATE"
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"abstract": "To compare the efficacy and safety of nonvitamin K oral anticoagulants (NOACs) and vitamin K antagonists (VKAs) following bioprosthetic cardiac valve replacement.\n\n\n\nThis was a retrospective analysis conducted at a community teaching hospital in the southeastern United States between August 2015 and August 2018. Patients 18 years of age and older who underwent cardiac valve replacement and were prescribed oral anticoagulation were screened for inclusion. Patients were excluded if they had a mechanical valve replacement, experienced a venous thromboembolism, cerebrovascular accident, or acute coronary syndrome within 1 month before valve replacement, changed oral anticoagulation during the study period, were lost to follow-up, or declined to participate in the follow-up survey. The primary outcome was a composite of thromboembolic events within 90 days following bioprosthetic cardiac valve replacement. The safety outcome was major bleeding within 180 days of bioprosthetic cardiac valve replacement.\n\n\n\nThe primary outcome of a composite of thromboembolic events within 90 days following bioprosthetic cardiac valve replacement occurred in 1 patient (4.3%) in the VKA group and 4 patients (7.4%) in the NOAC group. Major bleeding occurred in 2 patients (8.7%) in the VKA group and 0 patients in the NOAC group.\n\n\n\nOur study is the first to report the efficacy and safety of NOACs compared with VKA therapy following bioprosthetic cardiac valve replacement irrespective of an atrial fibrillation diagnosis. Notably, two of the thromboembolic events in the NOAC group occurred while therapy was held or inappropriately dosed; when these events are removed, the rate of thromboembolism is 3.8%. This rate is consistent with the VKA group. Our study adds to a small pool of literature regarding the use of NOACs following bioprosthetic cardiac valve replacement and suggests that NOACs may have similar efficacy and improved safety as compared with VKA therapy. Large randomized controlled trials are warranted to confirm our observations.",
"affiliations": "From the Department of Pharmacy Services, Princeton Baptist Medical Center, Birmingham, Alabama, the Department of Pharmacy Services, Vanderbilt Wilson County Hospital, Lebanon, Tennessee, and the Department of Pharmacy Practice, Harrison School of Pharmacy, Auburn University, Auburn, Alabama.;From the Department of Pharmacy Services, Princeton Baptist Medical Center, Birmingham, Alabama, the Department of Pharmacy Services, Vanderbilt Wilson County Hospital, Lebanon, Tennessee, and the Department of Pharmacy Practice, Harrison School of Pharmacy, Auburn University, Auburn, Alabama.;From the Department of Pharmacy Services, Princeton Baptist Medical Center, Birmingham, Alabama, the Department of Pharmacy Services, Vanderbilt Wilson County Hospital, Lebanon, Tennessee, and the Department of Pharmacy Practice, Harrison School of Pharmacy, Auburn University, Auburn, Alabama.;From the Department of Pharmacy Services, Princeton Baptist Medical Center, Birmingham, Alabama, the Department of Pharmacy Services, Vanderbilt Wilson County Hospital, Lebanon, Tennessee, and the Department of Pharmacy Practice, Harrison School of Pharmacy, Auburn University, Auburn, Alabama.;From the Department of Pharmacy Services, Princeton Baptist Medical Center, Birmingham, Alabama, the Department of Pharmacy Services, Vanderbilt Wilson County Hospital, Lebanon, Tennessee, and the Department of Pharmacy Practice, Harrison School of Pharmacy, Auburn University, Auburn, Alabama.",
"authors": "Stuart|Mary K|MK|;Blackwell|Sarah B|SB|;Holder|Hillary B|HB|;Wood|Elizabeth L|EL|;Starr|Jessica A|JA|",
"chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.14423/SMJ.0000000000001193",
"fulltext": null,
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"issn_linking": "0038-4348",
"issue": "114(1)",
"journal": "Southern medical journal",
"keywords": null,
"medline_ta": "South Med J",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005260:Female; D006350:Heart Valve Prosthesis; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D015144:Southeastern United States; D054556:Venous Thromboembolism",
"nlm_unique_id": "0404522",
"other_id": null,
"pages": "46-50",
"pmc": null,
"pmid": "33398361",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and Safety of Nonvitamin K Oral Anticoagulants following Cardiac Valve Replacement.",
"title_normalized": "efficacy and safety of nonvitamin k oral anticoagulants following cardiac valve replacement"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-047341",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"activesubstancename": "APIXABAN"
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"abstract": "Tracheobronchial tuberculosis (TBTB) is reported in approximately 10% to 39% of the patients with pulmonary tuberculosis. It is defined as the tubercle infection of the trachea and or bronchi. Due to its non-specific presentation, insidious onset and normal chest radiography in about 10-20% of the patients, the diagnosis is delayed. Bronchoscopy is the most definite method of diagnosis which provides adequate specimens for microbiological and histopathological diagnosis. Tracheobronchial stenosis is one of the most common long term complications of TBTB resulting in significant morbidity. It is estimated that 90% of patients with TBTB have some degree of tracheal and or bronchial stenosis. In this review article, we will discuss the pathogenesis, symptoms, imaging, bronchoscopic findings, and treatment of TBTB and management of tracheobronchial stenosis.",
"affiliations": "Departments of Pulmonary Disease and Critical Care Medicine, WakeMed Health and Hospitals, Raleigh, North Carolina, USA.;Departments of Pulmonary Disease and Critical Care Medicine, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA.;Departments of Pulmonary Disease and Critical Care Medicine, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA.",
"authors": "Pathak|Vikas|V|;Shepherd|Ray W|RW|;Shojaee|Samira|S|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/jtd.2016.12.75",
"fulltext": null,
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"issue": "8(12)",
"journal": "Journal of thoracic disease",
"keywords": "Tuberculosis induced stenosis; bronchial stenosis; endobronchial stenosis; endobronchial tuberculosis; tracheobronchial stenosis; tracheobronchial tuberculosis (TBTB)",
"medline_ta": "J Thorac Dis",
"mesh_terms": null,
"nlm_unique_id": "101533916",
"other_id": null,
"pages": "3818-3825",
"pmc": null,
"pmid": "28149582",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "19387262;3420565;14830798;25197570;5776050;7504608;2248533;13717136;23088170;8449050;20299630;12114385;1414809;8246548;1504420;3698702;24409353;3154619;12989007;9657581;8519452;16971412;27621353;11192556;23207464;10401855;14195575;9211594;8617068;15358688;15482190;10669679;15486402;1395814;20696643;26798513;9122509;18173878;24189863;27516382;3105965;7991884;9434324;9275870",
"title": "Tracheobronchial tuberculosis.",
"title_normalized": "tracheobronchial tuberculosis"
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"abstract": "Patients with sickle cell disease (N = 3) and thalassemia (N = 1) with high-risk features received hematopoietic stem cell transplantations (HCT) to induce stable (full or partial) donor engraftment. Patients were 9-30 years of age. Fludarabine, rabbit anti-thymocyte globulin (ATG), and 200 cGy total body irradiation were administered pre-transplant. Patients received bone marrow (N = 3) or peripheral blood stem cells (N = 1) from HLA-identical siblings, followed by mycophenolate mofetil and cyclosporine for post-grafting immunosuppression. Significant lymphopenia, but only moderate neutropenia and thrombocytopenia developed post transplant. No grade IV nonhematological toxicities or acute graft-versus-host disease (GVHD) were observed. At 3 months after transplantation, three of four patients had evidence of donor myeloid chimerism (range, 15-100%). However, after post transplant immunosuppression was discontinued, graft rejection occurred in all but one patient. This patient is now doing well 27 months post transplant with full donor engraftment. One patient died after a second transplant, and another patient experienced a stroke as her graft was being rejected. These results suggest that stable donor engraftment after nonmyeloablative HCT is difficult to achieve among immunocompetent patients with hemoglobinopathies and that new approaches will need to be developed before wider application of this transplantation method for hemoglobinopathies.",
"affiliations": "Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. john.horan@choa.org",
"authors": "Horan|J T|JT|;Liesveld|J L|JL|;Fenton|P|P|;Blumberg|N|N|;Walters|M C|MC|",
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"issue": "35(2)",
"journal": "Bone marrow transplantation",
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"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell; D000961:Antilymphocyte Serum; D002648:Child; D003131:Combined Modality Therapy; D005260:Female; D006084:Graft Rejection; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006453:Hemoglobinopathies; D006801:Humans; D007166:Immunosuppressive Agents; D007239:Infections; D008297:Male; D010198:Pancytopenia; D013789:Thalassemia; D065227:Transfusion Reaction; D018183:Transplantation Chimera; D014184:Transplantation, Homologous; D014740:Vidarabine; D014916:Whole-Body Irradiation",
"nlm_unique_id": "8702459",
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"pages": "171-7",
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"pmid": "15531901",
"pubdate": "2005-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-dose total body irradiation, fludarabine, and rabbit anti-thymocyte globulin.",
"title_normalized": "hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low dose total body irradiation fludarabine and rabbit anti thymocyte globulin"
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"abstract": "Compared to conventional chemotherapy, Immune checkpoint inhibitors (ICI) are known to have a distinct toxicity profile commonly identified as immune-related adverse events (irAEs). These irAEs that are believed to be related to immune dysregulations triggered by ICI can be serious and lead to treatment interruptions and in severe cases, precipitate permanent discontinuation. Isolated neutropenia secondary to ICI has been rarely documented in the literature and needs further description. We report a case of pembrolizumab related severe isolated neutropenia in a patient with metastatic non-small cell lung cancer. We were also able to obtain serial blood and plasma-based biomarkers for this patient during treatment and during neutropenia to understand trends that may correlate with the irAE. In addition we summarize important findings from other studies reporting on ICI related neutropenia.\n\n\n\nA 74 years old Caucasian male treated with single-agent pembrolizumab for metastatic non-small cell lung cancer presented with fevers, chills, and an isolated neutrophil count (ANC) of 0 2 weeks after the fourth dose. In addition to antibiotics, due to the strong suspicion of this neutropenia being immune-mediated, he was started on 1 mg/kg of steroids and also received filgrastim to accelerate neutrophil recovery. Serial trends in C-reactive protein and certain other inflammatory cytokines demonstrated a corresponding rise at the time of neutropenia. Post recovery, his pembrolizumab was kept on hold. Eight weeks later he had a second episode of neutropenia which was again managed similar to the first episode. Despite permanent discontinuation of ICI after the first neutropenia, his disease showed an ongoing complete metabolic response on imaging. Our literature review reveals that hematological toxicities constitute < 1% irAEs with isolated neutropenia roughly accounting for one-fourth of the hematological irAEs. Based on the handful of ICI related neutropenia cases reported to date, we identified nivolumab to be the most common offender. The median number of ICI cycles administered before presenting with neutropenia was three, and the median time to recovery was approximately two weeks. All of these neutropenic episodes were ≥ grade 3 and led to permanent ICI discontinuation. Using immunosuppressive therapies in conjunction with granulocyte-colony stimulating factor was the most common strategy described to have favorable results.\n\n\n\nNeutropenia as an isolated irAE secondary to ICI is rare but represents a severe toxicity that needs early recognition and can often result in treatment discontinuations. Careful monitoring of these patients with the prompt initiation of immunosuppressive and supportive measures to promote rapid recovery as well as prevent and treat infectious complications should be part of the management algorithms. Serial monitoring of blood and plasma-based biomarkers from more extensive studies may help in identifying patients at risk for irAEs and thus guide patient selection for ICI.",
"affiliations": "Division of Hematology/Oncology, East Carolina University, 600 Moye Boulevard, Greenville, NC, 27834, USA. naqasha16@ecu.edu.;Division of Hematology/Oncology, East Carolina University, 600 Moye Boulevard, Greenville, NC, 27834, USA.;Division of Hematology/Oncology, East Carolina University, 600 Moye Boulevard, Greenville, NC, 27834, USA.;Division of Hematology/Oncology, East Carolina University, 600 Moye Boulevard, Greenville, NC, 27834, USA.;Division of Hematology/Oncology, East Carolina University, 600 Moye Boulevard, Greenville, NC, 27834, USA.;Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC, 27834, USA.;Division of Hematology/Oncology, East Carolina University, 600 Moye Boulevard, Greenville, NC, 27834, USA.;Division of Hematology/Oncology, East Carolina University, 600 Moye Boulevard, Greenville, NC, 27834, USA.;Division of Hematology/Oncology, East Carolina University, 600 Moye Boulevard, Greenville, NC, 27834, USA.",
"authors": "Naqash|Abdul Rafeh|AR|0000-0001-7622-720X;Appah|Ebenezer|E|;Yang|Li V|LV|;Muzaffar|Mahvish|M|;Marie|Mona A|MA|;Mccallen|Justin D|JD|;Macherla|Shravanti|S|;Liles|Darla|D|;Walker|Paul R|PR|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; C582435:pembrolizumab",
"country": "England",
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"doi": "10.1186/s40425-019-0648-3",
"fulltext": "\n==== Front\nJ Immunother CancerJ Immunother CancerJournal for Immunotherapy of Cancer2051-1426BioMed Central London 64810.1186/s40425-019-0648-3Case ReportIsolated neutropenia as a rare but serious adverse event secondary to immune checkpoint inhibition http://orcid.org/0000-0001-7622-720XNaqash Abdul Rafeh 516-324-9835naqasha16@ecu.edu 1Appah Ebenezer appahe17@ecu.edu 1Yang Li V. yangl@ecu.edu 1Muzaffar Mahvish muzaffarm@ecu.edu 1Marie Mona A. mariem17@students.edu.edu 1Mccallen Justin D. mccallenj17@students.ecu.edu 2Macherla Shravanti macherlas17@ecu.edu 1Liles Darla lilesd@ecu.edu 1Walker Paul R. walkerp@ecu.edu 11 0000 0001 2191 0423grid.255364.3Division of Hematology/Oncology, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834 USA 2 0000 0001 2191 0423grid.255364.3Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834 USA 5 7 2019 5 7 2019 2019 7 16928 3 2019 21 6 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nCompared to conventional chemotherapy, Immune checkpoint inhibitors (ICI) are known to have a distinct toxicity profile commonly identified as immune-related adverse events (irAEs). These irAEs that are believed to be related to immune dysregulations triggered by ICI can be serious and lead to treatment interruptions and in severe cases, precipitate permanent discontinuation. Isolated neutropenia secondary to ICI has been rarely documented in the literature and needs further description.\n\nWe report a case of pembrolizumab related severe isolated neutropenia in a patient with metastatic non-small cell lung cancer. We were also able to obtain serial blood and plasma-based biomarkers for this patient during treatment and during neutropenia to understand trends that may correlate with the irAE. In addition we summarize important findings from other studies reporting on ICI related neutropenia.\n\nCase presentation\nA 74 years old Caucasian male treated with single-agent pembrolizumab for metastatic non-small cell lung cancer presented with fevers, chills, and an isolated neutrophil count (ANC) of 0 2 weeks after the fourth dose. In addition to antibiotics, due to the strong suspicion of this neutropenia being immune-mediated, he was started on 1 mg/kg of steroids and also received filgrastim to accelerate neutrophil recovery. Serial trends in C-reactive protein and certain other inflammatory cytokines demonstrated a corresponding rise at the time of neutropenia. Post recovery, his pembrolizumab was kept on hold. Eight weeks later he had a second episode of neutropenia which was again managed similar to the first episode. Despite permanent discontinuation of ICI after the first neutropenia, his disease showed an ongoing complete metabolic response on imaging. Our literature review reveals that hematological toxicities constitute < 1% irAEs with isolated neutropenia roughly accounting for one-fourth of the hematological irAEs. Based on the handful of ICI related neutropenia cases reported to date, we identified nivolumab to be the most common offender. The median number of ICI cycles administered before presenting with neutropenia was three, and the median time to recovery was approximately two weeks. All of these neutropenic episodes were ≥ grade 3 and led to permanent ICI discontinuation. Using immunosuppressive therapies in conjunction with granulocyte-colony stimulating factor was the most common strategy described to have favorable results.\n\nConclusion\nNeutropenia as an isolated irAE secondary to ICI is rare but represents a severe toxicity that needs early recognition and can often result in treatment discontinuations. Careful monitoring of these patients with the prompt initiation of immunosuppressive and supportive measures to promote rapid recovery as well as prevent and treat infectious complications should be part of the management algorithms. Serial monitoring of blood and plasma-based biomarkers from more extensive studies may help in identifying patients at risk for irAEs and thus guide patient selection for ICI.\n\nKeywords\nImmune checkpoint inhibitorsNeutropeniaImmune-related adverse eventC-reactive proteinIL-6ImmunosuppressionLung Cancer Initiative of North Carolina East Carolina University Coach Rock Fundissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nDue to their ability to modulate certain inhibitory pathways, immune checkpoint inhibitors (ICIs) promote a T-cell mediated attack against tumor cells and thus harness the immune system to generate anti-tumor immunity. The recent advent of ICIs has radically altered the treatment approaches and revolutionized the outcomes for several tumor types that until recently were known to have dismal outcomes [1]. Non-Small Cell lung cancer (NSCLC) especially has witnessed a paradigm shift with significant improvements in survival, response rates, and durability of disease control, both in upfront and second line setting [2]. Based on results from Keynote-024 [3], single agent pembrolizumab was approved by the US Food and Drug Administration in 2018 in the frontline treatment of metastatic NSCLC having PD-L1 of ≥50%. Recently reported updated results from this trial show a 16-month overall survival benefit of pembrolizumab over platinum-based chemotherapy in patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations. [4]\n\nCompared to conventional chemotherapy, ICIs have been noted to display distinct patterns of immune toxicities, commonly labeled as immune-related adverse events (irAEs). IrAEs differ from usual toxicities in terms of having a more than likely immunological basis and can have a broad spectrum of manifestations that can involve different organ systems [5]. The incidence, distinct tissue specificity, timing, and severity of irAEs are variable and considered to be dependent on the type of ICI antibody and underlying malignancy [6]. In general, data from ICI related clinical trials and retrospective studies have indicated the incidence of irAEs such as colitis, pneumonitis, and thyroiditis to be higher compared to nephritis, myocarditis, or myositis. The incidence of the hematological adverse effects in general, and neutropenia, in particular, have rarely been documented as an adverse event secondary to ICI, with an overall reported incidence of < 1.0% [7]. A recent study that queried a World Health Organization (WHO) pharmacovigilance database (VigiBase) for ICI related hematological toxicities described autoimmune anemia and immune thrombocytopenia as the most common hematologic toxicities [8]. Conversely, a French pharmacovigilance study reported neutropenic irAEs to account for approximately one fourth (26%; n = 9/35) of all immune hematological irAEs [9]. In addition to these studies, to the best of our knowledge, there are nine other individual cases of neutropenia-related to ICI treatment published so far ([10–17]; Table 1).Table 1 Summary of recently pubmished cases with neutropenia due to immune checkpoint inhibitors\n\nAuthors\tAge, Gender\tCancer type\tImmune checkpoint inhibitor\tNo. of cycles before neutropenia\tCTCAE (4.03) Grade/ ANC Nadir /mm3\tRheumatological/autoimmune disease or serology\tDuration of neutropenia\tBone marrow findings\tAssociated or preceding irAE\tTreatment\tOutcome\tICI restarted\t\nAkhtari et al. [9]\t42 Female\tMelanoma\tIpilimumab\t4\tG4 ANC - 380\tAntineutrophil and platelet autoantibodies.\t60 days\tNormocellular marrow, myeloid hypoplasia. Second bone marrow: hypocellular; granulocytic hypoplasia and lymphohistiocytic aggregates.\tRash\tPegfilgrastim Prednisone Dexamethasone IVIg, Cyclosporine\tProlonged neutropenia with multiple relapses. Recovery of counts after second course of IVIg. Developed anemia and thrombocytopenia\tNo\t\nBan-Hoefen et al. [10]\t54 Male\tMelanoma\tIpilimumab\t4\tG4- ANC - 0\tNo serology\t52 days\tHypercellular; increase bland histiocytes, lymphocytosis; near complete absence of granulocyte precursors\tRash\tPrednisone IVIG, Cyclosporine Filgrastim, Anti-thymocyte globulin (ATG)\tRecovery of counts with ATG/cyclosporine/prednisone combination with filgrastim. Steroids tapered off after 4 months. Normal ANC after 6 months.\tNo\t\nTabchi et al. [11]\t74 Female\tNSCLC\tNivolumab\t2\tSevere neutropenia likely G-4 (ANC not reported)\tUlcerative colitis in remission\t16 days\tAbsence of myeloid precursors\tHepatitis\tFilgrastim, IVIG Prednisone Methylprednisolone\tResponded to high dose methylprednisolone.\tNo\t\nWozniak et al. [12]\t35 Male\tMelanoma\tIpilimumab\t3\tG-4 ANC - 0\tNo serology\t16 days\tGranulocytes with features of rejuvenation and preserved maturation; poorly represented erythrocytes.\tRash\tMethylprednisolone Filgrastim (both started after 8 days)\tRecovery of counts 16 days.\tN/A\t\nBarbacki et al. [13]\t73 Female\tNSCLC\tPembrolizumab\t2\tG-4 ANC-0\tAutoimmune myositis (in remission) Crohn’s disease\t12 days\tNot performed\tNone\tGCSF, Methylprednisolone, IVIG, Cyclosporine\tRecovered counts after 12 days. No recurrence at 3 months\tNo\t\nSun et al. [14]\t64 Male\tProstate Cancer\tIpilumumab\t2\tG-3 ANC-770\tWeak neutrophil reactive IgM antibodies\t14 days\tNot performed\tNone\tMethyl prednisone followed by prednisone\tCount recovery with no recurrent neutropenia. PSA remained undetectable and patient started lepurolide\tNo\t\nMeti et al. [15]\t59 Male\tMelanoma\tIpilimumab/Nivolumab\t2\tG-4 ANC-0\tNo serology\t16 days\tVariable cellularity, hypoplastic granulocytic, unremarkable erythroid and megakaryocytic lineages.\tRash, hepatitis, colitis\tMethylprednisolone, IVIG, filgrastim, mycophenolate mofetil (MMF).\tRecovered counts after addition of MMF.\tNo\t\nTurgeman et al. [16]\t73 Male\tNSCLC\tNivolumab\t5\tG-4 ANC - 0\tCrohn’s disease No serology\t7 days\tNot performed\tDiarrhea\tMethylprednisolone, GCSF\tNeutrophils started improving after a week..\tN/A\t\n\t74 Male\tNSCLC\tNivolumab\t11\tG4 ANC-0\tNegative Serology\t2 days\tMildly hypercellular, unremarkable erythropoiesis and megakaryopoiesis, hyperplasia of myelocytic precursors\tNone\tG-CSF, prednisolone\tRecovered ANC after 2 days. Developed multiple relapses. Placed on Erlotinib, prophylactic GCSF.\tNo\t\nAbbreviations: CTCAE Common terminology criteria for adverse events, ANC Absolute neutrophil count, G Grade, G-CSF Granulocyte colony stimulating factor, NSLC Non-small cell lung cancer, IVIG Intravenous immune globulin, ATG Anti-thymocyte globulin\n\nResults are presented as cumulative of all cases. The median number of ICI cycles before patients presented with neutropenia was 3. All most all patients had nuetropenia ≥ G3. Median time to resolution of neutropenia wa approximaely 2 weeks. Rash seemed to be the most common associated irAE that preceeded or occurred concurrently with neutropenia. Prednisone. IVIG and filgrastim were the most common modalites used in management with variable sequence of administration. None of the patients restarted ICI after resolution of neutropenia\n\n\n\nWe report a case of recurrent isolated severe neutropenia in a patient with metastatic adenocarcinoma of the lung treated with pembrolizumab. Coincidentally we were also able to obtain serial cytokine levels, and peripheral T-cell counts for this patient during his treatment and neutropenia as this patient was part of a study cohort with institutional approval for a biomarker study that allowed the collection of serial blood and plasma for relevant translational studies (ECU IRB 16–000719). Herein we also summarize essential findings from previously reported cases of neutropenia, discuss possible mechanisms contributing to this toxicity and elaborate briefly on management strategies that seem to work best for this toxicity.\n\nCase report\nA 74-year-old Caucasian male with an Eastern Cooperative Group performance status of 1 and a 150 pack -year smoking history initially presented with progressive right upper extremity weakness. Further workup revealed a 1.4 cm frontal lobe mass on magnetic resonance imaging. Computerized tomography (CT) of the chest identified a spiculated mass lesion measuring 1.6 × 1.1 cm in the right hilar region. Apart from hypermetabolic activity in the lung mass, a staging positron emission tomography (PET) identified avidity in the mediastinal and hilar lymph nodes. Biopsy of the lung mass and hilar nodes identified moderately differentiated adenocarcinoma of lung origin. Based on this tumor size and nodal involvement, his intrathoracic disease was staged as IIIA (AJCC 7th). His solitary left precentral gyrus mass was treated with gamma knife radiosurgery, and he was subsequently placed on steroids with improvement in his limb weakness. His intrathoracic disease was treated with four cycles of cisplatin and pemetrexed with concurrent definitive radiation therapy. During follow-up, a surveillance PET scan approximately 11 months later was notable for new metastatic liver, mediastinal, para-aortic and right lower lobe lesions. Due to his original biopsied tissue having PD-L1 expression of 50% (22c3 antibody), he was started on single agent pembrolizumab 200 mg every 3 weeks. His baseline blood counts before starting pembrolizumab were all within the normal range. Two weeks after completing the fourth cycle of pembrolizumab, he presented to the emergency department with fever, chills, and general malaise. He was noted to be neutropenic with an absolute neutrophil count (ANC) of 0, which previously was noted to be normal the day of his fourth dose of pembrolizumab (Fig. 1). Hemoglobin was 12.6 g/dl, and platelet count was normal. The patient was hospitalized with febrile neutropenia and started on broad-spectrum antibiotics. As part of our programmatic approach, a serum C-reactive protein (CRP) level was obtained, which was markedly elevated at 175.4 mg/L (Fig. 1). He was started on prednisone 80 mg daily and filgrastim dose of 5 mcg/kg daily for 4 days. All his infectious workup, including blood cultures, were negative. Bone marrow biopsy showed normocellular marrow with left-shifted trilineage hematopoiesis, with a predominance of early erythroid and myeloid precursors and no increase in blasts or significant morphologic dysplasia. Cytogenetics and myelodysplastic syndrome panel were normal. His ANC started to improve by day four of prednisone and filgrastim (Fig. 1). From his serial blood samples, he also had T-cell counts and cytokines checked (Fig. 2). He had complete recovery of his neutrophil count with ANC of 2400/ μL by day six of admission. Computerized Tomography imaging of the chest done during admission showed intrathoracic disease response compared to the CT performed 6 weeks earlier. His steroid taper schedule was 80 mg daily for week 1, 40 mg daily for week 2, 20 mg daily for week 3, 10 mg daily for week 4 and then stopping. His pembrolizumab was kept on hold.Fig. 1 Graph showing the trend of the ANC and CRP for the first and second episode of neutropenia. 1D0 = Day 0 for first neutropenic episode, 2 D0 = Day 0 for second neutropenic episode. Corresponding days are measured based on days from the first neutropenic episode (1D0) and day of the second neutropenic episode (2D0). Note rise in CRP corresponds to fall in ANC in both instances. ANC improved with the use of filgrastim daily for 4 days at the first neutropenic episode and one dose of pegfilgrastim with the second neutropenic episode. Steroid taper for the first neutropenic episode was completed on day + 28 from neutropenia onset. ANC recovery in both episodes was observed 4 to 5 days from neutropenia onset\n\nFig. 2 Cytokine concentration during the treatment course and at the time of neutropenia. Post-C4 levels are not displayed as the patient was admitted two weeks after C3, i.e., prior to C4 sample collection. Compared to baseline, a significant rise in IL-6, IL-10 and IL-17 are seen at the point of irAE. These co-relate with rise in CRP (Fig. 1). Two weeks post irAE, IL-6 and IL-17 levels demonstrate a downtrend while IL-10 level was noted to be rising. Sample collection at neutropenia was a day after treatment with steroids. Hence the treatment effect cannot be entirely excluded.\n\n\n\nHowever, eight weeks after being discharged, he was readmitted again with fever, cough, and shortness of breath. He was again noted to be neutropenic with ANC of 0 / μL (Fig. 1). Other complete blood count parameters were within the normal range. His CRP had again increased to 43.5 mg/L, from 7.7 mg/L at the last clinic visit 6 weeks prior. He was started on broad-spectrum antibiotics, prednisone 1 mg/kg, and a single dose of peg-filgrastim. Viral studies (HIV, Hepatitis-B, Hepatitis-C, and CMV) were negative. EBV IgG and Parvovirus B19 IgG titers were elevated and thus consistent with prior infection. Antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), rheumatoid factor (RF), and neutrophil-associated antibodies were negative, and C3 and C4 levels were normal. His neutrophil counts recovered to > 1500 on day seven of the second hospitalization.\n\nHis neutrophil counts were 5440/ μL at his post-discharge clinic follow up a week later. A restaging PET scan showed continued response with some areas of complete metabolic response. He continued prednisone taper for 8 weeks. Although his ANC showed persistent recovery and remained > 5000 / μL after his second hospitalization, his pembrolizumab was kept on hold. Repeat PET scan 7 weeks after the second neutropenia showed the metabolic activity of a mass like consolidation with air bronchogram in the posterior right upper lung and moderate focal uptake in the enlarged portocaval lymph node and tiny periaortic lymph nodes suggesting recurrent malignancy with likely a post-obstructive pneumonia. Unfortunately, despite adequate outpatient management, he had recurrent episodes of bacterial pneumonia complicated by hospitalizations due to which his performance status declined considerably. Due to this, he could not be initiated on any further treatment. Three months after his second neutropenic episode, he died from hypoxemic respiratory failure secondary to bacterial pneumonia that was unrelated to ICI use or neutropenia.\n\nDiscussion\nNeutropenia, as an irAE secondary to ICI is a rare finding with no comprehensive reports or clear management guidelines published to date. Here we discuss a unique case of isolated neutropenia secondary to ICI and also summarize previously reported cases with similar findings published in the literature. The absence of confounders, such as recent chemotherapy or medications that can cause cytopenias strongly supports our diagnosis of ICI as the primary etiology for the neutropenia. Furthermore, from a biomarker standpoint, we have also attempted to correlate serial inflammatory markers derived from blood and plasma with the ICI treatment course and the occurrence of neutropenia, an aspect that has not been documented to date.\n\nAlthough immunotherapy has revolutionized the management of several tumor types, the occurrence of irAEs as a side effect can lead to significant morbidity as well as premature treatment discontinuations. Currently, the putative relationship between anti-tumor immunity and irAEs is not well understood. IrAEs are believed to be related to ICI mediated alterations in the roles that immune checkpoints play in maintaining immunologic homeostasis leading to the generation of auto-inflammatory responses [18]. Thus irAEs are more likely to reflect an exaggerated host immune function. Both auto-reactive T-cell and antibody-mediated processes have been speculated to mediate irAEs [6]. These theories are supported by some emerging data demonstrating T-cell clone cross-reactivity with antigens/epitopes shared between tumors and healthy tissue in patients presenting with irAEs [19, 20]. Also, alterations in various B-cell subsets correlating with timing and incidence of irAEs has been observed [21]. Similar to other irAEs, the mechanisms proposed for hematologic toxicities include generation of autoreactive T and B-cells as well as a decrease in T-regulatory phenotype [7].\n\nThe first neutropenia occurrence in our patient was after 4 cycles of pembrolizumab. This is similar to other reported cases (Table 1) where the median time to onset of neutropenia was after 3 cycles (range 2–11). Based on our literature review, the median time to onset of hematological toxicities has been noted to be shorter for anti-CTLA-4 monotherapy or the combination anti-CTLA-4/anti-PD-1 therapy compared to anti-PD-1 therapy alone [8]. In a majority of the cases we have reported (Table 1), and in nine other patients in the French study [9], nivolumab was the most common ICI resulting in neutropenia. However, given the limited number of patients, establishing a causal relationship between a specific ICI and neutropenia is not possible. A significant majority of documented cases (Table 1), including data reported from the French registry, were grade-4. Per the French study, more than 60% of isolated neutropenias were associated with febrility, which corresponds to our patient’s presentation [9]. Most of the patients in the previously published cases had other concurrent irAEs that manifested as rash, hepatitis, and colitis (Table 1). Based on data from 168 hematological toxicities observed in the WHO VigiBase, around 23% had concurrent non-hematological toxicities [8]. Our patient, however, presented with isolated neutropenia and no other accompanying irAEs. Due to the scarcity of data on ICI related neutropenia, for now, it is unclear which concurrent non-hematological irAEs have a stronger association with neutropenia and whether outcomes differ among these irAE subsets.\n\nDue to the severity of the index neutropenic event, neither our patient nor any of the other reported patients were resumed on ICI. This permanent discontinuation of ICI broadly conforms to recent treatment guidelines for irAEs published by the American Society of Clinical Oncology where all leukopenias have been grouped as a single entity [22]. Intriguingly, our patient’s course was complicated by a recurrence of severe neutropenia despite holding ICI and complete resolution of the first neutropenic episode. Although evidence from literature supports that a majority irAEs occur within the first 5–15 weeks of starting ICI, similar to our case there are some reports of late-onset toxicities both in the setting of ongoing immunotherapy and after stopping treatment [23, 24]. Durable responses have been linked to ICI induced persistent CD8+ T effector memory subset against tumor cells [25]. The potential cross-reactivity of these T-cells against normal tissue after stopping treatment is one of the plausible mechanisms that has been suggested to contribute to this phenomenon [18]. In addition, following infusion anti-PD-1 antibodies have a prolonged receptor occupancy of > 2 months on T-cells and a half-life that spans three to four weeks with a steady state concentration achieved in 19 weeks [26, 27]. We speculate all these factors in conjunction contributed to the delayed recurrence of neutropenia in our patient. A two-month post neutropenia PET in our patient showed ongoing near complete metabolic response despite treatment discontinuation. This ongoing response despite stopping pembrolizumab after neutropenia conforms to the premise of emerging data suggesting that irAEs may act as a marker of ongoing anti-tumor activity and benefit from ICI [28]. However, the patient passed away due to unrelated hypoxemia secondary to pneumonia.\n\nBone marrow evaluation of our patient did not reveal involvement with the underlying malignancy but demonstrated a normocellular marrow with left-shifted trilineage hematopoiesis. A majority of previously reported cases also underwent bone marrow biopsy demonstrating variable findings (Table 1). Our findings of a normocellular BM in the setting of severe neutropenia raises suspicion of ICI induced peripheral destruction of neutrophils. However, given the limited scope of our serological and biomarker studies, we could not establish if this were a T-cell or an antibody driven process. Nevertheless, in the context of ICI induced cytopenias that persist despite treatment discontinuation and immunosuppressive strategies, it is essential to rule out bone marrow etiologies, including obtaining genetic panels for myeloid disorders, especially in the elderly.\n\nElevation in C-reactive protein (CRP) with neutropenia and subsequent fall with neutropenia resolution was a unique observation in our patient. We have previously reported on findings of elevations in CRP during irAEs compared to baseline levels before starting ICI [29]. Furthermore, we have also shown elevated levels of interleukin-6 (IL-6) corresponding to elevated CRP in a patient with pneumonitis [30]. This observation was again reproduced in the current patient where neutropenia corresponded to an elevation of not only IL-6 but also elevations in IL-17 and IL-10 levels (Fig. 2) compared to baseline. Altered levels of baseline cytokines/chemokines, including IL-6/IL-10, have also been described by others where lower baseline levels followed by a subsequent increase during treatment was seen in patients with irAEs [31]. Furthermore we have recently reported on the use of tocilizumab, an anti-IL-6 receptor antibody in the context of steroid-refractory irAEs, where we observed a significant benefit in terms of resolution of irAE symptoms and duration of hospitalization [32]. Although these observations are indirectly suggestive of altered cytokine physiology in promoting an immune dysregulation during irAEs, prospective validation to account for confounding etiologies (potential infection in our patient) that can contribute to dysregulation of cytokines is required. It is also important to note that both CD4 and CD8 cell counts were higher on the post-cycle-3 blood draw compared to post-cycle-2 (Fig. 3). A sustained and early rise in tumor-specific CD8 has been seen to co-relate with benefit from ICI [33]. This makes an argument that in addition to denoting ICI benefit, a rise in specific T-cell subsets beyond a critical threshold compared to baseline or significant alterations between subsequent cycles could be a marker for impending immune dysregulation leading to irAE. Thus understanding the relationships between T-cell subsets, cytokines, and irAEs in larger cohorts could be critical in identifying biomarkers for early detection of irAEs and choosing optimal candidates for ICI.Fig. 3 Changes in CD-4 and CD-8 cell counts during immunotherapy. Serial CD4/CD8 T –cell counts were obtained from peripheral blood and are plotted on a Log10 scale showing changes during immunotherapy course. Post-C2 refers to the sample collected on the day of C3 day-1 before anti-PD-1 administration. Post C3 refers to the sample collected on the day of C4 day-1 before anti-PD-1 administration and also represents the sample obtained prior to hospitalization due to neutropenia. Post-C3, when compared to post-C2, was noted to have a 1.2 and 1.5 fold increase for CD8 and CD4 counts, respectively. Drop in CD4/CD8 cell counts at neutropenia was likely because the in-hospital sample collection was after treatment with immunosuppression. Post neutropenia sample collection was at clinic follow up after discharge\n\n\n\nDue to its rarity, the optimal management strategy for ICI-related neutropenia is not established. As with most irAEs, response to immunosuppression after stopping the ICI has been documented in most of the published case reports (Table 1). Various combinations of high-dose steroidal and non-steroidal immunosuppression (cyclosporine, anti-thymocyte globulin, and mycophenolate mofetil) in addition to G-CSF or IVIG have been used to manage ICI-related neutropenia (Table 1). Despite some concern due to the potential of exacerbating underlying bacterial or fungal infections, steroid use has been consistently reported as part of initial management of ICI induced neutropenia. We recommend a slow tape of steroids after the index event to decrease chances of cyclic/recurrent exacerbation of neutropenia even after ICI has been discontinued. Thus, initiating prompt treatment can help in reducing the duration of neutropenia and thus prevent potentially life-threatening consequences.\n\nConclusion\nWith rapid advances in the field of immuno-oncology and frequent use of newer ICI for multiple indications, we speculate that the potential for encountering unique irAEs secondary to ICI will rise. Our case adds to the growing body of evidence alluding to the unique immune adverse effect profiles of ICI. Evidence from our review establishes that ICI related neutropenia, although rare, tends to be severe, with a majority being grade-4. These immune-mediated neutropenias can lead to significant morbidity and mortality arising from infectious complications. Permanent ICI discontinuation needs to be strongly considered in almost all patients. Hence ICI related neutropenia as an irAE requires early identification with prompt interventions using immune suppression and granulocyte colony-stimulating factors to perhaps mitigate duration and thus prevent potentially fatal outcomes.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nLung Cancer Initiative of NC and ECU Coach Rock Foundation.\n\nAuthors’ contributions\nARN was primarily involved in conceptualizing the study, manuscript writing and editing the tables/ figures. EA and SM were involved in patient data collection, creating tables/figures, and editing the manuscript. LY, MAM, and JM were involved in conducting translational cytokine and T-cell studies from the patient’s blood. MM and DL were involved in providing important insights about the manuscript as well as editing relevant sections. PRW was involved in the clinical care of the patient. All authors have read and approved the final version.\n\nFunding\nFunding for conducting translational studies presented in this manuscript was provided by the Lung Cancer Initiative of North Carolina and the ECU Coach Rock Foundation.\n\nAvailability of data and materials\nData sharing does not apply to this article as no datasets were generated or analyzed during the current study.\n\nEthics approval and consent to participate\nAppropriate consent for conducting and reporting patient biomarker data presented in this manuscript was obtained from the ECU IRB (IRB 16–000719).\n\nConsent for publication\nIndividual patient consent was not applicable as no information in this article including the images, can be categorized as identifiable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Ribas A Wolchok JD Cancer immunotherapy using checkpoint blockade Science. 2018 359 6382 1350 1355 10.1126/science.aar4060 29567705 \n2. Doroshow DB, Sanmamed MF, Hastings K, Politi K, Rimm DL, Chen L, et al. Immunotherapy in non-small cell lung cancer: facts and hopes. Clin Cancer Res. 2019. 10.1158/1078-0432.CCR-18-1538.\n3. Reck M Rodriguez-Abreu D Robinson AG Hui R Csoszi T Fulop A Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer N Engl J Med 2016 375 19 1823 1833 10.1056/NEJMoa1606774 27718847 \n4. Reck M Rodríguez–Abreu D Robinson AG Hui R Csőszi T Fülöp A Updated analysis of KEYNOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non–small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater J Clin Oncol 2019 37 7 537 546 10.1200/JCO.18.00149 30620668 \n5. Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019. 10.1038/s41571-019-0218-0.\n6. Postow MA Sidlow R Hellmann MD Immune-related adverse events associated with immune checkpoint blockade N Engl J Med 2018 378 2 158 168 10.1056/NEJMra1703481 29320654 \n7. Petrelli F Ardito R Borgonovo K Lonati V Cabiddu M Ghilardi M Haematological toxicities with immunotherapy in patients with cancer: a systematic review and meta-analysis Eur J Cancer 2018 103 7 16 10.1016/j.ejca.2018.07.129 30196108 \n8. Davis EJ Salem JE Young A Green JR Ferrell PB Ancell KK Hematologic complications of immune checkpoint inhibitors Oncologist. 2019 24 5 584 588 10.1634/theoncologist.2018-0574 30819785 \n9. Delanoy N Michot JM Comont T Kramkimel N Lazarovici J Dupont R Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study Lancet Haematol 2019 6 1 e48 e57 10.1016/S2352-3026(18)30175-3 30528137 \n10. Akhtari M Waller EK Jaye DL Lawson DH Ibrahim R Papadopoulos NE Neutropenia in a patient treated with ipilimumab (anti-CTLA-4 antibody) J Immunother 2009 32 3 322 324 10.1097/CJI.0b013e31819aa40b 19242368 \n11. Ban-Hoefen Makiko Burack Richard Sievert Lynn Sahasrabudhe Deepak Ipilimumab-Induced Neutropenia in Melanoma Journal of Investigative Medicine High Impact Case Reports 2016 4 3 232470961666183 10.1177/2324709616661835 \n12. Tabchi S Weng X Blais N Severe agranulocytosis in a patient with metastatic non-small-cell lung cancer treated with nivolumab Lung Cancer 2016 99 123 126 10.1016/j.lungcan.2016.06.026 27565926 \n13. Wozniak S Mackiewicz-Wysocka M Krokowicz L Kwinta L Mackiewicz J Febrile neutropenia in a metastatic melanoma patient treated with ipilimumab - case report Oncol Res Treat 2015 38 3 105 108 10.1159/000377650 25792081 \n14. Barbacki A Maliha PG Hudson M Small D A case of severe Pembrolizumab-induced neutropenia Anti-Cancer Drugs 2018 29 8 817 819 29889673 \n15. Sun Y Lee SK Oo TH Rojas-Hernandez CM Management of immune-mediated Cytopenias in the era of cancer immunotherapy: a report of 4 cases J Immunother 2018 41 1 32 34 10.1097/CJI.0000000000000194 29111982 \n16. Meti N Petrogiannis-Haliotis T Esfahani K Refractory neutropenia secondary to dual immune checkpoint inhibitors that required second-line immunosuppression J Oncol Pract 2018 14 8 514 516 10.1200/JOP.18.00177 30004823 \n17. Turgeman I Wollner M Hassoun G Bonstein L Bar-Sela G Severe complicated neutropenia in two patients with metastatic non-small-cell lung cancer treated with nivolumab Anti-Cancer Drugs 2017 28 7 811 814 10.1097/CAD.0000000000000520 28574922 \n18. Young A Quandt Z Bluestone JA The balancing act between cancer immunity and autoimmunity in response to immunotherapy Cancer Immunol Res 2018 6 12 1445 1452 10.1158/2326-6066.CIR-18-0487 30510057 \n19. Rapisuwon S Izar B Batenchuk C Avila A Mei S Sorger P Exceptional response and multisystem autoimmune-like toxicities associated with the same T cell clone in a patient with uveal melanoma treated with immune checkpoint inhibitors J Immunother Cancer 2019 7 1 61 10.1186/s40425-019-0533-0 30832716 \n20. Berner F, Bomze D, Diem S, Ali OH, Fässler M, Ring S, et al. Association of checkpoint inhibitor–induced toxic effects with shared cancer and tissue antigens in non–small cell lung cancer. JAMA Oncol. 2019. 10.1001/jamaoncol.2019.0402.\n21. Das R Bar N Ferreira M Newman AM Zhang L Bailur JK Early B cell changes predict autoimmunity following combination immune checkpoint blockade J Clin Invest 2018 128 2 715 720 10.1172/JCI96798 29309048 \n22. Brahmer JR Lacchetti C Schneider BJ Atkins MB Brassil KJ Caterino JM Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline J Clin Oncol 2018 36 17 1714 1768 10.1200/JCO.2017.77.6385 29442540 \n23. Parakh S Cebon J Klein O Delayed autoimmune toxicity occurring several months after cessation of anti-PD-1 therapy Oncologist. 2018 23 7 849 851 10.1634/theoncologist.2017-0531 29666298 \n24. Wang LL Patel G Chiesa-Fuxench ZC McGettigan S Schuchter L Mitchell TC Timing of onset of adverse cutaneous reactions associated with programmed cell death protein 1 inhibitor therapy JAMA Dermatol 2018 154 9 1057 1061 10.1001/jamadermatol.2018.1912 30027278 \n25. Ribas A Shin DS Zaretsky J Frederiksen J Cornish A Avramis E PD-1 blockade expands Intratumoral memory T cells Cancer Immunol Res 2016 4 3 194 203 10.1158/2326-6066.CIR-15-0210 26787823 \n26. Brahmer JR Drake CG Wollner I Powderly JD Picus J Sharfman WH Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates J Clin Oncol 2010 28 19 3167 3175 10.1200/JCO.2009.26.7609 20516446 \n27. Longoria TC Tewari KS Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma Expert Opin Drug Metab Toxicol 2016 12 10 1247 1253 10.1080/17425255.2016.1216976 27485741 \n28. Haratani K Hayashi H Chiba Y Kudo K Yonesaka K Kato R Association of immune-related adverse events with Nivolumab efficacy in non-small-cell lung cancer JAMA Oncol 2018 4 3 374 378 10.1001/jamaoncol.2017.2925 28975219 \n29. Naqash AR Stroud CRG Cherry C Muzaffar M Bowling M Walker PR 4A.03 predictive utility of c-reactive protein (CRP) in advanced stage lung cancer treated with anti-programmed cell death-1 (PD-1) therapy: topic: medical oncology J Thorac Oncol 2017 12 11 S1559 10.1016/j.jtho.2017.09.027 \n30. Naqash AR Yang LV Sanderlin EJ Atwell DC Walker PR Interleukin-6 as one of the potential mediators of immune-related adverse events in non-small cell lung cancer patients treated with immune checkpoint blockade: evidence from a case report Acta Oncol 2018 57 5 705 708 10.1080/0284186X.2017.1406668 29171332 \n31. Khan S Khan SA Luo X Fattah FJ Saltarski J Gloria-McCutchen Y Immune dysregulation in cancer patients developing immune-related adverse events Br J Cancer 2019 120 1 63 68 10.1038/s41416-018-0155-1 30377338 \n32. Stroud CR Hegde A Cherry C Naqash AR Sharma N Addepalli S Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade J Oncol Pharm Pract 2019 25 3 551 557 10.1177/1078155217745144 29207939 \n33. Kamphorst AO Pillai RN Yang S Nasti TH Akondy RS Wieland A Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1–targeted therapy in lung cancer patients Proc Natl Acad Sci 2017 114 19 4993 4998 10.1073/pnas.1705327114 28446615\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2051-1426",
"issue": "7(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "C-reactive protein; IL-6; Immune checkpoint inhibitors; Immune-related adverse event; Immunosuppression; Neutropenia",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; D002289:Carcinoma, Non-Small-Cell Lung; D016207:Cytokines; D017809:Fatal Outcome; D006801:Humans; D018836:Inflammation Mediators; D008175:Lung Neoplasms; D008297:Male; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009503:Neutropenia",
"nlm_unique_id": "101620585",
"other_id": null,
"pages": "169",
"pmc": null,
"pmid": "31277704",
"pubdate": "2019-07-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "30819785;30027278;29207939;29111982;29442540;26787823;27565926;30620668;31021392;31092901;30824587;19242368;29320654;30377338;29171332;29567705;30528137;30832716;27718847;30004823;29666298;27485741;30196108;29309048;28574922;29889673;30510057;27570779;25792081;28446615;28975219;20516446",
"title": "Isolated neutropenia as a rare but serious adverse event secondary to immune checkpoint inhibition.",
"title_normalized": "isolated neutropenia as a rare but serious adverse event secondary to immune checkpoint inhibition"
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{
"companynumb": "US-009507513-1907USA014410",
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"activesubstancename": "PEMBROLIZUMAB"
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... |
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"abstract": "The novel Coronavirus disease 2019 (COVID-19) had rapidly spread and became a worldwide pandemic since its detection in Wuhan, China. The disease has caused significant morbidity and mortality, particularly among patients with comorbidities. The current treatment involves supportive management alongside antiviral therapy and immunosuppressant therapy in severely affected patients. We describe a case of a patient with underlying lupus nephritis (LN) who presented with severe COVID-19 infection and concomitant LN flare with acute kidney injury (AKI). The patient was treated with antiviral therapy, Favipiravir, considering his risk of developing severe COVID-19 infection. As the patients would usually have AKI alongside LN flare, we administered initial steroid therapy at a lower dose (Methylprednisolone 50mg daily) and oral hydroxychloroquine despite the initial concerns on immunosuppressant usage in COVID-19 infections. Although our patient recovered relatively well from COVID- 19 infection, he continued to have positive reverse transcriptase-polymerase chain reaction (RT-PCR) nasopharyngeal swab for COVID-19 up to 29 days of illness. His kidney function stabilised despite having persistent nephrotic range proteinuria. Hence, the attending team decided to pulse the patient with a high dose steroid (IV Methylprednisolone 250mg OD for three days) after two weeks of illness despite the persistent positive swab. The patient's condition continued to improve, and this case illustrates an approach in treating COVID-19 with concomitant active immune-mediated glomerulonephritis. We find that it is safe to institute high dose immunosuppressant in recovered COVID-19 patients two weeks after the illness.",
"affiliations": "Universiti Kebangsaan Malaysia Medical Centre, Faculty of Medicine, Department of Internal Medicine, Nephrology Unit, Kuala Lumpur, Malaysia. mdyusuf@ppukm.ukm.edu.my.;Universiti Kebangsaan Malaysia Medical Centre, Faculty of Medicine, Department of Internal Medicine, Kuala Lumpur, Malaysia.;Universiti Kebangsaan Malaysia Medical Centre, Faculty of Medicine, Department of Internal Medicine, Nephrology Unit, Kuala Lumpur, Malaysia.;Universiti Kebangsaan Malaysia Medical Centre, Faculty of Medicine, Department of Internal Medicine, Infectious Disease Unit, Kuala Lumpur, Malaysia.;Universiti Kebangsaan Malaysia Medical Centre, Faculty of Medicine, Department of Internal Medicine, Nephrology Unit, Kuala Lumpur, Malaysia.",
"authors": "Yusuf|A S|AS|;Cheong|X K|XK|;Rozita|M|M|;Periyasamy|P|P|;Ruslinda|M|M|",
"chemical_list": null,
"country": "Malaysia",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0300-5283",
"issue": "76(5)",
"journal": "The Medical journal of Malaysia",
"keywords": null,
"medline_ta": "Med J Malaysia",
"mesh_terms": "D000086382:COVID-19; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008181:Lupus Nephritis; D008297:Male; D000086402:SARS-CoV-2; D000067251:Symptom Flare Up",
"nlm_unique_id": "0361547",
"other_id": null,
"pages": "757-761",
"pmc": null,
"pmid": "34508391",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of lupus nephritis flare-up in severe COVID-19 infection.",
"title_normalized": "a case of lupus nephritis flare up in severe covid 19 infection"
} | [
{
"companynumb": "MY-LUPIN PHARMACEUTICALS INC.-2021-25220",
"fulfillexpeditecriteria": "2",
"occurcountry": "MY",
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"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
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{
"abstract": "OBJECTIVE\nThe aim of the present study was to compare the efficacy and safety of 2 protocols of maintenance therapy with infliximab (IFX) and an immunomodulatory agent in pediatric patients with Crohn disease (CD): withdrawal of immunomodulators versus continuation of immunosuppressants.\n\n\nMETHODS\nThe present multicenter randomized open-label trial included 99 patients with CD (ages 14.5 ± 2.6 years) who were administered IFX (5 mg/kg body weight) along with an immunomodulatory agent (azathioprine 1.5-3 mg/kg body weight per day, methotrexate 10-25 mg/week). After 10 weeks of the induction therapy, 84 responders were centrally randomized into 1 of the following groups: group I (n = 45) in which IFX and an immunomodulatory agent were continued up to week 54 and group II (n = 39) in which the immunomodulatory agent was discontinued after 26 weeks.\n\n\nRESULTS\nThe induction therapy was reflected by a significant decrease in Pediatric Crohn's Disease Activity Index (PCDAI) and Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD) values. After the maintenance phase, the analyzed groups did not differ significantly in terms of the clinical response loss rates and final PCDAI and SES-CD scores. Furthermore, no significant intragroup differences were documented between mean PCDAI scores determined at the end of induction and maintenance phases. Intensification/modification of the treatment was required in 13 of 45 (29%) and 11 of 39 (28%) patients of groups I and II, respectively. A total of 9 serious adverse events were documented; none of the patients died during the trial.\n\n\nCONCLUSIONS\nTwenty-six weeks likely represent the safe duration of combined IFX/immunomodulatory therapy in our sample of pediatric patients with CD.",
"affiliations": "*Children's Memorial Health Institute, Warsaw †Department of Pediatrics, Gastroenterology and Nutrition, Medical University of Wroclaw ‡Department of Paediatrics, Medical University of Silesia, Gastroenterology Unit, Upper-Silesian Child Health Care Centre, Katowice §Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw ||Wl. Buszkowski Kielce Province Children's Hospital, Kielce ¶Department of Paediatric Allergology, Gastroenterology and Nutrition, Medical University of Lodz #Paediatric Nursery Unit of Pomeranian Medical University, Division of Paediatrics, Gastroenterology and Rheumatology of Zdroje Hospital in Szczecin **Department of Pediatrics, Allergology and Gastroenterology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun ††Department of Pediatrics, Gastroenterology and Nutrition Jagiellonian University School of Medicine, Cracow, Poland.",
"authors": "Kierkuś|Jarosław|J|;Iwańczak|Barbara|B|;Wegner|Agnieszka|A|;Dadalski|Maciej|M|;Grzybowska-Chlebowczyk|Urszula|U|;Łazowska|Izabella|I|;Maślana|Jolanta|J|;Toporowska-Kowalska|Ewa|E|;Czaja-Bulsa|Grażyna|G|;Mierzwa|Grażyna|G|;Korczowski|Bartosz|B|;Czkwianianc|Elżbieta|E|;Żabka|Alicja|A|;Szymańska|Edyta|E|;Krzesiek|Elżbieta|E|;Więcek|Sabina|S|;Sładek|Małgorzata|M|",
"chemical_list": "D005765:Gastrointestinal Agents; D007166:Immunosuppressive Agents; D000069285:Infliximab; D001379:Azathioprine; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1097/MPG.0000000000000684",
"fulltext": null,
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"issn_linking": "0277-2116",
"issue": "60(5)",
"journal": "Journal of pediatric gastroenterology and nutrition",
"keywords": null,
"medline_ta": "J Pediatr Gastroenterol Nutr",
"mesh_terms": "D000293:Adolescent; D001379:Azathioprine; D002648:Child; D003424:Crohn Disease; D004359:Drug Therapy, Combination; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D060046:Maintenance Chemotherapy; D008297:Male; D008727:Methotrexate; D012074:Remission Induction; D012720:Severity of Illness Index",
"nlm_unique_id": "8211545",
"other_id": null,
"pages": "580-5",
"pmc": null,
"pmid": "25564804",
"pubdate": "2015-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Monotherapy with infliximab versus combination therapy in the maintenance of clinical remission in children with moderate to severe Crohn disease.",
"title_normalized": "monotherapy with infliximab versus combination therapy in the maintenance of clinical remission in children with moderate to severe crohn disease"
} | [
{
"companynumb": "PL-JNJFOC-20150500088",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nABO-incompatible liver transplantation (ABOi LT) is considered to be a rescue option in emergency transplantation. Herein, we have reported our experience with ABOi LT including long-term survival and major complications in these situations.\n\n\nMETHODS\nABOi LT was performed in cases of severe hepatic failure with imminent death. The standard immunosuppression consisted of basiliximab, corticosteroids, tacrolimus, and mycophenolate mofetil. Pretransplantation patients with anti-ABO titers above 16 underwent plasmapheresis. If the titer was above 128, intravenous immunoglobulin (IVIG) was added at the end of plasmapheresis. The therapeutic approach was based on the clinical situation, hepatic function, and titer evolution. A rapid increase in titer required five consecutive plasmapheresis sessions followed by administration of IVIG, and at the end of the fifth session, rituximab.\n\n\nRESULTS\nFrom January 2009 to July 2012, 10 patients, including 4 men and 6 women of mean age 47.8 years (range, 29 to 64 years), underwent ABOi LT. At a mean follow-up of 19.6 months (range, 2 days to 39 months), 5 patients are alive including 4 with their original grafts. One patient was retransplanted at 9 months. Major complications were infections, which were responsible for 3 deaths due to multiorgan septic failure (2 during the first month); rejection episodes (4 biopsy-proven of humoral rejections in 3 patients and 1 cellular rejection) and biliary.\n\n\nCONCLUSIONS\nThe use of ABOi LT as a life-saving procedure is justifiable in emergencies when no other donor is available. With careful recipient selection close monitoring of hemagglutinins and specific immunosuppression we have obtained acceptable outcomes.",
"affiliations": "Department of Nephrology, Centro Hospitalar de Lisboa Central, Hospital Curry Cabral, Lisbon, Portugal. marcomendes82@gmail.com",
"authors": "Mendes|M|M|;Ferreira|A C|AC|;Ferreira|A|A|;Remédio|F|F|;Aires|I|I|;Cordeiro|A|A|;Mascarenhas|A|A|;Martins|A|A|;Pereira|P|P|;Gloria|H|H|;Perdigoto|R|R|;Veloso|J|J|;Ferreira|P|P|;Oliveira|J|J|;Silva|M|M|;Barroso|E|E|;Nolasco|F|F|",
"chemical_list": "D000017:ABO Blood-Group System; D058846:Antibodies, Monoclonal, Murine-Derived; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "45(3)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000017:ABO Blood-Group System; D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D010956:Plasmapheresis; D011174:Portugal; D000069283:Rituximab",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1110-5",
"pmc": null,
"pmid": "23622639",
"pubdate": "2013-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "ABO-incompatible liver transplantation in acute liver failure: a single Portuguese center study.",
"title_normalized": "abo incompatible liver transplantation in acute liver failure a single portuguese center study"
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"companynumb": "PT-MYLANLABS-2020M1001314",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
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"abstract": "BACKGROUND\nEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are associated with favorable response in EGFR mutant lung cancer. Acquired resistance to reversible EGFR TKIs remains a significant barrier, and acquired EGFR T790M-mutation is the major mechanism. Second-generation irreversible EGFR TKI, afatinib, had also been approved for treating EGFR mutant lung cancer patients, but the mechanism of acquired resistance to afatinib has not been well studied.\n\n\nRESULTS\nForty-two patients had tissue specimens taken after acquiring resistance to afatinib. The sensitizing EGFR mutation were all consistent between pre- and post-afatinib tissues. Twenty patients (47.6%) had acquired T790M mutation. T790M rate was not different between first-generation EGFR TKI-naïve patients (50%) and first-generation EGFR TKI-treated patients (46.4%) (p = 0.827). No clinical characteristics or EGFR mutation types were associated with the development of acquired T790M. No other second-site EGFR mutations were detected. There were no small cell or squamous cell lung cancer transformation. Other genetic mutations were not identified in PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2.\n\n\nMETHODS\nAfatinib-prescription record of our department of pharmacy from January 2007 and December 2014 was retrieved. We investigated patients with tissue specimens available after acquiring resistance to afatinib. Enrolled patients should have partial response or durable stable disease of treatment response to afatinib. Various mechanisms of acquired resistance to first-generation EGFR TKIs were evaluated. Histology and cytology were reviewed. EGFR, PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2 genetic alterations were evaluated by sequencing. Statistical analysis was performed using Chi-square test and Kaplan-Meier method.\n\n\nCONCLUSIONS\nT790M was detected in half of the lung adenocarcinoma after acquiring resistance to afatinib. T790M is still the major acquired resistance mechanism. First-generation EGFR TKI exposure did not influence the prevalence of T790M in lung cancer acquired resistance to afatinib.",
"affiliations": "Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei, Taiwan.;Department of Molecular Biotechnology, Da-Yeh University, Chang-Hua, Taiwan.;Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.;Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.;Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.;Department of Oncology, National Taiwan University Hospital, and Graduate Institute of Oncology, Cancer Research Center, National Taiwan University, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan.;Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.",
"authors": "Wu|Shang-Gin|SG|;Liu|Yi-Nan|YN|;Tsai|Meng-Feng|MF|;Chang|Yih-Leong|YL|;Yu|Chong-Jen|CJ|;Yang|Pan-Chyr|PC|;Yang|James Chih-Hsin|JC|;Wen|Yueh-Feng|YF|;Shih|Jin-Yuan|JY|",
"chemical_list": "D000970:Antineoplastic Agents; D011799:Quinazolines; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.7189",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 26862733718910.18632/oncotarget.7189Research PaperThe mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients Wu Shang-Gin 12Liu Yi-Nan 3Tsai Meng-Feng 4Chang Yih-Leong 5Yu Chong-Jen 23Yang Pan-Chyr 23Yang James Chih-Hsin 6Wen Yueh-Feng 7Shih Jin-Yuan 231 Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan2 Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan3 Department of Internal Medicine, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei, Taiwan4 Department of Molecular Biotechnology, Da-Yeh University, Chang-Hua, Taiwan5 Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan6 Department of Oncology, National Taiwan University Hospital, and Graduate Institute of Oncology, Cancer Research Center, National Taiwan University, Taipei, Taiwan7 Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, TaiwanCorrespondence to: Jin-Yuan Shih, jyshih@ntu.edu.tw15 3 2016 4 2 2016 7 11 12404 12413 8 10 2015 23 1 2016 Copyright: © 2016 Wu et al.2016This 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.Introduction\nEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are associated with favorable response in EGFR mutant lung cancer. Acquired resistance to reversible EGFR TKIs remains a significant barrier, and acquired EGFR T790M-mutation is the major mechanism. Second-generation irreversible EGFR TKI, afatinib, had also been approved for treating EGFR mutant lung cancer patients, but the mechanism of acquired resistance to afatinib has not been well studied.\n\nResults\nForty-two patients had tissue specimens taken after acquiring resistance to afatinib. The sensitizing EGFR mutation were all consistent between pre- and post-afatinib tissues. Twenty patients (47.6%) had acquired T790M mutation. T790M rate was not different between first-generation EGFR TKI-naïve patients (50%) and first-generation EGFR TKI-treated patients (46.4%) (p = 0.827). No clinical characteristics or EGFR mutation types were associated with the development of acquired T790M. No other second-site EGFR mutations were detected. There were no small cell or squamous cell lung cancer transformation. Other genetic mutations were not identified in PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2.\n\nMethods\nAfatinib-prescription record of our department of pharmacy from January 2007 and December 2014 was retrieved. We investigated patients with tissue specimens available after acquiring resistance to afatinib. Enrolled patients should have partial response or durable stable disease of treatment response to afatinib. Various mechanisms of acquired resistance to first-generation EGFR TKIs were evaluated. Histology and cytology were reviewed. EGFR, PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2 genetic alterations were evaluated by sequencing. Statistical analysis was performed using Chi-square test and Kaplan-Meier method.\n\nConclusions\nT790M was detected in half of the lung adenocarcinoma after acquiring resistance to afatinib. T790M is still the major acquired resistance mechanism. First-generation EGFR TKI exposure did not influence the prevalence of T790M in lung cancer acquired resistance to afatinib.\n\nlung adenocarcinomaafatinibT790Macquired resistanceEGFR TKI\n==== Body\nINTRODUCTION\nLung cancer is a leading cause of cancer-related mortality worldwide [1]. Use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) produces dramatic response and favorable prognosis in patients with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations, especially exon 19 deletion and exon 21 L858R point mutations [2]. First-generation EGFR TKIs consisted of gefitinib and erlotinib, which reversibly bind to EGFR and block EGFR signaling. Several phase III trials had proven the effect and benefit of the use gefitinib and erlotinib as first-line agents [3–5].\n\nSecond-generation EGFR TKI, afatinib, is an irreversible EGFR TKI which has more potent EGFR inhibition and targets other ErbB-family members. According to LUX-Lung 3 and LUX-Lung 6 studies, afatinib had a significant better response rate and prolonged progression-free survival (PFS) as compared with pemetrexed plus cisplatin or gemcitabine plus cisplatin in patients with treatment-naïve advanced lung adenocarcinoma harboring activating EGFR mutations [6, 7]. Afatinib as first-line treatment even prolongs overall survival in patients with exon 19 deletion [8].\n\nHowever, patients with EGFR mutant lung cancer develop disease progression after a median of 10 to 14 months on EGFR TKI. Different mechanisms of acquired resistance to first-generation EGFR TKIs had been reported [9, 10]. Acquired T790M was the major mechanism of acquired resistance to first-generation EGFR TKIs, and it accounts for about a half of the cases with acquired resistance to gefitinib or erlotinib. Several third-generation EGFR TKIs, which irreversibly block T790M mutant EGFR, have shown to be effective in patients with acquired EGFR mutant lung cancer patients who acquired T790M after treatment failure with previous EGFR TKIs [11, 12]. In addition, other acquired resistance mechanism has been reported; including the development of small cell lung cancer or squamous cell transformation, second point mutations (D761Y or L747S), MET amplification, acquired PIK3CA or BRAF mutation, and epithelial-to-mesenchymal transition [9, 10, 13–16].\n\nAlthough a preclinical study showed that afatinib could inhibit EGFR T790M and block the growth of non-small cell lung cancer (NSCLC) cell lines harboring T790M mutations [17], the clinical trial did not show the overall survival benefit in patients after failure of platinum doublet and first-generation EGFR TKIs [18]. The emergence of acquired resistance remains a significant barrier for afatinib-treated patient in clinical practice. There was only one case report that showed the detection of acquired T790M in lung cancer cells after the development of resistance to afatinib [19]. However, the prevalence of T790M in lung cancer patients with acquired resistance to afatinib has not been studied. In vitro, fibroblast growth factor receptor 1 (FGFR1) activation was reported as an escape mechanism in human lung cancer cells resistant to afatinib [20]. The other gene mutations and histological evolution of lung cancers after acquiring resistance to afatinib remained poorly understood.\n\nIn this study, we explore the prevalence of different acquired resistance mechanisms in tissue specimens taken from patients with acquired resistance to afatinib.\n\nRESULTS\nPatient collection\nFrom January 2007 to December 2014, there were 518 patients who had taken afatinib according to the afatinib-prescription record from the department of pharmacy, NTUH. Those whose lung cancer harboring TKI-sensitive mutations with partial response or durable stable disease (PFS ≥ 6 months) under afatinib treatment and having post-afatinib tissue specimen collected for analysis were enrolled. We enrolled 42 patients in this study (Figure 1).\n\nFigure 1 Patient collection flow chart\nOf the 42 patients, there were 25 females (59.5%) and 33 never smokers (78.6%). All of them had EGFR mutation reports before afatinib treatments, including: 14 deletions in exon-19, 22 L858R and 6 other EGFR mutations (L861Q, D770_N711 dupSVD, G719S + S768I, G719C + S768I, L858R + E709G, L858R + S768I). Treatment responses of afatinib were 37 partial response and 5 stable disease (Table 1). Fourteen patients were first-generation EGFR TKI-naïve patients. Twenty-eight patients belonged to first-generation EGFR TKI-treated group, and they received prior first-generation EGFR TKIs treatment before taking afatinib, including: 5 gefitinib, 9 erlotinib, and 14 gefitinib and erlotinib.\n\nTable 1 Clinical characteristics of lung adenocarcinoma patients with acquired resistance to afatinib\n\t\tAll patients\t(%)\t\nTotal No.\t42\t(100)\t\nAge, median years\t57.5\t\t\n(range)\t(35.2–81.1)\t\t\nSex\t\t\t\n\tFemale\t25\t(59.5)\t\n\tMale\t17\t(40.5)\t\nSmoking\t\t\t\n\tNever-smokers\t33\t(78.6)\t\n\tSmokers\t9\t(21.4)\t\nEGFR mutation\t\t\t\n\tDel-19\t14\t(33.3)\t\n\tL858R\t22\t(52.4)\t\n\tOther\t6\t(14.3)\t\nPre-afatinib\t\t\t\n\tTKI-naïve\t14\t(33.3)\t\n\tTKI using\t28\t(66.7)\t\n\tGefitinib\t5\t\t\n\tErlotinib\t9\t\t\n\tGefitinib and Erlotinib\t14\t\t\nLine of afatinib\t\t\t\n\t1\t7\t(16.7)\t\n\t2\t7\t(16.7)\t\n\t3\t3\t(7.1)\t\n\t≥ 4\t25\t(59.5)\t\nAfatinib response\t\t\t\n\tPR\t37\t(88.1)\t\n\tSD\t5\t(11.9)\t\nEGFR: epidermal growth factor receptor, Del-19: deletion in exon 19, TKI: tyrosine kinase inhibitor, PR: partial response, SD: stable disease.\n\nThe specimens of acquired resistance came from different sites, and the majority was lung tissue via computed tomography or echo-guided biopsy or malignant pleural effusions (MPEs) via thoracentesis. The details of rebiopsy sites and procedure were described in Table 2.\n\nTable 2 Details of rebiopsy sites, tissue specimens and the prevalence of T790M\nSite\tProcedure\tSpecimen No.\tT790M (+)\tPrevalence\t\nRight chest wall\techo-guided biopsy\t1\t0\t0%\t\nMediastinum LN\tVATS lymphadenectomy\t1\t0\t0%\t\nRight hip skin\tExcisional biopsy\t1\t0\t0%\t\nCSF\tlumbar puncture\t2\t0\t0%\t\nMPE\tThoracentesis\t18\t8\t44.4%\t\nLung\t6 CT-guided biopsy\n7 Echo-guided biopsy\n3 Bronchoscopic brushing\n1 Bronchoscopic biopsy\n1 VATS lobectomy\n1 autopsy\t19\t12\t63.2%\t\nLN: lymph node, CSF: cerebrospinal fluid, MPE: malignant pleural effusion, CT: computer tomography, VATS: video-assisted thoracic surgery.\n\nT790M prevalence of acquired resistance to afatinib in lung adenocarcinoma patients\nThe specimens with acquired resistance to afatinib all showed the same sensitizing EGFR mutations as the paired treatment-naïve or pre-afatinib treatments tissue specimens. We detected a second-site T790M-EGFR mutation in 20 (47.6%) of the 42 specimens with acquired resistance to afatinib, including: 8 MPEs (44.4%) and 12 lung tissues (63.2%) (Table 2). We did not detect other secondary substitutions or point mutation of EGFR, including D761Y, L747S and C797S.\n\nOf the 20 patients with acquired T790M, there were 7 from 14 (50.0%) first-generation EGFR TKI-naïve group and 13 from 28 (46.4%) first-generation EGFR TKI-treated group (p = 0.827). The sensitizing EGFR mutation types of the 20 tumors with acquired T790M included 9 deletion in exon-19 (64.3%; 9 of 14), 10 L858R (45.5%; 10 of 22) and one L861Q (16.7%; 1 of 6) (p = 0.142). The clinical factors, including age, smoking, sex, afatinib treatment response, prior first-generation EGFR TKI use were not associated with the detection of T790M after acquired resistance to afatinib (Table 3).\n\nTable 3 Comparison of clinical characteristics between patients with acquired T790M and those without T790M\n\tAll patients\tAcquired T790M (+)\tAcquired T790M (−)\tp value\t\nTotal No.\t42\t20 (47.6%)\t22 (52.4%)\t\t\nAge, median years\t57.5\t58.2\t54.5\t0.314a\t\n (range)\t(35.2–81.1)\t(35.9–81.1)\t(35.2–78.8)\t\nSex\t\t\t\t\t\t0.952\t\n Female\t25\t12\t(48.0%)\t13\t(52.0%)\t\t\n Male\t17\t8\t(47.1%)\t9\t(52.9%)\t\t\nSmoking\t\t\t\t\t\t0.714*\t\n Never-smokers\t33\t15\t(45.5%)\t18\t(54.5%)\t\t\n Smokers\t9\t5\t(55.6%)\t4\t(44.4%)\t\t\nPre-afatinib\t\t\t\t\t\t0.827\t\n TKI-naïve\t14\t7\t(50.0%)\t7\t(50.0%)\t\t\n Prior TKI exposure\t28\t13\t(46.4%)\t15\t(53.6%)\t\t\nEGFR mutation\t\t\t\t\t\t0.142\t\n Del-19\t14\t9\t(64.3%)\t5\t(35.7%)\t\t\n L858R\t22\t10\t(45.5%)\t12\t(54.5%)\t\t\n Others\t6\t1#\t(16.7%)\t5\t(83.3%)\t\t\nAfatinib response\t\t\t\t\t\t0.175*\t\n PR\t37\t16\t(43.2%)\t21\t(56.8%)\t\t\n SD\t5\t4\t(80/0%)\t1\t(20.0%)\t\t\n# L861Q + T790M.\n\n* By Fisher exact test.\n\na By Mann-Whitney U test.\n\nEGFR: epidermal growth factor receptor, Del-19: deletion in exon 19, TKI: tyrosine kinase inhibitor, PR: partial response, SD: stable disease.\n\nOther genetic mutation after acquired resistance to afatinib\nThe afatinib resistant specimens were examined for histological transformation or genetic mutations. All specimens with acquired resistance to afatinib showed adenocarcinoma. There were no small cell lung cancer or squamous cell transformations.\n\nBecause of the limited amount of available specimens, we cannot analyze all possible genes in all samples. The sample numbers for gene mutation analysis were 26 for PIK3CA, 25 for HER2, 26 for BRAF, 26 for KRAS, 24 for NRAS, 26 for MEK1, 24 for AKT2, 20 for JAK2 and 18 for LKB1. We did not identify any genetic alternation (0%) in these genes.\n\nProgression-free survival and post-progression survival of afatinib\nOf the 42 patients with acquired resistance to afatinib, there was no difference in PFS following afatinib treatment between patients with and without acquired T790M-mutations (median, 8.9 months vs. 8.2 months; p = 0.938) (Figure 2A). First-generation EGFR TKI exposure had influence on PFS of afatinib. The difference in PFS of afatinib reached a statistical significance between 14 first-generation EGFR TKI-naïve and 28 first-generation EGFR TKI-treated patients (median, 21.0 months vs. 7.0 months; p < 0.001) (Figure 2B).\n\nFigure 2 Kaplan–meier curve of afatinib progression-free survival in patients with acquired resistance to afatinib\n(A) The difference in progression-free survival of afatinib treatment between patients with (solid line, n = 20) and without acquired T790M-mutations (dashed line, n = 22) did not reach statistically significant (median, 8.9 months vs. 8.2 months; p = 0.938, by the log-rank test). (B) The difference in progression-free survival of afatinib treatment between first-generation EGFR TKI-naïve (solid line, n = 14) and first-generation EGFR TKI-treated patients (dash line, n = 28) reached statistically significant (median, 21.0 months vs. 7.0 months; p < 0.001, by the log-rank test).\n\nTo clarify the effect of afatinib, we focused on the 14 first-generation EGFR TKI-naïve patients. PFS were 21.0 months in patients with acquired T790M and 33.8 months in patients without acquired T790M (p = 0.648) (Figure 3A). Although patients with acquired T790M had longer median post-afatinib-progression survival (35.3 months) than patients without acquired T790M mutations (17.8 months), the difference did not reach statistical significance (p = 0.616) (Figure 3B).\n\nFigure 3 Kaplan–meier curve of post-afatinib-progression survival in 14 first-generation EGFR TKI-naïve patients who acquired resistance to afatinib\n(A) The difference in progression-free survival between patients with (solid line, n = 7) and without T790M-mutations (dashed line, n = 7) did not reach statistically significant (median, 21.0 months vs. 33.8 months; p = 0.648, by the log-rank test). (B) Patients with acquired T790M had a longer median post-afatinib-progression survival than patients without acquired T790M mutations, but the difference did not reach statistical significance (median, 35.3 months vs. 17.8 months; p = 0.616, by the log-rank test).\n\nDISCUSSION\nThe study showed that approximately half of lung cancer patients with acquired resistance to afatinib had a second EGFR T790M mutation. Acquired T790M mutation is still the most common mechanism of acquired resistance to afatinib, a second-generation EGFR TKI. The prevalence of acquired T790M were similar in patients with and without prior exposure to first-generation EGFR TKI. Other acquired resistance mechanisms, including small cell lung cancer or squamous cell transformation, mutation in PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2, were not detected.\n\nOf the acquired resistance mechanisms of first-generation EGFR TKIs, acquired T790M, was found in approximately 50–60% of EGFR-mutant resistance cases [21–23]. The present study showed that acquired T790M in 47.6% of the specimens with acquired resistance to afatinib. This is compatible with prior studies about acquired resistance to first-generation EGFR TKI. In addition, our study showed that the prevalence of T790M in the tissue samples with acquired resistance to afatinib was not different whether patients took first-generation EGFR TKIs before afatinib or not. This may result from that we only enrolled those with partial response or durable stable disease to afatinib. Acquired T790M formation is still the main mechanism of acquired resistance to afatinib.\n\nIn addition to T790M, other acquired EGFR mutations to first-generation EGFR TKIs, including T854A, D761Y, and L747S, have been reported, but the number of cases were small [14, 24, 25]. The present study did not detect second-site EGFR mutations, besides T790M. In addition, our study did not detect acquired C797S mutation which mediates acquired resistance to third-generation EGFR TKI, AZD9291 although afatinib and AZD9291 both acts as an irreversible covalent inhibitor of the EGFR [26, 27]. More cases may be necessary to identify those rare second-site EGFR mutations.\n\nSmall cell lung cancer transformation has been reported as a mechanism of acquired resistance to EGFR TKI, and it accounts for 3–14% of cases who had acquired resistance to EGFR TKIs [9, 28]. A possible theory may be that both adenocarcinoma and small-cell lung cancer (SCLC) come from a common precursor, alveolar type II cells. When EGFR TKI blocks EGFR signaling related proliferation and differentiation of type II alveolar cells, these cells transform to SCLC if additional key genetic events such as RB1 inactivation occurs [29]. Although our study did not detect cases with SCLC transformation, identification of histological transformation via rebiopsy is still important because results may significantly alters treatment recommendations.\n\nThe study did not detect other known mutations in PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2. Ohashi et al. identified acquired BRAF mutation in 2 (1%) patients from 195 tumor samples with acquired resistance to erlotinib [16]. Sequist et al. reported that acquired PIK3CA mutation was 5% (2 of 37) [9]. The frequencies of acquired PIK3CA and BRAF mutations were very rare. It may result in undetected acquired PIK3CA or BRAF mutation in the present study because of our small sample size.\n\nOxnard et al. showed that patients with T790M had significantly longer PPS [30]. Presence of T790M causes more indolent progression in lung cancer [30, 31]. The present study showed similar results, but the difference did not reach statistical significance. This may result from our small number of patients. More patients are necessary to confirm the result, especially in clinical practice.\n\nAlthough secondary T790M is still the major mechanism of acquired resistance to afatinib, third-generation EGFR TKI, CO1686 (Rociletinib) and AZD9291, had promising treatment response for patients with resistance to EGFR-TKIs related to T790M mutation [11, 12], with about 60% of response rate and median progression free survival of 9.6–13.1 months [11, 12]. Therefore, finding EGFR T790M in tumor specimens after initial therapy with first- and second-generation EGFR TKIs is important to identify patients who may respond favorably to third-generation EGFR TKIs. Rebiopsy after disease progression may be indicated to guide future treatment plans based on different acquired resistance mechanisms.\n\nThis study had some limitations. First, the sample size was small although the present study has the largest patient number who had both pre- and post-afatinib tissue samples. However, obtaining tissue specimens for molecular analysis when patients experience disease progression is a persistent problem. Patients may be in extremely poor condition following initial TKI failure, and may not be suitable for rebiopsy. T790M detection from circulating cancer cells or cell-free DNA from blood might change the situation. Second, we did not analyze the amplifications of c-MET, HER2 or FGFR1 by fluorescence in situ hybridization because of the small quantity of specimens.\n\nT790M was detected in half of lung adenocarcinoma with acquired resistance to afatinib. T790M is the major mechanism of acquired resistance to afatinib and those with acquired T790M mutations might benefit from the T790M-specific third-generation EGFR TKIs.\n\nMATERIALS AND METHODS\nPatients and tissue procurement\nWe retrieved afatinib-prescription records from the pharmacy department of National Taiwan University Hospital (NTUH) from January 2007 to December 2014. We enrolled afatinib-treated patients who had tissue specimens taken after acquiring resistance to afatinib. Patients included in the final analysis had to have both pre-afatinib and post-afatinib tumor specimens available for testing. This study was approved by the NTUH Research Ethics Committee. Some of the pre-afatinib samples were previously examined and reported [32].\n\nThe clinical characteristics and medical records were recorded, including demographic information and treatment courses. Patients who had smoked less than 100 cigarettes in their lifetime were categorized as never smokers [33]. Adenocarcinoma histology was confirmed either by pathology reports of the primary or metastatic tumors, or by cell blocks of malignant pleural effusion (MPE) with positive thyroid transcription factor-1 staining by immunocytochemistry [34].\n\nWe collected tumor specimens, including frozen tissues of surgical specimens, bronchoscopic or fine needle biopsies, and malignant pleural effusions. Written informed consent to use tissue for molecular analysis was obtained from patients at the time of specimen collection. Tissue sections were examined for adequacy by microscopy with hematoxylin and eosin staining.\n\nAcquired resistance to afatinib\nCategorization as acquired resistance to afatinib was modified from Jackman's criteria [35]. All patients received single-agent treatment with afatinib. They had both tumor harboring a TKI-sensitive EGFR mutation and objective treatment response, including partial response or durable stable disease (progression free survival [PFS] ≥ 6 months) to treatment with afatinib. Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was adapted to evaluate the objective treatment effect [36]. PFS was defined as days from the date of drug treatment until disease progression or death. Post-afatinib progression survival (PPS) was measured from the date of disease progression under afatinib treatment until the date of death.\n\nFirst-generation EGFR TKI-naïve group was defined as patients receiving afatinib treatment without prior first-generation EGFR TKI exposure. Patients received prior first-generation EGFR TKIs treatment before taking afatinib were defined as first-generation EGFR TKI-treated group.\n\nSequencing of EGFR exons 18–21\nTissue specimens came from lung tumors, metastatic sites and malignant effusion cell blocks. The process of tissue specimen preparation for EGFR mutation analysis was as described previously [37, 38]. RNA was extracted from different tissue specimens for gene mutation analysis with Qiamp RNA Mini Kit (Qiagen) according to the manufacturer's protocol. Spectrophotometry was used to quantify extracted RNA.\n\nThe cDNA was obtained from the extracted RNA by the Qiagen OneStep reverse transcription polymerase chain reaction (RT-PCR) kit (Qiagen). Exons 18–21 of EGFR were amplified. The tyrosine kinase domain of the EGFR coding sequence, exons 18, 19, 20 and 21, were amplified with forward primer (5′- GGA- TCG- GCC- TCT- TCA- TGC-3′) and reverse primer (5′-TAA-AAT-TGA-TTC-CAA-TGC-CAT-CC-3′) by independent polymerase chain reaction (PCR) amplifications. The associated primers and conditions of RT-PCR have been revealed in our prior published reports [32, 39]. Finally, EGFR sequences of PCR amplicons were analyzed using ABI PRISM 3100 or 3700 (Applied Biosystems) in both sense and antisense directions.\n\nSequencing of PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2 mutation\nGenetic mutations of PIK3CA, HER2 and BRAF have been reported as the mechanism of acquired resistance to EGFR TKIs [9, 10]. In addition, other possible gene mutations were also studied in previous report, including, KRAS, NRAS and MEK1 [28]. After collection of the tissue specimens, we performed a series of genetic mutation analyses, including: PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2. Genes were amplified by RT-PCR using QIAGEN OneStep RT-PCR kit (Qiagen). The primers of the different genes were listed in the Supplementary Table S1.\n\nRT-PCR conditions were based on manufacturer's protocol. PCR amplicons were sequenced using the same method described for EGFR mutation analysis.\n\nStatistical analysis\nCategorical variables were analyzed using Chi-square test. Univariate analysis of patient characteristics was used for comparison between post-afatinib T790M-positive and T790M-negative patients with acquired resistance to afatinib. PFS and PPS were plotted by the Kaplan–Meier method and compared by log-rank test. Two-sided p-values less than 0.05 were considered significant. SPSS software (version 17.0 for Windows; SPSS Inc.) was used for all analyses.\n\nSUPPLEMENTARY MATERIALS TABLE\n The authors thank NTU Center for Genomic Medicine, National Taiwan University College of Medicine and the Office of Research and Development of NTUH for facility support and the pharmacy department of National Taiwan University Hospital for patient collection support.\n\nCONFLICTS OF INTEREST\n\nDr. Yu, Dr. C-H Yang and Dr. Shih received honoraria for speeches from Astra Zeneca, Boehringer Ingelheim and Roche.\n\nFUNDING\n\nThis study was supported by grants NSC 101-2314-B-002-167-MY3 (National Science Council, Taiwan), 102-S2158, 103-FTN17, 104-S2675 (National Taiwan University Hospital, Taiwan), MOHW103-TDU-PB-211-144002 (Ministry of Health and Welfare) and NTUHYL 104.M001 (National Taiwan University, Y Yun-Lin Branch, Yun-Lin, Taiwan).\n==== Refs\nREFERENCES\n1 Siegel R Ma J Zou Z Jemal A Cancer statistics 2014 CA: a cancer journal for clinicians 2014 64 9 29 24399786 \n2 Lynch TJ Bell DW Sordella R Gurubhagavatula S Okimoto RA Brannigan BW Harris PL Haserlat SM Supko JG Haluska FG Louis DN Christiani DC Settleman J Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib The New England journal of medicine 2004 350 2129 2139 15118073 \n3 Mok TS Wu YL Thongprasert S Yang CH Chu DT Saijo N Sunpaweravong P Han B Margono B Ichinose Y Nishiwaki Y Ohe Y Yang JJ Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma The New England journal of medicine 2009 361 947 957 19692680 \n4 Zhou C Wu YL Chen G Feng J Liu XQ Wang C Zhang S Wang J Zhou S Ren S Lu S Zhang L Hu C Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study The Lancet Oncology 2011 12 735 742 21783417 \n5 Mitsudomi T Morita S Yatabe Y Negoro S Okamoto I Tsurutani J Seto T Satouchi M Tada H Hirashima T Asami K Katakami N Takada M Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial The Lancet Oncology 2010 11 121 128 20022809 \n6 Sequist LV Yang JC Yamamoto N O'Byrne K Hirsh V Mok T Geater SL Orlov S Tsai CM Boyer M Su WC Bennouna J Kato T Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations Journal of clinical oncology 2013 31 3327 3334 23816960 \n7 Wu YL Zhou C Hu CP Feng J Lu S Huang Y Li W Hou M Shi JH Lee KY Xu CR Massey D Kim M Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial The lancet oncology 2014 15 213 222 24439929 \n8 Yang JC Wu YL Schuler M Sebastian M Popat S Yamamoto N Zhou C Hu CP O'Byrne K Feng J Lu S Huang Y Geater SL Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials The Lancet Oncology 2015 16 141 151 25589191 \n9 Sequist LV Waltman BA Dias-Santagata D Digumarthy S Turke AB Fidias P Bergethon K Shaw AT Gettinger S Cosper AK Akhavanfard S Heist RS Temel J Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors Science translational medicine 2011 3 75ra26 \n10 Camidge DR Pao W Sequist LV Acquired resistance to TKIs in solid tumours: learning from lung cancer Nature reviews Clinical oncology 2014 11 473 481 \n11 Janne PA Yang JC Kim DW Planchard D Ohe Y Ramalingam SS Ahn MJ Kim SW Su WC Horn L Haggstrom D Felip E Kim JH AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer The New England journal of medicine 2015 372 1689 1699 25923549 \n12 Sequist LV Soria JC Goldman JW Wakelee HA Gadgeel SM Varga A Papadimitrakopoulou V Solomon BJ Oxnard GR Dziadziuszko R Aisner DL Doebele RC Galasso C Rociletinib in EGFR-mutated non-small-cell lung cancer The New England journal of medicine 2015 372 1700 1709 25923550 \n13 Levin PA Mayer M Hoskin S Sailors J Oliver DH Gerber DE Histologic Transformation from Adenocarcinoma to Squamous Cell Carcinoma as a Mechanism of Resistance to EGFR Inhibition J Thorac Oncol 2015 10 e86 88 26291017 \n14 Costa DB Halmos B Kumar A Schumer ST Huberman MS Boggon TJ Tenen DG Kobayashi S BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations PLoS medicine 2007 4 1669 1679 discussion 1680 17973572 \n15 Toyooka S Date H Uchida A Kiura K Takata M The epidermal growth factor receptor D761Y mutation and effect of tyrosine kinase inhibitor Clinical cancer research 2007 13 3431 author reply 3431–3432 17545553 \n16 Ohashi K Sequist LV Arcila ME Moran T Chmielecki J Lin YL Pan Y Wang L de Stanchina E Shien K Aoe K Toyooka S Kiura K Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1 Proceedings of the National Academy of Sciences of the United States of America 2012 109 E2127 2133 22773810 \n17 Kim Y Ko J Cui Z Abolhoda A Ahn JS Ou S-H Ahn M-J Park K The EGFR T790M Mutation in Acquired Resistance to an Irreversible Second-Generation EGFR Inhibitor Molecular Cancer Therapeutics 2012 11 784 791 22228822 \n18 Miller VA Hirsh V Cadranel J Chen YM Park K Kim SW Zhou C Su WC Wang M Sun Y Heo DS Crino L Tan EH Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial The Lancet Oncology 2012 13 528 538 22452896 \n19 Kim Y Ko J Cui Z Abolhoda A Ahn JS Ou SH Ahn MJ Park K The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor Mol Cancer Ther 2012 11 784 791 22228822 \n20 Azuma K Kawahara A Sonoda K Nakashima K Tashiro K Watari K Izumi H Kage M Kuwano M Ono M Hoshino T FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor Oncotarget 2014 5 5908 5919 10.18632/oncotarget.1866 25115383 \n21 Kobayashi S Boggon TJ Dayaram T Janne PA Kocher O Meyerson M Johnson BE Eck MJ Tenen DG Halmos B EGFR mutation and resistance of non-small-cell lung cancer to gefitinib The New England journal of medicine 2005 352 786 792 15728811 \n22 Pao W Miller VA Politi KA Riely GJ Somwar R Zakowski MF Kris MG Varmus H Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain PLoS medicine 2005 2 e73 15737014 \n23 Kuiper JL Heideman DA Thunnissen E Paul MA van Wijk AW Postmus PE Smit EF Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients Lung cancer 2014 85 19 24 24768581 \n24 Balak MN Gong Y Riely GJ Somwar R Li AR Zakowski MF Chiang A Yang G Ouerfelli O Kris MG Ladanyi M Miller VA Pao W Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors Clinical cancer research 2006 12 6494 6501 17085664 \n25 Bean J Riely GJ Balak M Marks JL Ladanyi M Miller VA Pao W Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma Clinical cancer research 2008 14 7519 7525 19010870 \n26 Thress KS Paweletz CP Felip E Cho BC Stetson D Dougherty B Lai Z Markovets A Vivancos A Kuang Y Ercan D Matthews SE Cantarini M Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M Nat Med 2015 21 560 562 25939061 \n27 Solca F Dahl G Zoephel A Bader G Sanderson M Klein C Kraemer O Himmelsbach F Haaksma E Adolf GR Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker Journal of Pharmacology and Experimental Therapeutics 2012 343 342 350 22888144 \n28 Yu HA Arcila ME Rekhtman N Sima CS Zakowski MF Pao W Kris MG Miller VA Ladanyi M Riely GJ Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers Clinical cancer research 2013 19 2240 2247 23470965 \n29 Oser MG Niederst MJ Sequist LV Engelman JA Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin The Lancet Oncology 2015 16 e165 e172 25846096 \n30 Oxnard GR Arcila ME Sima CS Riely GJ Chmielecki J Kris MG Pao W Ladanyi M Miller VA Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation Clinical cancer research 2011 17 1616 1622 21135146 \n31 Hata A Katakami N Yoshioka H Takeshita J Tanaka K Nanjo S Fujita S Kaji R Imai Y Monden K Matsumoto T Nagata K Otsuka K Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations Cancer 2013 119 4325 4332 24105277 \n32 Wu SG Yu CJ Tsai MF Liao WY Yang CH Jan IS Yang PC Shih JY Survival of lung adenocarcinoma patients with malignant pleural effusion The European respiratory journal 2013 41 1409 1418 23018906 \n33 Centers for Disease C and Prevention Cigarette smoking among adults– United States, 2006 MMWR Morb Mortal Wkly Rep 2007 56 1157 1161 17989644 \n34 Travis WD Brambilla E Noguchi M Nicholson AG Geisinger KR Yatabe Y Beer DG Powell CA Riely GJ Van Schil PE Garg K Austin JH Asamura H International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma J Thorac Oncol 2011 6 244 285 21252716 \n35 Jackman D Pao W Riely GJ Engelman JA Kris MG Janne PA Lynch T Johnson BE Miller VA Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer Journal of clinical oncology 2010 28 357 360 19949011 \n36 Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R Dancey J Arbuck S Gwyther S Mooney M Rubinstein L Shankar L Dodd L New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) European journal of cancer 2009 45 228 247 19097774 \n37 Tsai TH Su KY Wu SG Chang YL Luo SC Jan IS Yu CJ Yu SL Shih JY Yang PC RNA is favourable for analysing EGFR mutations in malignant pleural effusion of lung cancer The European respiratory journal 2012 39 677 684 21719485 \n38 Tsai TH Yang CY Ho CC Liao WY Jan IS Chen KY Wang JY Ruan SY Yu CJ Yang JC Yang PC Shih JY Multi-gene analyses from waste brushing specimens for patients with peripheral lung cancer receiving EBUS-assisted bronchoscopy Lung cancer 2013 82 420 425 24183104 \n39 Wu SG Gow CH Yu CJ Chang YL Yang CH Hsu YC Shih JY Lee YC Yang PC Frequent epidermal growth factor receptor gene mutations in malignant pleural effusion of lung adenocarcinoma The European respiratory journal 2008 32 924 930 18508816\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "7(11)",
"journal": "Oncotarget",
"keywords": "EGFR TKI; T790M; acquired resistance; afatinib; lung adenocarcinoma",
"medline_ta": "Oncotarget",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines; D015398:Signal Transduction",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "12404-13",
"pmc": null,
"pmid": "26862733",
"pubdate": "2016-03-15",
"publication_types": "D016428:Journal Article",
"references": "25923550;17085664;23816960;22888144;22228822;19949011;25115383;18508816;17973572;24981256;23470965;25846096;24768581;21135146;22452896;15728811;24439929;26291017;22773810;17545553;25923549;15118073;19097774;20022809;19010870;15737014;21783417;23018906;21430269;24399786;17989644;21252716;24105277;24183104;19692680;25589191;25939061;21719485",
"title": "The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients.",
"title_normalized": "the mechanism of acquired resistance to irreversible egfr tyrosine kinase inhibitor afatinib in lung adenocarcinoma patients"
} | [
{
"companynumb": "TW-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-27404BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"d... |
{
"abstract": "BACKGROUND\nRomidepsin, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of relapsed and refractory peripheral T-cell lymphoma. However, the efficacy and safety of romidepsin has never been studied in patients with relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma (ENKTL).\n\n\nMETHODS\nWe conducted an open-label, prospective pilot study to evaluate the efficacy and feasibility of romidepsin in the treatment of patients with ENKTL. The treatment was intravenous infusion of romidepsin (14 mg/m(2)) for 4 h on days 1, 8, and 15 of a 28-day cycle, and was repeated until disease progression or the occurrence of unacceptable toxicity.\n\n\nRESULTS\nA total of five patients enrolled on to this pilot study. However, three patients developed fever and elevated liver enzyme and bilirubin levels immediately after their first administration of romidepsin. We suspected that these events were associated with Epstein-Barr virus (EBV) reactivation because of the rapidly elevated EBV DNA titers in blood from these patients. An in vitro study with the ENKTL cell line SNK-6 cells also showed that HDAC inhibitors including romidepsin increased the copy number of EBV DNA in a dose-dependent manner. These findings suggested that romidepsin-induced histone acetylation reversed the repressed state of the genes required for EBV reactivation and that romidepsin treatment may have caused EBV reactivation in EBV-infected tumor cells in ENKTL patients. Therefore, we discontinued the enrollment of patients into this pilot study.\n\n\nCONCLUSIONS\nOur study suggests that the use of romidepsin may cause severe EBV reactivation in patients with ENKTL.",
"affiliations": "Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul wskimsmc@skku.edu.;Samsung Biomedical Research Institute, Samsung Medical Center, Seoul.;Departments of Laboratory Medicine and Genetics.;Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul.;Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.",
"authors": "Kim|S J|SJ|;Kim|J H|JH|;Ki|C S|CS|;Ko|Y H|YH|;Kim|J S|JS|;Kim|W S|WS|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D004279:DNA, Viral; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C087123:romidepsin",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdv596",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "27(3)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "EBV reactivation; extranodal NK/T-cell lymphoma; romidepsin",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000903:Antibiotics, Antineoplastic; D045744:Cell Line, Tumor; D004279:DNA, Viral; D047630:Depsipeptides; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D054391:Lymphoma, Extranodal NK-T-Cell; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D014775:Virus Activation",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "508-13",
"pmc": null,
"pmid": "26658891",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Epstein-Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients: a previously unrecognized serious adverse event in a pilot study with romidepsin.",
"title_normalized": "epstein barr virus reactivation in extranodal natural killer t cell lymphoma patients a previously unrecognized serious adverse event in a pilot study with romidepsin"
} | [
{
"companynumb": "KR-CELGENE-286-22393-14080001",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ROMIDEPSIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nIncreasing active longevity has created an increasing surge of elderly trauma patients. The majority of these patients suffer blunt trauma and many are taking antithrombotic agents. The literature is mixed regarding the utility of routine repeat head CT in patients taking antithrombotic medications with a GCS of 15 and initial negative head CT. We hypothesized that scheduled delayed CT head 12 h after admission (D-CTH) in elderly blunt trauma victims would not identify clinically significant new hemorrhages or change management.\n\n\nMETHODS\nA retrospective chart review using our institutional trauma registry of patients ≥65 years sustaining blunt head injuries from 2010 to 2012 was performed. By hospital protocol, all such patients on antithrombotic therapy receive a routine D-CTH. All of these patients were included. Demographics, injuries, medications, laboratory values, LOS, mental status, and management were analyzed.\n\n\nRESULTS\nOf the 234 patients meeting inclusion criteria, 8 initially were identified as having D-ICH. Upon further review, five patients had the same findings on both initial and delayed CT scans and one patient was determined to actually have had a hemorrhage stroke. Ultimately, only two patients (0.85%, 95% CI 0.1-3.1%) had new ICH discovered on D-CTH. None of the patients on warfarin demonstrated any new injury on D-CTH (95% CI ≤ 4.6%). Only one patient taking aspirin as a sole agent had a delayed injury on D-CTH (1.1%, 95% CI 0-4.2%). The remaining patient was taking a combination of aspirin and clopidogrel representing 2.2% of 45 patients on combination therapy (95% CI 0.1-11.8%). Only two patients taking a direct thrombin inhibitor (dabigatran) met inclusion criteria and neither endured a bleed (95% CI ≤ 77.6%). Further analysis revealed no cases with clinical changes or surgical intervention for new ICH on delayed imaging. No inference could be made to predict which patients would suffer D-ICH.\n\n\nCONCLUSIONS\nD-CTH in elderly trauma patients taking antithrombotic agents shows no statistically significant or clinical benefit for diagnosing delayed intracranial hemorrhage after minor head injury. In those with delayed imaging showing new ICH, management was not significantly altered. Not enough data were available to predict which patients would develop D-ICH, even if asymptomatic.",
"affiliations": "Hahnemann University Hospital, Drexel University College of Medicine, 215 N 15th St MS 413, Philadelphia, PA, 19102, USA. dane.scantling@gmail.com.;Hahnemann University Hospital, Drexel University College of Medicine, 215 N 15th St MS 413, Philadelphia, PA, 19102, USA.;Hahnemann University Hospital, Drexel University College of Medicine, 215 N 15th St MS 413, Philadelphia, PA, 19102, USA.;Hahnemann University Hospital, Drexel University College of Medicine, 215 N 15th St MS 413, Philadelphia, PA, 19102, USA.;Hahnemann University Hospital, Drexel University College of Medicine, 215 N 15th St MS 413, Philadelphia, PA, 19102, USA.;AtlantiCare Regional Medical Center, 1925 Pacific Avenue, Atlantic City, NJ, 08401, USA.",
"authors": "Scantling|D|D|http://orcid.org/0000-0002-0744-9930;Fischer|C|C|;Gruner|R|R|;Teichman|A|A|;McCracken|B|B|;Eakins|J|J|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00068-017-0793-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1863-9933",
"issue": "43(6)",
"journal": "European journal of trauma and emergency surgery : official publication of the European Trauma Society",
"keywords": "Antithrombotics; Complications; Elderly; Head injury; Outcome assessment; Traumatology",
"medline_ta": "Eur J Trauma Emerg Surg",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005343:Fibrinolytic Agents; D006299:Health Services for the Aged; D006801:Humans; D020300:Intracranial Hemorrhages; D008297:Male; D012042:Registries; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed; D014481:United States; D014949:Wounds, Nonpenetrating",
"nlm_unique_id": "101313350",
"other_id": null,
"pages": "741-746",
"pmc": null,
"pmid": "28439613",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": "20938267;16374287;15187746;8172435;24458049;24014175;27485307;16966987;22182870;12394864;7671507;19741394;22626015;11356436;15622684;20016390;10891517;20440401;20938268;24887801",
"title": "The role of delayed head CT in evaluation of elderly blunt head trauma victims taking antithrombotic therapy.",
"title_normalized": "the role of delayed head ct in evaluation of elderly blunt head trauma victims taking antithrombotic therapy"
} | [
{
"companynumb": "US-BAYER-2017-086666",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Neuroendocrine carcinomas of the prostate (NEPCs) are rare tumors with poor prognosis. While platinum and etoposide-based chemotherapy regimens (PE) are commonly applied in first-line for advanced disease, evidence for second-line therapy and beyond is very limited.\nRetrospective analysis of all patients with NEPCs including mixed differentiation with adenocarcinoma component and well differentiated neuroendocrine tumors (NETs, carcinoids) at two high-volume oncological centers between 12/2000 and 11/2017.\nOf 46 identified patients 39.1 % had a prior diagnosis of prostatic adenocarcinoma only, 43.5 % had a mixed differentiation at NEPC diagnosis, 67.4 % developed visceral metastases, 10.9 % showed paraneoplastic syndromes. Overall survival (OS) from NEPC diagnosis was 15.5 months, and significantly shorter in patients with a prior prostatic adenocarcinoma (5.4 vs. 32.7 months, p=0.005). 34 patients received palliative first-line systemic therapy with a median progression-free survival (PFS) of 6.6 months, mostly PE. Overall response rate (ORR) for PE was 48.1 %. 19 patients received second-line therapy, mostly with poor responses. Active regimens were topotecan (1 PR, 3 PD), enzalutamide (1 SD), abiraterone (1 SD), FOLFIRI (1 SD), and ipilimumab+nivolumab (1 PR). One patient with prostatic carcinoid was sequentially treated with octreotide, peptide receptor radionuclide therapy and everolimus, and survived for over 9 years.\nEP in first-line shows notable ORR, however limited PFS. For second-line therapy, topotecan, FOLFIRI, enzalutamide, abiraterone and immune checkpoint blockade are treatment options. Prostatic carcinoids can be treated in analogy to well differentiated gastrointestinal NETs.",
"affiliations": "Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.;Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.;Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.;Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.;Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany.;Institute of Pathology, Klinikum Nuremberg, Paracelsus Medical University, Nuremberg, Germany.;Institute of Pathology, Klinikum Nuremberg, Paracelsus Medical University, Nuremberg, Germany.;Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.;Department of Urology, University Hospital Heidelberg, Heidelberg, Germany.;Department of Urology, Klinikum Nuremberg, Paracelsus Medical University, Nuremberg, Germany.;Department of Urology, Klinikum Nuremberg, Paracelsus Medical University, Nuremberg, Germany.;Department of Urology, Klinikum Nuremberg, Paracelsus Medical University, Nuremberg, Germany.;Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.",
"authors": "Apostolidis|Leonidas|L|;Nientiedt|Cathleen|C|;Winkler|Eva Caroline|EC|;Berger|Anne Katrin|AK|;Kratochwil|Clemens|C|;Kaiser|Annette|A|;Becker|Anne-Sophie|AS|;Jäger|Dirk|D|;Hohenfellner|Markus|M|;Hüttenbrink|Clemens|C|;Pahernik|Sascha|S|;Distler|Florian A|FA|;Grüllich|Carsten|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.26523",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 2652310.18632/oncotarget.26523Research PaperClinical characteristics, treatment outcomes and potential novel therapeutic options for patients with neuroendocrine carcinoma of the prostate Apostolidis Leonidas 1Nientiedt Cathleen 1Winkler Eva Caroline 1Berger Anne Katrin 1Kratochwil Clemens 2Kaiser Annette 3Becker Anne-Sophie 3Jäger Dirk 1Hohenfellner Markus 4Hüttenbrink Clemens 5Pahernik Sascha 5Distler Florian A. 5*Grüllich Carsten 1*1 Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany2 Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany3 Institute of Pathology, Klinikum Nuremberg, Paracelsus Medical University, Nuremberg, Germany4 Department of Urology, University Hospital Heidelberg, Heidelberg, Germany5 Department of Urology, Klinikum Nuremberg, Paracelsus Medical University, Nuremberg, GermanyCorrespondence to:Leonidas Apostolidis,leonidas.apostolidis@med.uni-heidelberg.de* These authors have contributed equally to this work\n\n01 1 2019 01 1 2019 10 1 17 29 19 9 2018 10 12 2018 Copyright: © 2019 Apostolidis et al.2019This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nNeuroendocrine carcinomas of the prostate (NEPCs) are rare tumors with poor prognosis. While platinum and etoposide-based chemotherapy regimens (PE) are commonly applied in first-line for advanced disease, evidence for second-line therapy and beyond is very limited.\n\nMethods\nRetrospective analysis of all patients with NEPCs including mixed differentiation with adenocarcinoma component and well differentiated neuroendocrine tumors (NETs, carcinoids) at two high-volume oncological centers between 12/2000 and 11/2017.\n\nResults\nOf 46 identified patients 39.1 % had a prior diagnosis of prostatic adenocarcinoma only, 43.5 % had a mixed differentiation at NEPC diagnosis, 67.4 % developed visceral metastases, 10.9 % showed paraneoplastic syndromes. Overall survival (OS) from NEPC diagnosis was 15.5 months, and significantly shorter in patients with a prior prostatic adenocarcinoma (5.4 vs. 32.7 months, p=0.005). 34 patients received palliative first-line systemic therapy with a median progression-free survival (PFS) of 6.6 months, mostly PE. Overall response rate (ORR) for PE was 48.1 %. 19 patients received second-line therapy, mostly with poor responses. Active regimens were topotecan (1 PR, 3 PD), enzalutamide (1 SD), abiraterone (1 SD), FOLFIRI (1 SD), and ipilimumab+nivolumab (1 PR). One patient with prostatic carcinoid was sequentially treated with octreotide, peptide receptor radionuclide therapy and everolimus, and survived for over 9 years.\n\nConclusions\nEP in first-line shows notable ORR, however limited PFS. For second-line therapy, topotecan, FOLFIRI, enzalutamide, abiraterone and immune checkpoint blockade are treatment options. Prostatic carcinoids can be treated in analogy to well differentiated gastrointestinal NETs.\n\nneuroendocrine carcinomaneuroendocrine tumorcarcinoidprostatechemotherapy\n==== Body\nINTRODUCTION\nNeuroendocrine Carcinoma (NEC) of the prostate (NEPC) is considered a rare tumor entity with a rising incidence [1]. Compared to conventional adenocarcinoma, NEPC is characterized by an aggressive tumor biology with loss of PSA secretion, unresponsiveness to androgen deprivation therapy (ADT), development of visceral metastases and limited prognosis [2]. NEPC can feature an adenocarcinoma component, resulting in a mixed differentiation. Besides NEPC arising de novo, more commonly they are described in the context of castration-resistant prostate cancer after ADT.\n\nCompared to adenocarcinoma, prognosis of NEPC is poor with survival ranging from 7 to 10 months. Due to the rarity of the disease, the optimal treatment strategy is up to debate. Like in NECs of other organ systems, platinum-based chemotherapy regimens are commonly applied in first-line for advanced disease [3–9]. Despite encouraging response rates in several phase II studies, progression-free (PFS) and overall survival (OS) are short. Clinical-grade evidence for systemic treatment options in second-line and beyond is extremely limited [3, 10, 11].\n\nOn the other hand, well differentiated Neuroendocrine Tumors (NETs, carcinoids) of the prostate are even rarer than highly proliferative NEPCs with only few reported cases in the literature [12, 13]. While the biology is more indolent than in poorly differentiated NEPC, response to chemotherapy is generally poor [14]. Treatment with somatostatin analogues, targeted agents and peptide receptor radionuclide therapy (PRRT) is considered standard of care for NETs of the gastrointestinal tract [15] but has not been evaluated in prostatic NETs (carcinoids) so far.\n\nThe aim of our study was to investigate the clinical characteristics and treatment outcome of patients with NEPC.\n\nRESULTS\nPatient characteristics\nA total of 46 male patients with a median age of 69 years were identified (Table 1). Median follow-up was 61.0 months. 39.1 % of patients had a prior diagnosis of prostatic adenocarcinoma only, the median interval between adenocarcinoma and NEPC diagnosis was 28.2 months (range 1.0-123.8). 20 men (43.5 %) showed a mixed differentiation at NEPC diagnosis. Small cell histology was documented in 45.7 % of patients. Median proliferation rate (Ki67) was 80 %. 1 Patient with non-small cell histology was classified as carcinoid (well differentiated NET) with a Ki67 of only 1 %. 8 patients (17.4 %) were diagnosed in a localized stage. The remaining 82.6 % of patients (75.0 % with de-novo NEPC, 94.4 % with prior adenocarcinoma) were diagnosed with synchronous metastatic NEPC, with 67.4 % developing visceral (i.e. non-bone, non-lymphatic) metastases and 65.2% developing bone metastases during the course of the disease. Median tumor marker levels were 3.2 x ULN (upper limit normal) for PSA, 6.1 x ULN (i.e. 518.0 ng/ml) for chromogranin A and 7.6 x ULN (i.e. 128.5 ng/ml) for NSE (neuron-specific enolase). 10.9 % of patients showed paraneoplastic syndromes, including 1 case of paraneoplastic neuropathy, 1 case of disseminated intravasal coagulation, 1 case of ectopic ACTH (adrenocorticotropic hormone) production and 2 cases of SIADH (syndrome of inappropriate antidiuretic hormone secretion).\n\nTable 1 Patient characteristics at NEPC diagnosis\n\t\t\tNumber of patients N=46\t%\t\nAge [years]\tMedian\t69\t\t\t\n\tRange\t51-82\t\t\t\nStage\tLocalized\t\t8\t17.4\t\n\tMetastatic\t\t38\t82.6\t\nMetastatic sites\tLymph nodes\t\t34\t73.9\t\n\tBone\t\t30\t65.2\t\n\tLiver\t\t20\t43.5\t\n\tLung\t\t14\t30.4\t\n\tBrain\t\t8\t17.4\t\n\tPleura\t\t3\t6.5\t\n\tAdrenal gland\t\t2\t4.3\t\n\tPeritoneum\t\t3\t6.5\t\n\tOther\t\t4\t8.7\t\nParaneoplastic\tSIADH\t\t2\t4.3\t\nsyndromes\tEctopic ACTH production\t\t1\t2.2\t\n\tNeuropathy\t\t1\t2.2\t\n\tDIC\t\t1\t2.2\t\nKi67 [%]\tMedian\t90\t\t\t\n\tRange\t1-100\t\t\t\n\t< 55\t\t9\t19.6\t\n\t≥ 55\t\t25\t54.3\t\nHistology\tSmall cell\t\t21\t45.7\t\n\tNon small cell\t\t25\t54.3\t\n\tMixed differentiation\t\t20\t43.5\t\n\tCarcinoid\t\t1\t2.2\t\nPrior prostatic adenocarcinoma\t\t\t18\t39.1\t\nTumor markers\tPSA > ULN\t\t26\t56.5\t\n\tPSA ≤ ULN\t\t6\t13.0\t\n\tNSE > ULN\t\t21\t45.7\t\n\tNSE ≤ ULN\t\t3\t6.5\t\n\tCgA > ULN\t\t12\t26.1\t\n\tCgA ≤ ULN\t\t3\t6.5\t\n\tLDH > ULN\t\t13\t28.3\t\n\tLDH ≤ ULN\t\t18\t39.1\t\nTherapy prior to NEPC diagnosis\tSurgery of primary\t\t19\t41.3\t\n\tRadiotherapy of primary\t\t9\t19.6\t\n\tAndrogen deprivation therapy\t\t17\t27.0\t\n\tAbiraterone\t\t4\t8.7\t\n\tEnzalutamide\t\t3\t6.5\t\n\tDocetaxel\t\t6\t13.0\t\n\tCabazitaxel\t\t2\t4.3\t\n\tPSMA radionuclide therapy\t\t1\t2.2\t\nSurvival\nMedian OS from the timepoint of diagnosis of any prostatic malignancy was 32.1 months, from the timepoint of NEPC diagnosis it was 15.5 months (Figure 1) with 6-month survival rate of 0.76 (95 % CI 0.63-0.87) and 12-month survival rate of 0.57 (95 % CI 0.41-0.73). In a univariate analysis of OS in different subgroups, patients with previous history of prostatic adenocarcinoma had a significantly worse prognosis (5.4 vs. 32.7 months, p=0.005) (Table 2, see Supplementary Table 1 for 6-month and 12-month survival proportion estimates). There was no significant difference in OS of patients with mixed vs. purely neuroendocrine differentiation. Patients with elevated levels of lactate dehydrogenase (LDH) showed a strong trend towards a shortened OS of 5.4 vs. 17.3 months (p=0.064). For patients with metastatic disease not receiving any palliative systemic therapy for NEPC, median OS was 3.9 months.\n\nFigure 1 Overall survival from diagnosis of any prostatic malignancy (A) and from diagnosis of NEPC (B).\n\nTable 2 Overall survival from the timepoint of NEPC diagnosis in different subgroups\n\t\tMedian OS [months]\tp\t\nHistology\tSmall cell\t15.5\t0.828\t\n\tNon-small cell\t17.1\t\t\nMixed differentiation\tYes\t15.5\t0.970\t\n\tNo\t17.3\t\t\nPrior adenocarcinoma\tYes\t5.4\t0.005\t\n\tNo\t32.7\t\t\nKi67\t≥ 55 %\t10.4\t0.325\t\n\t< 55 %\t17.1\t\t\nPSA\t> ULN\t10.7\t0.719\t\n\t≤ ULN\t33.1\t\t\nNSE\t> ULN\t9.6\t0.105\t\n\t≤ ULN\tNR\t\t\nCgA\t> ULN\t15.5\t0.330\t\n\t≤ ULN\t9.6\t\t\nLDH\t> ULN\t5.4\t0.064\t\n\t≤ ULN\t17.3\t\t\nStage\tLocalized\t32.7\t0.411\t\n\tMetastatic\t15.5\t\t\nVisceral metastases\tYes\t13.5\t0.166\t\n\tNo\tNR\t\t\nPalliative systemic therapy\tYes\t17.4\t0.192\t\n\tNo\t3.9\t\t\nEfficacy of first-line therapy\n34 patients received palliative first-line systemic therapy, mostly platinum and etoposide (PE) (n=27). A median of 5 cycles of PE was administered (range 1-9). Median PFS was 6.6 months (Figure 2). Overall response rate (ORR) for PE was 48.1 % (1 complete response [CR], 12 partial responses [PR], 1 stable disease [SD]). ORR was higher in patients with small cell vs. non-small cell histology (56.3 % vs. 36.4 %), however similar in patients with mixed vs. pure neuroendocrine differentiation (45.5 vs. 50.0 %). Of the patients receiving PE, 10 patients were treated with cisplatin and 12 patients received carboplatin. 5 patients switched from cisplatin to carboplatin because of toxicity after a median of 2 cycles. Patients primarily treated with carboplatin showed a trend towards a prolonged PFS of 7.5 months vs. those receiving cisplatin (3.9 months, p=0.114) (Figure 3A). PFS for patients who switched to carboplatin was similar to those who only received cisplatin (3.9 months). Only 3 Patients with proliferation rate (Ki67) of < 55 % were treated with PE. They showed a strong trend towards a lower PFS of 1.9 months vs. patients with a Ki67 ≥ 55 % (5.6 months, p=0.071, Figure 3B). Of patients who received another first-line therapy than PE, only 6 were evaluable for response, 1 PD with docetaxel, 1 SD and 1 PR with FOLFIRI, 1 SD with abiraterone, 1 SD with enzalutamide. The sixth patient was treated with the somatostatin analogue octreotide for his well differentiated NET (carcinoid), which resulted in a disease stabilization for 31.1 months.\n\nFigure 2 Progression-free survival of first-line therapy\nFigure 3 Progression-free survival for platinum and etoposide regarding type of platinum (A) and Ki67 (≥ 55 % vs. < 55 %) (B).\n\nSecond-line therapy and beyond\n19 patients received second-line therapy, mostly with poor response rates (Table 3).\n\nTable 3 Overview of second-line therapies\n\tTotal\tCR\tPR\tSD\tPD\tNE\tmedian DoR [months] (for CR, PR, SD)\t\nPE\t5\t\t3\t1\t\t1\t8.0\t\nTopotecan\t5\t\t1\t\t3\t1\t5.9\t\nFOLFIRI\t1\t\t\t1\t\t\t8.4\t\nFOLFOX\t1\t\t\t\t1\t\t\t\nDocetaxel\t1\t\t\t\t\t1\t\t\nEnzalutamide\t1\t\t\t1\t\t\t8.1\t\nAbiraterone\t1\t\t\t\t\t1\t\t\nEverolimus\t1\t\t\t\t1\t\t\t\nPRRT\t1\t\t1\t\t\t\t37.5\t\nSIRT\t1\t\t\t\t1\t\t\t\nIpilimumab+nivolumab\t1\t\t1\t\t\t\t7.1\t\nBeside PE, regimens with notable activity were topotecan, enzalutamide, and FOLFIRI. Most notably, 1 patient primary refractory to PE showed a very good PR under dual immune checkpoint blockade with ipilimumab+nivolumab for more than 6 months (Figure 4). The patient with the prostatic carcinoid showed prolonged disease stabilization for 37.9 months under PRRT targeting the somatostatin receptor.\n\nFigure 4 Case example of sustained partial remission to immune checkpoint blockade\nCT scans of a 70-year old patient with small cell NEPC with minor adenocarcinoma component, Ki67 85 %. After direct progression to PE, the patient was treated with 4 cycles of dual immune checkpoint blockade with ipilimumab+nivolumab, following nivolumab maintenance therapy. He showed a very good PR for more than 6 months.\n\nThird-line therapy was applied to 6 patients only. Of those, only the carcinoid patient showed disease stabilization under everolimus, 1 patient showed a CR to re-exposition with PE. The patient treated with ipilimumab+nivolumab showed a progressive bone metastasis after 7.1 months under nivolumab maintenance therapy. Upon reinduction with ipilimumab, immunotherapy had to be stopped due to a grade 3 autoimmune colitis after the first cycle. After palliative bone radiotherapy, he received enzalutamide which resulted in short-term disease stabilization. The other 3 patients showed PD (1x FOLFIRI, 1x docetaxel, 1x carboplatin+paclitaxel).\n\nThe carcinoid patient received a salvage PRRT with an alpha emitter, the therapy had to be discontinued due to progressive bone marrow carcinosis and increasing bone marrow insufficiency. Finally, he died from progressive disease 109.3 months after NET diagnosis. The sequence of systemic therapies and chromogranin A levels are summarized in Figure 5.\n\nFigure 5 Overview of systemic therapy sequence and tumor marker chromogranin A (CgA) of a patient with metastatic prostatic well differentiated NET (carcinoid)\nInsert: representative DOTATOC-PET/CT scan showing somatostatin receptor positive lesions. EVE: everolimus; PRRT: peptide receptor radionuclide therapy; ULN: upper limit normal.\n\nDISCUSSION\nThe clinical characteristics of our NEPC patient cohort are in line with previous reports, including the frequent presence of visceral metastases and paraneoplastic syndromes, as well as elevated neuroendocrine tumor markers (chromogranin A, NSE) [2, 16]. The worse prognosis of patients with a prior history of adenocarcinoma can be most likely explained by the several lines of systemic therapies those patients have already received for adenocarcinoma when they are diagnosed with NEPC, leading to a selection of a more resistant disease. On the other hand, the similar behavior of patients with pure neuroendocrine and mixed adeno-neuroendocrine differentiation (regarding OS and response to first-line therapy) might indicate that the neuroendocrine component seems to be the main prognostic driver of the disease regardless of a coexisting adenocarcinoma component.\n\nPlatinum and etoposide-based chemotherapy is considered standard of care for high grade NEC in different locations, including lung and gastrointestinal tract [17]. Several phase II trials have examined platinum-based combination treatments in NEPC [3–9]. The trials are difficult to compare since in some histological proof for NEPC was mandatory, whereas others recruited also patients with only clinical features suggestive for NEPC. However, response rates and survival were not considerably higher in trials examining a platinum-based combination therapy employing 3 agents compared to those with 2 agents. In general, both cisplatin and carboplatin-based chemotherapy regimens are considered equally effective in NEC [17]. However, in our study there was a slight trend for a prolonged PFS with carboplatin. This may be due to a selection bias in our small retrospective cohort. Additionally, the toxicity profile of cisplatin might contribute to more frequent treatment interruptions and delays in an elderly patient population. Patients with a lower Ki67 of < 55 % showed a strong trend for a shortened PFS under PE, this difference failed to reach significance most likely due to the small patient numbers in this group. This phenomenon has already been described in several retrospective analyses of NEC of the gastrointestinal tract [18–20], and finally led to a newly defined tumor entity of well differentiated neuroendocrine tumors grade 3 (NET G3) which has been officially introduced with the World Health Organization Classification of Tumors of Endocrine Organs of 2017. Current treatment guidelines recommend alternative treatment protocols to PE for NET G3 which have shown notable activity in second-line after PE failure [17, 21, 22], but have not been evaluated in first-line situation yet. The entity of NET G3 has not been established in NEPC so far.\n\nRegarding second-line therapy or alternatives to platinum-based chemotherapy, evidence for NEPC is very scarce. One of the above-mentioned studies applied second-line therapy with cisplatin and etoposide after progression to the first-line treatment with carboplatin and docetaxel [3]. Combination therapy of doxorubicin, cyclophosphamide and vincristine [9] as well as amrubicin monotherapy [23] showed some activity in small case series. Molecular alterations in NEPCs have been extensively studied. Besides alterations common to prostatic adenocarcinoma like TMPRSS2-ERG fusion and alterations in DNA damage repair proteins (e.g. BRCA1, BRCA2, FANCA), several genes have been identified specific for neuroendocrine transdifferentiation, like TP53, RB1, AURKA (Aurora Kinase A), MYCN, and MTOR [24–30]. A comprehensive genomic characterization of treatment related NEPC, reported further transcriptomic markers like PDX1, EZH2, BRN2, FOXA2 and ASCL1 [31]. Recently, a phase II trial with the AURKA inhibitor alisertib was presented with a median PFS of 8.7 weeks [11]. Although it failed to meet its primary endpoint with a 6-month PFS of only 12.6 %, 3 of 59 patients showed exceptional remissions or disease stabilizations. In a preliminary retrospective analysis of 7 patients treated with the MTOR inhibitor everolimus a decrease in tumor markers was noted in 5 patients [10]. In our analysis, the single patient receiving everolimus for highly proliferative NEPC showed PD; however, a disease stabilization and tumor marker decrease was noted in the patient with well differentiated NET (carcinoid).\n\nRegarding the limited evidence, second-line treatments recommended for non-prostatic NEC can also be considered an option for NEPC. Topotecan is a standard of care therapy for small cell NEC of the lung [32]. However, the activity of topotecan in extrapulmonary NEC is very limited [33, 34]. 1 of 4 patients treated with topotecan showed a PR in our analysis. FOLFIRI has been studied in NEC of the gastrointestinal tract [35]. In our study, it showed disease stabilization in first-line, as well as in pretreated patients.\n\nImmune checkpoint blockade has shown promising activity in multiple types of NEC, including small cell lung cancer [36], Merkel cell carcinoma [37, 38], as well as in NEC of the pancreas [39] and cervix [40]. Here we report an extremely good response of NEPC to combined immune checkpoint blockade with ipilimumab and nivolumab.\n\nNEPC is considered to be refractory to ADT [41] and a recent study-cohort showed a high resistance to modern androgen receptor–targeting therapies of up to 73% [31]. However, 3 of our patients showed a short disease stabilization under enzalutamide and abiraterone. This is in line with several recent reports for large-cell NEPC which have shown expression of androgen receptor as well as sustained responses to conventional ADT [42, 43]. This contributes to the evidence that some androgen dependency might still exist in selected cases, but especially by considering the background of the lineage plasticity model [26], the precise circumstances of the androgen receptor for developing and/or treating a NEPC demands further exploration.\n\nFinally, we reported the first patient with a metastatic well differentiated NET (carcinoid) of the prostate receiving several lines of systemic therapy. He was treated in analogy to NETs of the gastrointestinal tract with octreotide [44], PRRT [45] and everolimus [46]. All systemic therapies were effective in disease stabilization, the patient survived for more than 9 years. Notably, also well differentiated NET have been rarely reported to develop from prostatic adenocarcinoma under ADT [47]; furthermore, somatostatin receptor expression can also be detected in high grade NEPC, indicating that PRRT might be a possible treatment option not only for well differentiated NETs [48].\n\nOur study has several limitations due to its retrospective nature. However, it provides important evidence for potentially active therapeutic regimens in NEPC. PFS seems to be prolonged for carboplatin vs. cisplatin-based regimens, and activity of PE seems lower in patients with a Ki67 < 55 %. The limited prognosis especially of patients with prior history of prostatic adenocarcinoma should be taken into consideration regarding the further clinical decision making for these patients. Most notably, efficacy of FOLFIRI, novel antiandrogens and immune checkpoint blockade should be further evaluated prospectively. Responses should be correlated to clinical parameters as well biomarkers, to further optimize the treatment of this rare disease. Furthermore, the even rarer well differentiated NETs of the prostate (carcinoids) can be treated very successfully in analogy to NETs of the gastrointestinal tract with somatostatin analogues, PRRT and everolimus.\n\nPATIENTS AND METHODS\nWe retrospectively reviewed the medical records of all patients with histologically proven NEPC who were treated at the National Center for Tumor Diseases, University Hospital Heidelberg as well as at the Department of Urology, Klinikum Nuremberg, Paracelsus Medical University between 12/2000 and 11/2017. NEPCs with mixed differentiation including an adenocarcinoma component were included at the analysis, as well as well differentiated NETs (carcinoids).\n\nThe duration of each therapy as well as the response according to RECIST criteria were recorded, PFS and OS were calculated. PFS was defined as the time span between the start of the respective therapy and the date of progression or death due to any cause. OS was defined on the one hand as the time length between diagnosis of any prostatic malignancy and the date of death from any cause, on the other hand as the time length between NEPC diagnosis and the date of death from any cause.\n\nStatistical analysis was carried out using SPSS™ for Windows™ Software V22.0 (SPSS, Chicago, IL, USA). Survival analysis was calculated using the Kaplan-Meier method, and differences in survival were analyzed using the log-rank test. A p-value of < 0.05 was considered significant.\n\nThe trial was approved by the institutional research ethics committee (approval S-428/2014).\n\nSUPPLEMENTARY MATERIALS TABLE\n Author contributions\n\nL.A., F.D. and C.G. designed the study, analyzed and interpreted the data and wrote the manuscript. L.A. and F.D. acquired the data. C.N., E.C.W., A.K.B., C.K., A.K., A.-S.B., D.J., M.H., C.H. and S.P. revised the manuscript for intellectual content. F.D. and C.G. contributed equally.\n\nCONFLICTS OF INTEREST\n\nThe authors declare no conflict of interest in relation to the work described.\n\nAbbreviations\nACTHadrenocorticotropic hormone\n\nADTandrogen deprivation therapy\n\nAURKAAurora Kinase A\n\nCgAchromogranin A\n\nCIconfidence interval\n\nCRcomplete response\n\nDICdisseminated intravascular coagulation\n\nDoRduration of response\n\nLDHlactate dehydrogenase\n\nNEnot evaluated\n\nNECneuroendocrine carcinoma\n\nNEPCneuroendocrine carcinoma of the prostate\n\nNETneuroendocrine tumor\n\nNRnot reached\n\nNSEneuron-specific enolase\n\nORRoverall response rate\n\nOSoverall survival\n\nPDprogressive disease\n\nPEplatinum+etoposide\n\nPFSprogression-free survival\n\nPRpartial response\n\nPRRTpeptide receptor radionuclide therapy\n\nPSMAprostate-specific membrane antigen\n\nSDstable disease\n\nSIADHsyndrome of inappropriate antidiuretic hormone secretion\n\nSIRTselective internal radiotherapy\n\nULNupper limit normal,\n==== Refs\nREFERENCES\n1 Zaffuto E Pompe R Zanaty M Bondarenko HD Leyh-Bannurah SR Moschini M Dell'Oglio P Gandaglia G Fossati N Stabile A Zorn KC Montorsi F Briganti A Contemporary Incidence and Cancer Control Outcomes of Primary Neuroendocrine Prostate Cancer: A SEER Database Analysis Clin Genitourin Cancer 2017 15 e793 e800 10.1016/j.clgc.2017.04.006 28506524 \n2 Wang HT Yao YH Li BG Tang Y Chang JW Zhang J Neuroendocrine Prostate Cancer (NEPC) progressing from conventional prostatic adenocarcinoma: factors associated with time to development of NEPC and survival from NEPC diagnosis-a systematic review and pooled analysis J Clin Oncol 2014 32 3383 90 10.1200/JCO.2013.54.3553 25225419 \n3 Aparicio AM Harzstark AL Corn PG Wen S Araujo JC Tu SM Pagliaro LC Kim J Millikan RE Ryan C Tannir NM Zurita AJ Mathew P Platinum-based chemotherapy for variant castrate-resistant prostate cancer Clin Cancer Res 2013 19 3621 30 10.1158/1078-0432.CCR-12-3791 23649003 \n4 Culine S El Demery M Lamy PJ Iborra F Avances C Pinguet F Docetaxel and cisplatin in patients with metastatic androgen independent prostate cancer and circulating neuroendocrine markers J Urol 2007 178 844 8 ; discussion 8https://doi.org/10.1016/j.juro.2007.05.044 17631339 \n5 Flechon A Pouessel D Ferlay C Perol D Beuzeboc P Gravis G Joly F Oudard S Deplanque G Zanetta S Fargeot P Priou F Droz JP Phase II study of carboplatin and etoposide in patients with anaplastic progressive metastatic castration-resistant prostate cancer (mCRPC) with or without neuroendocrine differentiation: results of the French Genito-Urinary Tumor Group (GETUG) P01 trial Ann Oncol 2011 22 2476 81 10.1093/annonc/mdr004 21436186 \n6 Loriot Y Massard C Gross-Goupil M Di Palma M Escudier B Bossi A Fizazi K Combining carboplatin and etoposide in docetaxel-pretreated patients with castration-resistant prostate cancer: a prospective study evaluating also neuroendocrine features Ann Oncol 2009 20 703 8 10.1093/annonc/mdn694 19179557 \n7 Papandreou CN Daliani DD Thall PF Tu SM Wang X Reyes A Troncoso P Logothetis CJ Results of a phase II study with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate J Clin Oncol 2002 20 3072 80 10.1200/JCO.2002.12.065 12118020 \n8 Steineck G Reuter V Kelly WK Frank R Schwartz L Scher HI Cytotoxic treatment of aggressive prostate tumors with or without neuroendocrine elements Acta Oncol 2002 41 668 74 14651212 \n9 Amato RJ Logothetis CJ Hallinan R Ro JY Sella A Dexeus FH Chemotherapy for small cell carcinoma of prostatic origin J Urol 1992 147 935 7 1311396 \n10 Shimomura T Kurauchi T Sakanaka K Egawa S Treatment outcome of everolimus against neuroendocrine prostate cancer (NEPC) J Clin Oncol 2018 36 365 10.1200/JCO.2018.36.6_suppl.365 \n11 Beltran H Danila D Montgomery B Szmulewitz R Vaishampayan U Armstrong A Stein M Hoimes C Pinski J Scher H Puca L Bareja R Wong W A phase 2 study of the aurora kinase A inhibitor alisertib for patients with neuroendocrine prostate cancer (NEPC) Ann Oncol 2016 27 LBA29 LBA 10.1093/annonc/mdw435.21 \n12 Murali R Kneale K Lalak N Delprado W Carcinoid tumors of the urinary tract and prostate Arch Pathol Lab Med 2006 130 1693 706 17076534 \n13 Giordano S Tolonen T Tolonen T Hirsimaki S Kataja V A pure primary low-grade neuroendocrine carcinoma (carcinoid tumor) of the prostate Int Urol Nephrol 2010 42 683 7 10.1007/s11255-009-9660-8 19866370 \n14 Lim KH Huang MJ Yang S Hsieh RK Lin J Primary carcinoid tumor of prostate presenting with bone marrow metastases Urology 2005 65 174 10.1016/j.urology.2004.07.010 \n15 Pavel M O'Toole D Costa F Capdevila J Gross D Kianmanesh R Krenning E Knigge U Salazar R Pape UF Oberg K Vienna Consensus Conference participants ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of Unknown Primary Site Neuroendocrinology 2016 103 172 85 10.1159/000443167 26731013 \n16 Hong MK Kong J Namdarian B Longano A Grummet J Hovens CM Costello AJ Corcoran NM Paraneoplastic syndromes in prostate cancer Nat Rev Urol 2010 7 681 92 10.1038/nrurol.2010.186 21139643 \n17 Garcia-Carbonero R Sorbye H Baudin E Raymond E Wiedenmann B Niederle B Sedlackova E Toumpanakis C Anlauf M Cwikla JB Caplin M O'Toole D Perren A ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas Neuroendocrinology 2016 103 186 94 10.1159/000443172 26731334 \n18 Sorbye H Welin S Langer SW Vestermark LW Holt N Osterlund P Dueland S Hofsli E Guren MG Ohrling K Birkemeyer E Thiis-Evensen E Biagini M 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 24 152 60 10.1093/annonc/mds276 22967994 \n19 Heetfeld M Chougnet CN Olsen IH Rinke A Borbath I Crespo G Barriuso J Pavel M O'Toole D Walter T other Knowledge Network members Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms Endocr Relat Cancer 2015 22 657 64 10.1530/ERC-15-0119 26113608 \n20 Velayoudom-Cephise FL Duvillard P Foucan L Hadoux J Chougnet CN Leboulleux S Malka D Guigay J Goere D Debaere T Caramella C Schlumberger M Planchard D Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr Relat Cancer 2013 20 649 57 10.1530/ERC-13-0027 23845449 \n21 Welin S Sorbye H Sebjornsen S Knappskog S Busch C Oberg K Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy Cancer 2011 117 4617 22 10.1002/cncr.26124 21456005 \n22 Hadoux J Malka D Planchard D Scoazec JY Caramella C Guigay J Boige V Leboulleux S Burtin P Berdelou A Loriot Y Duvillard P Chougnet CN Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma Endocr Relat Cancer 2015 22 289 98 10.1530/ERC-15-0075 25770151 \n23 Katou M Soga N Onishi T Arima K Sugimura Y Small cell carcinoma of the prostate treated with amrubicin Int J Clin Oncol 2008 13 169 72 10.1007/s10147-007-0702-x 18463964 \n24 Beltran H Rickman DS Park K Chae SS Sboner A MacDonald TY Wang Y Sheikh KL Terry S Tagawa ST Dhir R Nelson JB de la Taille A Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets Cancer Discov 2011 1 487 95 10.1158/2159-8290.CD-11-0130 22389870 \n25 Chen R Dong X Gleave M Molecular model for neuroendocrine prostate cancer progression BJU Int 2018 122 560 70 10.1111/bju.14207 29569310 \n26 Rickman DS Beltran H Demichelis F Rubin MA Biology and evolution of poorly differentiated neuroendocrine tumors Nat Med 2017 23 1 10 10.1038/nm.4341 \n27 Beltran H Eng K Mosquera JM Sigaras A Romanel A Rennert H Kossai M Pauli C Faltas B Fontugne J Park K Banfelder J Prandi D Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response JAMA Oncol 2015 1 466 74 10.1001/jamaoncol.2015.1313 26181256 \n28 Kanayama M Hayano T Koebis M Maeda T Tabe Y Horie S Aiba A Hyperactive mTOR induces neuroendocrine differentiation in prostate cancer cell with concurrent up-regulation of IRF1 Prostate 2017 77 1489 98 10.1002/pros.23425 28905415 \n29 Hsieh TC Lin CY Lin HY Wu JM AKT/mTOR as Novel Targets of Polyphenol Piceatannol Possibly Contributing to Inhibition of Proliferation of Cultured Prostate Cancer Cells ISRN Urol 2012 2012 272697 10.5402/2012/272697 22567414 \n30 Zhang W Liu B Wu W Li L Broom BM Basourakos SP Korentzelos D Luan Y Wang J Yang G Park S Azad AK Cao X Targeting the MYCN-PARP-DNA Damage Response Pathway in Neuroendocrine Prostate Cancer Clin Cancer Res 2018 24 696 707 10.1158/1078-0432.CCR-17-1872 29138344 \n31 Aggarwal R Huang J Alumkal JJ Zhang L Feng FY Thomas GV Weinstein AS Friedl V Zhang C Witte ON Lloyd P Gleave M Evans CP Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study J Clin Oncol 2018 36 2492 503 10.1200/JCO.2017.77.6880 29985747 \n32 von Pawel J Schiller JH Shepherd FA Fields SZ Kleisbauer JP Chrysson NG Stewart DJ Clark PI Palmer MC Depierre A Carmichael J Krebs JB Ross G Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer J Clin Oncol 1999 17 658 67 10080612 \n33 Apostolidis L Bergmann F Jager D Winkler EC Efficacy of topotecan in pretreated metastatic poorly differentiated extrapulmonary neuroendocrine carcinoma Cancer Med 2016 5 2261 7 10.1002/cam4.807 27456539 \n34 Olsen IH Knigge U Federspiel B Hansen CP Skov A Kjaer A Langer SW Topotecan monotherapy in heavily pretreated patients with progressive advanced stage neuroendocrine carcinomas J Cancer 2014 5 628 32 10.7150/jca.9409 25157273 \n35 Hentic O Hammel P Couvelard A Rebours V Zappa M Palazzo M Maire F Goujon G Gillet A Levy P Ruszniewski P FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3 Endocr Relat Cancer 2012 19 751 7 10.1530/ERC-12-0002 22940375 \n36 Antonia SJ Lopez-Martin JA Bendell J Ott PA Taylor M Eder JP Jager D Pietanza MC Le DT de Braud F Morse MA Ascierto PA Horn L Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial Lancet Oncol 2016 17 883 95 10.1016/S1470-2045(16)30098-5 27269741 \n37 Kaufman HL Russell J Hamid O Bhatia S Terheyden P D'Angelo SP Shih KC Lebbe C Linette GP Milella M Brownell I Lewis KD Lorch JH Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial Lancet Oncol 2016 17 1374 85 10.1016/S1470-2045(16)30364-3 27592805 \n38 Nghiem PT Bhatia S Lipson EJ Kudchadkar RR Miller NJ Annamalai L Berry S Chartash EK Daud A Fling SP Friedlander PA Kluger HM Kohrt HE PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma N Engl J Med 2016 374 2542 52 10.1056/NEJMoa1603702 27093365 \n39 Ugwu JK Nwanyanwu C Shelke AR Dramatic Response of a Metastatic Primary Small-Cell Carcinoma of the Pancreas to a Trial of Immunotherapy with Nivolumab: A Case Report Case Rep Oncol 2017 10 720 5 10.1159/000479315 28878656 \n40 Paraghamian SE Longoria TC Eskander RN Metastatic small cell neuroendocrine carcinoma of the cervix treated with the PD-1 inhibitor, nivolumab: a case report Gynecol Oncol Res Pract 2017 4 3 10.1186/s40661-017-0038-9 28174665 \n41 Moore SR Reinberg Y Zhang G Small cell carcinoma of prostate: effectiveness of hormonal versus chemotherapy Urology 1992 39 411 6 1315995 \n42 Acosta-Gonzalez G Qin J Wieczorek R Melamed J Deng FM Zhou M Makarov D Ye F Pei Z Pincus MR Lee P De novo large cell neuroendocrine carcinoma of the prostate, case report and literature review Am J Clin Exp Urol 2014 2 337 42 25606580 \n43 Azad AA Jones EC Chi KN Metastatic large-cell neuroendocrine prostate carcinoma: successful treatment with androgen deprivation therapy Clin Genitourin Cancer 2014 12 e151 3 10.1016/j.clgc.2014.03.006 24787970 \n44 Rinke A Muller HH Schade-Brittinger C Klose KJ Barth P Wied M Mayer C Aminossadati B Pape UF Blaker M Harder J Arnold C Gress T Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group J Clin Oncol 2009 27 4656 63 10.1200/JCO.2009.22.8510 19704057 \n45 Strosberg J El-Haddad G Wolin E Hendifar A Yao J Chasen B Mittra E Kunz PL Kulke MH Jacene H Bushnell D O'Dorisio TM Baum RP Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors N Engl J Med 2017 376 125 35 10.1056/NEJMoa1607427 28076709 \n46 Yao JC Fazio N Singh S Buzzoni R Carnaghi C Wolin E Tomasek J Raderer M Lahner H Voi M Pacaud LB Rouyrre N Sachs C Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study Lancet 2016 387 968 77 10.1016/S0140-6736(15)00817-X 26703889 \n47 Gilani S Guo CC Li-Ning EM Pettaway C Troncoso P Transformation of prostatic adenocarcinoma to well-differentiated neuroendocrine tumor after hormonal treatment Hum Pathol 2017 64 186 90 10.1016/j.humpath.2017.01.006 28159676 \n48 Gofrit ON Frank S Meirovitz A Nechushtan H Orevi M PET/CT With 68Ga-DOTA-TATE for Diagnosis of Neuroendocrine: Differentiation in Patients With Castrate-Resistant Prostate Cancer Clin Nucl Med 2017 42 1 6 10.1097/RLU.0000000000001424 27775942\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "10(1)",
"journal": "Oncotarget",
"keywords": "carcinoid; chemotherapy; neuroendocrine carcinoma; neuroendocrine tumor; prostate",
"medline_ta": "Oncotarget",
"mesh_terms": null,
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "17-29",
"pmc": null,
"pmid": "30713600",
"pubdate": "2019-01-01",
"publication_types": "D016428:Journal Article",
"references": "10080612;12118020;1311396;1315995;14651212;15667891;17076534;17631339;18463964;19179557;19704057;19866370;21139643;21436186;21456005;22389870;22567414;22940375;22967994;23649003;23845449;24787970;25157273;25225419;25606580;25770151;26113608;26181256;26703889;26731013;26731334;27093365;27269741;27456539;27592805;27775942;28076709;28159676;28174665;28506524;28586335;28878656;28905415;29138344;29569310;29985747",
"title": "Clinical characteristics, treatment outcomes and potential novel therapeutic options for patients with neuroendocrine carcinoma of the prostate.",
"title_normalized": "clinical characteristics treatment outcomes and potential novel therapeutic options for patients with neuroendocrine carcinoma of the prostate"
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"abstract": "Human papilloma virus (HPV) is a prevalent pathogen whose persistent infection can lead to a variety of cancers. To protect against this threat, an HPV vaccine has been developed and is routinely administered to adolescents. The HPV vaccine has a reassuring safety profile, but reports have emerged of acute disseminated encephalomyelitis following its administration. Acute hemorrhagic leukoencephalitis (AHLE) is a severe inflammatory disease of the central nervous system and the most fulminant form of ADEM. We report a previously healthy 14-year-old boy who developed headache, fatigue, focal weakness, and confusion 3 weeks after receiving the HPV vaccine. Neuroimaging demonstrated multifocal demyelination. Despite treatment with high-dose steroids, his encephalopathy worsened. He developed severe cerebral edema and died of cerebral herniation. Postmortem histology revealed perivenular sleeves of tissue damage, myelin loss surrounding small parenchymal vessels, and diffuse hemorrhagic necrosis, consistent with AHLE. This is the first report of AHLE following HPV vaccination.",
"affiliations": "Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA, USA.;Department of Radiology, University of Iowa College of Medicine, Iowa City, IA, USA.;Department of Pediatrics, Atrium Health/Levine Children's Hospital, Charlotte, NC, USA.",
"authors": "Wellnitz|Kari|K|;Sato|Yutaka|Y|;Bonthius|Daniel J|DJ|https://orcid.org/0000-0001-8927-0661",
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"doi": "10.1177/2329048X211016109",
"fulltext": "\n==== Front\nChild Neurol Open\nChild Neurol Open\nCNO\nspcno\nChild Neurology Open\n2329-048X\nSAGE Publications Sage CA: Los Angeles, CA\n\n10.1177/2329048X211016109\n10.1177_2329048X211016109\nCase Report\nFatal Acute Hemorrhagic Leukoencephalitis Following Immunization Against Human Papillomavirus in a 14-Year-Old Boy\nWellnitz Kari MD 1\nSato Yutaka MD 2\nhttps://orcid.org/0000-0001-8927-0661\nBonthius Daniel J. MD, PhD 3\n1 Department of Pediatrics, 4083 University of Iowa College of Medicine, Iowa City, IA, USA\n2 Department of Radiology, 4083 University of Iowa College of Medicine, Iowa City, IA, USA\n3 Department of Pediatrics, Atrium Health/158310 Levine Children’s Hospital , Charlotte, NC, USA\nDaniel J. Bonthius, MD, PhD, Division of Child Neurology, Department of Pediatrics, Atrium Health Levine Children’s Hospital, 407 MEB 1000 Blythe Blvd, Charlotte, 28203, NC, USA. Email: daniel.bonthius@atriumhealth.org\n18 5 2021\nJan-Dec 2021\n8 2329048X21101610923 12 2020\n16 4 2011\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://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).\nHuman papilloma virus (HPV) is a prevalent pathogen whose persistent infection can lead to a variety of cancers. To protect against this threat, an HPV vaccine has been developed and is routinely administered to adolescents. The HPV vaccine has a reassuring safety profile, but reports have emerged of acute disseminated encephalomyelitis following its administration. Acute hemorrhagic leukoencephalitis (AHLE) is a severe inflammatory disease of the central nervous system and the most fulminant form of ADEM. We report a previously healthy 14-year-old boy who developed headache, fatigue, focal weakness, and confusion 3 weeks after receiving the HPV vaccine. Neuroimaging demonstrated multifocal demyelination. Despite treatment with high-dose steroids, his encephalopathy worsened. He developed severe cerebral edema and died of cerebral herniation. Postmortem histology revealed perivenular sleeves of tissue damage, myelin loss surrounding small parenchymal vessels, and diffuse hemorrhagic necrosis, consistent with AHLE. This is the first report of AHLE following HPV vaccination.\n\nautoimmune\nneuroimmunology\nchildren\nencephalitis\nneuroimaging\ncover-dateJanuary-December 2021\ntypesetterts3\n==== Body\nHuman papilloma virus (HPV) infection is common, and the prevalence of high-risk, oncogenic genital HPV infection is 22.7% in American adults.1 Persistent HPV infection with an oncogenic strain is associated with the development of cervical cancer and a substantial number of anogenital and oropharyngeal cancers. In response to this threat, the Centers for Disease Control and Prevention (CDC) recommends that adolescent boys and girls receive vaccination against HPV as part of their routine immunizations.2 While the HPV vaccine has a reassuring safety profile,3 there have been case reports of acute disseminated encephalomyelitis (ADEM) following bivalent and quadrivalent HPV vaccination.4,5,6,7\n\nAcute hemorrhagic leukoencephalitis (AHLE) is a rare, frequently fatal central nervous system inflammatory disorder thought to be the most fulminant form of ADEM. While the precise pathogenic mechanism underlying AHLE is unknown, it is an autoimmune process and is often triggered by a preceding respiratory tract infection or vaccination.8 This report describes the clinical, imaging, and neuropathological features of a 14-year-old boy who developed AHLE leading to severe cerebral edema and death several weeks after receiving the nonavalent HPV vaccine. To our knowledge, this is the first report of AHLE in association with HPV vaccination.\n\nCase Presentation\n\nA 14-year-old boy who was previously healthy developed a persistent headache 3 weeks after receiving the 9-valent human papilloma virus (HPV) vaccine (Gardasil 9 ®, Merck and Co, 0.5 mL intramuscularly). Over the following 2 weeks, the patient’s headache worsened, and he became increasingly fatigued.\n\nOn the day of presentation (40 days post-vaccination), he developed left-sided weakness, urinary incontinence, and confusion, which prompted his family to bring him to a local emergency department. There, head CT was normal and labs, including CBC, complete metabolic panel, and urine toxicology screen, were unremarkable. He was then transferred to our tertiary children’s hospital for further evaluation and management.\n\nNeurologic exam upon admission was notable for left-sided extremity weakness, tremors of left extremities, and mild confusion. Brain MRI revealed diffuse hyperintensities on T2 and FLAIR sequences within the subcortical white matter, thalamus, and basal ganglia (Figure 1 ). Cerebrospinal fluid examination showed a lymphocytic pleocytosis with 56 WBC (reference range 0-5), 77% of which were lymphocytes, along with normal protein and glucose. Extensive serologic and nucleic acid amplification testing of his CSF for bacterial and viral pathogens was negative, as were blood cultures. CRP was normal.\n\nFigure 1. Neuroimaging findings. MRI scan of the brain revealed diffuse signal abnormalities within the subcortical white matter, thalamus, and basal ganglia. T1-weighted, T2 FLAIR, gradient echo sequence, and ADC images at the level of midbrain (A), basal ganglia (B) and centrum semiovale (C). Bilateral asymmetric foci of increased T2-signals are demonstrated (arrows) involving the thickened cortices, thalami, and globus pallidi but sparing the posterior fossa structures (not shown), brainstem or centrum semiovale. Gradient echo sequence images showed no hemorrhagic areas. The areas of T2-prolongation did not show diffusion restriction or contrast enhancement (not shown).\n\nGiven the combination of his clinical picture, neuroimaging, and laboratory results, the patient was diagnosed with acute disseminated encephalomyelitis (ADEM) and started on treatment with intravenous methylprednisolone, 1 gram daily. Despite this treatment, the patient’s encephalopathy worsened, necessitating transfer to the Pediatric Intensive Care Unit (PICU) on the second day of hospitalization. Upon transfer to the PICU, the patient was non-verbal and only intermittently following commands. Exam at the time was notable for left-sided facial weakness, increased tone in the left extremities, bilateral ankle clonus, and left patellar hyperreflexia. After an episode of bilateral shoulder twitching concerning for seizure, continuous video electroencephalogram monitoring was initiated and revealed severe multifocal disturbance of cerebral function, but no epileptiform activity.\n\nOn the third day of hospitalization, the patient had a rapid deterioration in his neurologic exam and developed agonal breathing, emesis, tachycardia, and fixed and dilated pupils. Emergent non-contrast head CT showed severe cerebral edema with impending cerebral herniation, for which he was treated with hyperventilation, hypertonic saline and intravenous mannitol. An emergent right hemicraniectomy was performed. Post-operatively, 400 mg/kg of intravenous immunoglobulin (IVIG) daily was added as treatment for ADEM, but the patient had no neurologic recovery. Neurologic exam performed 3 days post-operatively was consistent with brain death. Following the patient’s death, the family consented to autopsy.\n\nNeuropathologic examination revealed an acute vascular inflammatory process with fibrinoid vascular necrosis, marked macrophage infiltrates, parenchymal necrosis, numerous hemorrhages, and areas of myelin and axonal loss ( Figure 2 ), consistent with acute hemorrhagic leukoencephalitis.\n\nFigure 2. Histopathologic findings from a biopsy specimen of the right parietal lobe. (A) A section stained with H&E revealed that parenchymal vessels were surrounded by a marked mixed inflammatory infiltrate with fibrinoid necrosis (white arrow) and perivascular hemorrhage (black arrow). (B) A section stained with Luxol fast blue and H&E revealed peri-vascular demyelination (arrow). (C) A section immunohistochemically stained for CD68 antigen revealed a marked macrophage infiltrate (arrow). (D) A section immunohistochemically stained for neurofilament revealed patchy axonal loss (arrow).\n\nDiscussion\n\nAcute hemorrhagic leukoencephalitis (AHLE) is a rare, fulminant disease, thought to be the most severe form of the central nervous system demyelinating diseases.9 A hyperacute subform of acute disseminated encephalomyelitis, AHLE represents only 2% of ADEM cases.10 ADEM and AHLE both are characterized by multifocal neurologic symptoms, including encephalopathy, along with neuroimaging showing multiple areas of demyelination. Both entities are frequently preceded by an upper respiratory tract infection, viral illness, or vaccination.\n\nWhile there are numerous similarities between ADEM and AHLE, there are epidemiological, clinical, pathologic, and prognostic differences.11 The mean age at presentation of ADEM is 5 to 8 years old, while AHLE is most frequently diagnosed in adolescents and young adults. The opening pressure is most often normal in ADEM, while it is often elevated in AHLE. Cerebrospinal fluid white blood cell counts are typically normal to slightly elevated and associated with lymphocytic predominance in patients with ADEM, while the CSF often has a more notable pleocytosis with neutrophilic predominance in AHLE. Patients with AHLE are also more likely to have an elevated ESR and peripheral leukocytosis with neutrophilic predominance, though this was not seen in our patient. Finally, while the mortality rate for ADEM is only 1-3%, death occurred in 66% of patients with AHLE in the only published pediatric case series.12\n\nDefinitive differentiation of AHLE from ADEM requires a brain biopsy. Histopathology in both disorders includes perivenular sleeves of tissue damage and myelin loss surrounding small parenchymal vessels. However, pathology in AHLE also includes diffuse hemorrhagic necrosis, which is absent in ADEM.13\n\nDeath from AHLE can occur within hours to days after symptom onset, highlighting the importance of rapid recognition and aggressive treatment. Among recent case reports of pediatric AHLE survivors, use of high dose corticosteroids (standard therapy for ADEM) was universal. Adjunctive treatments used in case reports of survivors have included administration of IVIG, plasmapheresis, therapeutic hypothermia, decompressive craniectomy, hyperosmolar therapy, and use of interleukin-1 receptor antagonist.\n\nADEM is a rare disease with an annual incidence of 0.6-0.8 per 100,000 individuals, and an antecedent vaccination is reported in 5-19% of cases.14 Vaccinations are thought to trigger ADEM through molecular mimicry, wherein certain pathogenic antigens contained in the vaccine share sequence homology with endogenous human CNS proteins, leading to immune cross-reactivity and subsequent autoimmune demyelination. Gardasil 9 is a recombinant vaccine that includes the major capsid (L1) protein of 9 HPV types in highly purified virus-like particles. Sequence homologies between astrocyte water channel aquaporin 4 and several of the HPV L1 capsid proteins have been identified,15 suggesting that molecular mimicry is a biologically plausible mechanism by which HPV vaccination could trigger demyelinating disease.\n\nIt is unclear why some individual patients develop ADEM or AHLE in response to an antigenic stimulus while most do not, but is likely due to differences in genes regulating the immune response. Indeed, ADEM has been associated with several specific major HLA histocompatibility class II alleles.16 In addition, partial complement factor I (FI) deficiency was identified in 2 pediatric patients with AHLE who were generally healthy prior to presentation. Other genes, besides those regulating the immune response, may also play a role in predisposing individuals to ADEM and AHLE. Mutation of the Ran binding protein (RANBP2) gene, which encodes a protein important for energy homeostasis in neurons, predisposes patients to AHLE.17\n\nThe HPV vaccine has a reassuring safety profile.3 The safety of HPV vaccines was extensively investigated pre-release and has been monitored through post-licensure surveillance programs.18,19 The multiple post-licensure studies, based on information from spontaneous reporting systems, have found no association between demyelinating disease and HPV vaccination.\n\nWhile the epidemiologic data have failed to show a significant statistical association between HPV vaccination and ADEM or AHLE on a population basis, there have been multiple case reports published describing patients who have developed ADEM in the weeks following HPV vaccination.4,5,6,7 These case reports strongly suggest that the HPV vaccination played a causal role in the onset of ADEM in the patients described. It is likely that the HPV vaccine can trigger demyelinating CNS disease in genetically susceptible individuals. Further research is needed to elucidate what those specific genetic factors are. Here, we present the first reported case of AHLE following immunization against HPV.\n\nAcknowledgments\n\nThe authors would like to thank Dr. Marco Hefti (University of Iowa) for his assistance in identifying and preparing representative neuropathologic images for publication.\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\nORCID iD: Daniel J. Bonthius, MD, PhD https://orcid.org/0000-0001-8927-0661\n==== Refs\nReferences\n\n1 McQuillan G Kruszon-Moran D Markowitz LE Unger ER Paulose-Ram R .Prevalence of HPV in Adults Aged 18-69: United States, 2011-2014. NCHS Data Brief. 2017;280 :1–8.\n2 Petrosky E Bocchini JA Hariri S , et al. Use of 9-Valent Human Papillomavirus (HPV) Vaccine: updatd HPV vaccination recommendations of the Advisory Committee on Immunization Practices. MMWR. 2015;64 (11 ):300–304.25811679\n3 Moreira ED Block SL Ferris D , et al. Safety Profile of the 9-Valent HPV Vaccine: A Combined Analysis of 7 Phase III Clinical Trials. Pediatrics. 2016;138 (2 ):e20154387.27422279\n4 Pellegrino P Carnovale C Perrone V , et al. Can HPV immunisation cause ADEM? Two case reports and literature review. Mult Scler. 2014;20 (6 ):762–763.23970503\n5 Wildemann B Jarius S Hartmann M Regula JU Hametner C . Acute disseminated encephalomyelitis following vaccination against human papilloma virus. Neurology. 2009;72 (24 ):2132–2133.19528522\n6 Sekiguchi K Yasui N Kowa H Kanda F Toda T . Two cases of acute disseminated encephalomyelitis following vaccination against human papilloma virus. Intern Med. 2016;55 (21 ):3181–3184.27803416\n7 Schäffer V Wimmer S Rotaru I Topakian R Haring HP Aichner FT . HPV vaccine: a cornerstone of female health a possible cause of ADEM? J Neurol. 2018;255 (11 ):1818–1820.\n8 Sinzobahamvya E. Borrelli S. Rutgers MP Clause D Gille M . Acute hemorrhagic leukoencephalitis after seasonal influenza vaccination. Acta Neurol Belg. 2018;118 , 127–129.29134580\n9 Tenembaum S Chitnis T Ness J Hahn JS , International Pediatric MS Study Group. Acute demyelinating encephalomyelitis. Neurology. 2007;68 (16 Suppl 2 ): S23–36.17438235\n10 Tenembaum S Chamoles N Fejerman N . Acute disseminated encephalomyelitis: a long term follow-up study of 84 pediatric patients. Neurology. 2002;59 (8 ):1224–1231.12391351\n11 Leake JAD Billman GF Nespeca MP , et al. Pediatric acute hemorrhagic leukoencephalitis: report of a surviving patient and review. Clin Infect Dis. 2002;34 (5 ):699–703.11810602\n12 Rosman NP Gottlieb SM Bernstein CA . Acute hemorrhagic leukoencephalitis: recovery and reversal of magnetic resonance imaging findings in a child. J Child Neurol. 1997;12 (7 ):448–454.9373802\n13 Lann MA Lovell MA Kleinschmidt-DeMasters BK . Acute hemorrhagic leukoencephalitis: a critical entity for forensic pathologists to recognize. Am J Forensic Med Pathol. 2010;31 (1 ):7–11.20010289\n14 Koelman DLH Mateen FJ . Acute disseminated encephalomyelitis: current controversies in diagnosis and outcome. J Neurol. 2015;262 (9 ):2013–2024.25761377\n15 Menge T Cree B Saleh A , et al. Neuromyelitis optica following human papillomavirus vaccination. Neurology. 2012;79 (3 ):285–287.22722628\n16 Idrissova ZhR Boldyreva MN Dekonenko EP , et al. Acute disseminated encephalomyelitis in children: clinical features and HLA-DR linkage. Eur J Neurol. 2003;10 (5 ):537–546.12940836\n17 Alawadhi A Saint-Martin C Bhanji F Srour M Atkinson J Sébire G Acute hemorrhagic encephalitis responding to combined decompressive craniectomy, intravenous immunoglobulin, and corticosteroid therapies: association with novel RANBP2 variant. Front Neurol. 2018;9 :130.29593631\n18 Mouchet J Salvo F Raschi E , et al. Human papillomavirus vaccine and demyelinating diseases- a systematic review and meta-analysis. Pharmacol Res. 2018;132 :108–118.29665426\n19 Angelo MG Zima J Tavares Da Silva F Baril L Arellano F . Post-licensure safety surveillance for human papillomavirus-16/18-AS04-adjuvanted vaccine: more than 4 years of experience. Pharmacoepidemiol Drug Saf. 2014;23 (5 ):456–465.24644078\n\n",
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"keywords": "autoimmune; children; encephalitis; neuroimaging; neuroimmunology",
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"title": "Fatal Acute Hemorrhagic Leukoencephalitis Following Immunization Against Human Papillomavirus in a 14-Year-Old Boy.",
"title_normalized": "fatal acute hemorrhagic leukoencephalitis following immunization against human papillomavirus in a 14 year old boy"
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"abstract": "BACKGROUND\nBevacizumab is an anti-angiogenesis agent used to treat patients with metastatic colorectal cancer and is associated with a variety of complications. We present a patient with rectal cancer who developed a delayed anastomotic leak more than 5 years after undergoing low anterior resection.\n\n\nMETHODS\nA 78-year-old man with hematochezia was diagnosed with two synchronous rectal cancers 7 years prior to presentation. Preoperative chemo-radiotherapy was given followed by a very low anterior resection. During follow-up, multiple lymph node metastases developed, which were treated with chemotherapy. First-line chemotherapy, capecitabine, oxizaliplatin, and bevacizumab, was given over 3 years, and second-line chemotherapy, capecitabine, irinotecan, and bevacizumab, was administered over a 3-month period. After the last treatment, the patient presented with pneumaturia and fecaluria. Computed tomography scan revealed extraluminal air between the prostate and rectum, adjacent to the anastomotic site. Ulceration and fistula formation were observed on colonoscopy, and contrast radiography demonstrated a fistula at the anastomotic site. An anastomotic-urethral fistula was diagnosed and transverse colostomy was performed.\n\n\nCONCLUSIONS\nThis patient highlights a rare late adverse event at the anastomotic site associated with bevacizumab treatment and preoperative chemo-radiotherapy. Signs and symptoms suggesting anastomotic complications should be thoroughly evaluated during bevacizumab treatment, even long after surgical resection.",
"affiliations": "Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitamashi, Saitamaken, 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitamashi, Saitamaken, 330-8503, Japan. miyakura@jichi.ac.jp.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitamashi, Saitamaken, 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitamashi, Saitamaken, 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitamashi, Saitamaken, 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitamashi, Saitamaken, 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitamashi, Saitamaken, 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitamashi, Saitamaken, 330-8503, Japan.;Department of Surgery, Jichi Medical University, Tochigi, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitamashi, Saitamaken, 330-8503, Japan.",
"authors": "Machida|Erika|E|;Miyakura|Yasuyuki|Y|http://orcid.org/0000-0002-4464-2465;Takahashi|Jun|J|;Tamaki|Sawako|S|;Ishikawa|Hideki|H|;Hasegawa|Fumi|F|;Kikugawa|Rina|R|;Tsujinaka|Shingo|S|;Lefor|Alan Kawarai|AK|;Rikiyama|Toshiki|T|",
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"fulltext": "\n==== Front\nSurg Case RepSurg Case RepSurgical Case Reports2198-7793Springer Berlin Heidelberg Berlin/Heidelberg 57310.1186/s40792-019-0573-1Case ReportBevacizumab is associated with delayed anastomotic leak after low anterior resection with preoperative radiotherapy for rectal cancer: a case report Machida Erika e.machida0810@gmail.com 1http://orcid.org/0000-0002-4464-2465Miyakura Yasuyuki +81-48-647-2111miyakura@jichi.ac.jp 1Takahashi Jun jun_takahashi_1222@yahoo.co.jp 1Tamaki Sawako swk.tamaki@gmail.com 1Ishikawa Hideki hishikawa@jichi.ac.jp 1Hasegawa Fumi fumihsgw@hotmail.com 1Kikugawa Rina rinamorita@nifty.com 1Tsujinaka Shingo tsujinakas@omiya.jichi.ac.jp 1Lefor Alan Kawarai alefor@jichi.ac.jp 2Rikiyama Toshiki trikiyama@jichi.ac.jp 11 0000000123090000grid.410804.9Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitamashi, Saitamaken 330-8503 Japan 2 0000000123090000grid.410804.9Department of Surgery, Jichi Medical University, Tochigi, Japan 31 1 2019 31 1 2019 12 2019 5 1428 11 2018 21 1 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nBevacizumab is an anti-angiogenesis agent used to treat patients with metastatic colorectal cancer and is associated with a variety of complications. We present a patient with rectal cancer who developed a delayed anastomotic leak more than 5 years after undergoing low anterior resection.\n\nCase report\nA 78-year-old man with hematochezia was diagnosed with two synchronous rectal cancers 7 years prior to presentation. Preoperative chemo-radiotherapy was given followed by a very low anterior resection. During follow-up, multiple lymph node metastases developed, which were treated with chemotherapy. First-line chemotherapy, capecitabine, oxizaliplatin, and bevacizumab, was given over 3 years, and second-line chemotherapy, capecitabine, irinotecan, and bevacizumab, was administered over a 3-month period. After the last treatment, the patient presented with pneumaturia and fecaluria. Computed tomography scan revealed extraluminal air between the prostate and rectum, adjacent to the anastomotic site. Ulceration and fistula formation were observed on colonoscopy, and contrast radiography demonstrated a fistula at the anastomotic site. An anastomotic-urethral fistula was diagnosed and transverse colostomy was performed.\n\nConclusions\nThis patient highlights a rare late adverse event at the anastomotic site associated with bevacizumab treatment and preoperative chemo-radiotherapy. Signs and symptoms suggesting anastomotic complications should be thoroughly evaluated during bevacizumab treatment, even long after surgical resection.\n\nKeywords\nRectal cancerBevacizumabChemo-radiotherapyDelayed anastomotic leakissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nBevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF)-A, is an anti-angiogenesis agent used to treat patients with metastatic colorectal cancer (CRC) in combination with 5-fluorouracil (5-FU)-based chemotherapy as both first- and second-line treatment [1, 2]. Bevacizumab can lead to a variety of adverse events such as arterial thrombosis [3], hemorrhage [4], and gastrointestinal perforation [5]. In addition, bevacizumab treatment increases the risk of developing an anastomotic leak in patients with rectal cancer who underwent low anterior resection. Delayed anastomotic leak, especially more than 3 months after surgery, is rare. A small number of case reports have described this complication [6–11]. We present a patient with rectal cancer who developed a delayed anastomotic leak more than 5 years after undergoing low anterior resection who had received preoperative chemo-radiotherapy (CRT).\n\nCase presentation\nA 78-year-old man with hematochezia was diagnosed with two synchronous rectal cancers 7 years prior to presentation. One tumor was located at the rectosigmoid junction (stage T3N1M0, well-differentiated tubular adenocarcinoma), and the second was in the distal rectum, (stage T3N1M0, well-differentiated tubular adenocarcinoma). The patient had a 10-year history of diabetes mellitus and hypertension treated with medication. No family history of CRC was noted. Physical examination was unremarkable. Preoperative CRT followed by a very low anterior resection with diverting ileostomy was performed. Preoperative CRT included 5 days of 5-FU/leucovorin infusion followed by radiation therapy delivered using the four-field technique with photon radiation administered five times per week with a daily fraction of 1.8 Gy, for a total of 40 Gy. The final pathological diagnosis revealed that the rectosigmoid cancer was ypT3N1M0, and the lower rectal cancer was ypT0N0M0 (no residual cancer, pathological complete response). The postoperative course was uneventful and the ileostomy was reversed 8 months later, after completion of postoperative adjuvant chemotherapy, which included 6 months of oral 5-FU/leucovorin.\n\nDuring follow-up, multiple lymph node metastases in the para-aortic and supraclavicular regions were found 20 months after resection and chemotherapy was given, including 14 days of oral capecitabine, 1 day of oxizaliplatin (CAPOX), and bevacizumab. Bevacizumab (7.5 mg/kg) was administered intravenously on day 1 for 1 cycle. CAPOX+bevacizumab was continued for 3 years for a total of 33 cycles of CAPOX (combined with 23 cycles of bevacizumab). Progression of lymph node metastases was noted and the chemotherapy regimen was changed. Second-line chemotherapy included 14 days of oral capecitabine, 1 day of irinotecan (XELIRI), and bevacizumab. Three cycles of XELIRI+bevacizumab (7.5 mg/kg) were continued over 3 months. One month after the last course of chemotherapy (5 years after resection), the patient presented with pneumaturia and fecaluria and described three previous episodes of hematochezia. The patient had no other symptoms associated with altered bowel habits. Laboratory tests demonstrated signs of mild inflammation (white blood cell count 11,200 μL, C-reactive protein 2.2 mg/dL). A small amount of extraluminal air between the prostate and rectum, adjacent to the anastomotic site, was observed on computed tomography (CT) scan (Fig. 1), which was not noted on the previous CT scans. Routine surveillance colonoscopy was not performed after the initial surgery as care was focused on management of multiple lymph node metastases. The latest colonoscopy revealed ulceration and fistula formation at the anastomotic site (Fig. 2). Contrast radiography was consistent with a fistula at the anastomotic site (Fig. 3). Only granulation tissue, including inflammatory changes, was seen in biopsies taken from the anastomotic site. Colonoscopy, contrast radiography, and cystoscopy demonstrated no recurrent tumor or obvious anastomotic-urethral fistula at the anastomosis, but an anastomotic-urethral fistula was suspected based on symptoms including pneumaturia and fecaluria. Transverse colostomy was performed and has not been reversed because of the continued need for chemotherapy. At this time, the patient has no symptoms associated with a leak and CT scan shows no air around the anastomotic site.Fig. 1 Computed tomography scan of the abdomen revealed a small amount of extraluminal air between the prostate and rectum, adjacent to the anastomotic site (white arrow)\n\nFig. 2 Ulceration and fistula formation are observed at the site of the colonic anastomosis on colonoscopy\n\nFig. 3 Fistula formation was observed at the anastomotic site after low anterior resection on contrast radiography. Arrow head and arrow indicate fistulae which go to the anterior and posterior side of the anastomosis, respectively. There was no anastomotic-urethral fistula seen on contrast enema\n\n\n\nDiscussion\nThe present patient developed a delayed anastomotic leak associated with bevacizumab treatment for metastatic rectal cancer, which presented more than 60 months after a very low anterior resection with primary anastomosis. Although multiple para-aortic lymph node metastases were observed, there was no recurrence of the tumor at the anastomotic site when the leak occurred. Previous treatment with preoperative CRT may be associated with this delayed anastomotic leak. This patient highlights a rare late adverse event at the anastomotic site associated with bevacizumab treatment and preoperative CRT.\n\nAnastomotic leak is one of the most serious complications following colorectal surgery, and generally occurs within 30 days postoperatively. However, recent studies have reported that anastomotic leaks can also occur more than 30 days after surgery. Risk factors for early anastomotic leak following rectal surgery include a low site of anastomosis, male gender, and the presence of intraoperative difficulties, which may correlate with the degree of surgical difficulty [12–14]. Delayed anastomotic leak does not seem to be associated with technical factors. The risk factors for delayed anastomotic leak include female gender, low anastomosis, preoperative CRT, and fistula formation [15, 16]. Of these risk factors for the development of delayed anastomotic leak, the present patient had a low anastomosis and preoperative CRT. Radiotherapy affects wound healing by inducing vascular injury, inhibiting angiogenesis and impairing fibroblasts [17]. Anastomosis creates a region of marginal vascularization, which may incur further ischemic damage by radiotherapy. Delayed anastomotic leak may occur regardless of bevacizumab administration.\n\nGastrointestinal perforation is a well-described complication of bevacizumab administration that has been reported in up to 2% of patients with CRC and can occur at any time during treatment [18]. The anastomosis is a well-known site for perforation. An intact primary tumor, concomitant use of non-steroidal anti-inflammatory drug, advanced age, and previous radiotherapy were found to be significant risk factors for the development of gastrointestinal perforation associated with bevacizumab treatment [19, 20]. Bevacizumab-related delayed anastomotic leak is extremely rare.\n\nThere have only been nine patients treated with bevacizumab in six reports of delayed anastomotic leak occurring more than 12 months postoperatively [6–11]. The clinical features of all 10 patients, including the present patient, are summarized in Table 1. All patients had rectal cancers and underwent preoperative CRT. The leaks occurred after beginning bevacizumab treatment, and 40% had a previous history of anastomotic leak. The median time to detecting the leak after the initial surgery was 30 months in the previously reported nine patients. We compared the duration of bevacizumab treatment between patients with a delayed leak occurring more or less than 30 months after primary anastomosis. The median duration of bevacizumab treatment in six patients with a greater than 30 month interval was longer (20 weeks) than the median in four patients with a less than 30 month interval (6 weeks). The interval between the last bevacizumab dose and leak was not different in the two groups. In the present patient, the leak occurred after 60 months, the longest reported interval following resection, and 3 years, the longest duration of bevacizumab treatment of the 10 patients reviewed. Long-term follow-up at the anastomotic site is needed for patients who receive bevacizumab treatment. Significant risk factors associated with the development of delayed anastomotic leak include a low anastomotic site, preoperative CRT, and bevacizumab treatment.Table 1 Clinical features of ten patients with delayed anastomotic leak associated with bevacizumab treatment\n\nReport\tAge/gender1\tPrimary tumor\tPreoperative radiation therapy\tPrevious history of anastomotic leak\tAnastomotic complication\tInterval between initial surgery and leak (months)\tDuration of bevacizumab treatment\tInterval between last bevacizumab dose and leak\t\nAdenis et al. [9]\t50/F\tRectum\tYes\tYes\tLeak ileovaginal fistula\t22\t1 month (2 doses)\t< 1 month\t\nLey et al. [7]\t72/F\tRectum\tYes\tNo\tLeak rectovaginal fistula\t30\t6 months\t< 1 month\t\nAugust et al. [6]\t58/M\tRectum\tYes\tYes\tLeak\t26\t6 weeks (3 doses)\tNot described\t\nAugust et al. [6]\t74/F\tRectum\tYes\tNo\tLeak\t33\t20 weeks\t4 months\t\nBege et al. [8]\t46/M\tRectum\tYes\tYes\tLeak\t52\tNot described\t1 week\t\nBege et al. [8]\t54/M\tRectum\tYes\tYes\tLeak\t57\tNot described\t2 weeks\t\nBege et al. [8]\t51/M\tRectum\tYes\tNo\tLeak\t21\tNot described\t2 weeks\t\nBorzomati et al. [10]\t68/M\tRectum\tYes\tYes\tLeak\t33\t24 weeks\t2 weeks\t\nO’Hare et al. [11]\t56/F\tRectum\tYes\tNo\tLeak\t17\t6 weeks (3 doses)\t1 month\t\nPresent patient\t78/M\tRectum\tYes\tNo\tLeak\t60\t3 years (26 doses)\t1 month\t\n1F female, M male\n\n\n\nIn the present patient, the delayed anastomotic leak was detected 3 cycles after beginning an irinotecan-based regimen. Irinotecan is also suspected to be associated with the development of delayed anastomotic leaks, but usually causes a range of toxicities including diarrhea and neutropenia, and the incidence of gastrointestinal perforation is much less than with bevacizumab-based treatment [5, 21, 22]. In addition, no previous report of delayed anastomotic leak due to irinotecan was identified. After creating the transverse colostomy for treatment of the leak, irinotecan plus anti EGF receptor drug has been given. There is no evidence of further leak. In consideration of previous reports, bevacizumab is the most likely drug to be associated with development of the delayed anastomotic leak in the present patient.\n\nPrevious CT scan showed that the circumferential staple line was observed at the anastomotic site (Fig. 4) but was no longer apparent at the time the leak was noted (Fig. 1). Staples might be spontaneously extruded at the anastomotic site during bevacizumab treatment. Some studies demonstrated possible deleterious effects of agents targeting VEGF on healing of colonic anastomoses [23, 24]. Stapled anastomoses are commonly used in rectal cancer surgery and granulation tissue develops around the anastomotic site. There may be ongoing healing and tissue remodeling for years following a low anterior resection in a patient who had received radiation therapy [17]. Bevacizumab may interfere with the ongoing healing process, and an inflamed wound is more at risk of complications from VEGF inhibition at any time during such treatment.Fig. 4 Computed tomography scan 3 months before the patient presented with symptoms of a leak shows a circumferential staple line at the anastomotic site\n\n\n\nConclusions\nA delayed anastomotic leak with fistula formation after low anterior resection for rectal cancer associated with bevacizumab treatment and preoperative CRT must be considered. Signs or symptoms suggestive of anastomotic complications should be evaluated during bevacizumab treatment, even long after the initial surgery.\n\nAbbreviations\n5-FU5-Fluorouracil\n\nCRCColorectal cancer\n\nCRTChemo-radiotherapy\n\nCTComputed tomography\n\nGyGray\n\nVEGFVascular endothelial growth factor\n\nAcknowledgements\nNot applicable.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nEM wrote the manuscript and participated in the postoperative care. YM supervised the writing of the manuscript and was responsible for the out-patient care. JT, ST, HI, FH, RK, and ST participated in the postoperative care. AKL and TR critically revised the manuscript. All authors have read and approved the final manuscript for submission.\n\nEthics approval and consent to participate\nThe institutional ethics committee determined that approval was not necessary for a case report. However, patient anonymity has been preserved and personal information has been protected. Informed consent was obtained from the patient.\n\nConsent for publication\nWritten consent for the publication of this case report with accompanying images was obtained from the patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. 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Adenis A Vanseymortier L Foissey D Colombel JF Bevacizumab and postponed suture leakages after surgery for ulcerative colitis and rectal cancer Gut 2007 56 5 734 10.1136/gut.2006.112524 17440191 \n10. Borzomati D Nappo G Valeri S Vincenzi B Ripetti V Coppola R Infusion of bevacizumab increases the risk of intestinal perforation: results on a series of 143 patients consecutively treated Updat Surg 2013 65 2 121 124 10.1007/s13304-013-0207-2 \n11. O'Hare T McDermott R Hannon R Late anastomotic breakdown with bevacizumab in colorectal cancers, a case-based review Ir J Med Sci 2018 187 2 333 336 10.1007/s11845-017-1676-y 28852961 \n12. Kingham TP Pachter HL Colonic anastomotic leak: risk factors, diagnosis, and treatment J Am Coll Surg 2009 208 2 269 278 10.1016/j.jamcollsurg.2008.10.015 19228539 \n13. Qu H Liu Y Bi DS Clinical risk factors for anastomotic leakage after laparoscopic anterior resection for rectal cancer: a systematic review and meta-analysis Surg Endosc 2015 29 12 3608 3617 10.1007/s00464-015-4117-x 25743996 \n14. Kawada K Sakai Y Preoperative, intraoperative and postoperative risk factors for anastomotic leakage after laparoscopic low anterior resection with double stapling technique anastomosis World J Gastroenterol 2016 22 25 5718 5727 10.3748/wjg.v22.i25.5718 27433085 \n15. Shin US Kim CW Yu CS Kim JC Delayed anastomotic leakage following sphincter-preserving surgery for rectal cancer Int J Color Dis 2010 25 9 843 849 10.1007/s00384-010-0938-1 \n16. Lim SB Yu CS Kim CW Yoon YS Park IJ Kim JC Late anastomotic leakage after low anterior resection in rectal cancer patients: clinical characteristics and predisposing factors Color Dis 2016 18 4 O135 O140 10.1111/codi.13300 \n17. Tibbs MK Wound healing following radiation therapy: a review Radiother Oncol 1997 42 2 99 106 10.1016/S0167-8140(96)01880-4 9106919 \n18. Botrel TEA Clark LGO Paladini L Clark OAC Efficacy and safety of bevacizumab plus chemotherapy compared to chemotherapy alone in previously untreated advanced or metastatic colorectal cancer: a systematic review and meta-analysis BMC Cancer 2016 16 677 10.1186/s12885-016-2734-y 27558497 \n19. Kozloff M Yood MU Berlin J Flynn PJ Kabbinavar FF Purdie DM Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE observational cohort study Oncologist 2009 14 9 862 870 10.1634/theoncologist.2009-0071 19726453 \n20. Hatake K Doi T Uetake H Takahashi Y Ishihara Y Shirao K Bevacizumab safety in Japanese patients with colorectal cancer Jpn J Clin Oncol 2016 46 3 234 240 10.1093/jjco/hyv182 26774113 \n21. Saltz LB Cox JV Blanke C Rosen LS Fehrenbacher L Moore MJ Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group N Engl J Med 2000 343 13 905 914 10.1056/NEJM200009283431302 11006366 \n22. de Man FM Goey AKL van Schaik RHN Mathijssen RHJ Bins S Individualization of irinotecan treatment: a review of pharmacokinetics, pharmacodynamics, and pharmacogenetics Clin Pharmacokinet 2018 57 10 1229 1254 10.1007/s40262-018-0644-7 29520731 \n23. Hendriks JM Hubens G Wuyts FL Vermeulen P Hubens A Eyskens E Experimental study of intraperitoneal suramin on the healing of colonic anastomoses Br J Surg 1999 86 9 1171 1175 10.1046/j.1365-2168.1999.01223.x 10504372 \n24. te Velde EA Voest EE van Gorp JM Verheem A Hagendoorn J Gebbink MF Adverse effects of the antiangiogenic agent angiostatin on the healing of experimental colonic anastomoses Ann Surg Oncol 2002 9 3 303 309 10.1245/aso.2002.9.3.303 11923139\n\n",
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"abstract": "Coronavirus 2019 disease (COVID-19) is a deadly disease that was first seen in Wuhan, China, and primarily affects the respiratory system, but also has different systemic involvements. It has caused 89 million cases and 1.9 million deaths worldwide. COVID-19 positive renal transplant recipients have a higher mortality rate than COVID-19 patients in the normal population. There is no specific treatment and follow-up protocol for COVID-19 infection in transplant recipients. COVID-19 treatment and immunosuppressive therapy choices are controversial. Recently, pulse steroid therapies have been used in cases with severe COVID-19 pneumonia. Convalescent plasma therapy is used limitedly in COVID-19 patients. Our 49-year-old male patient has been a recipient of a renal transplant from a cadaver for 6 years. We aimed to make an additional contribution by presenting our patient to the literature whose COVID-19 PCR-RT test performed in the emergency department due to the complaints of fever, shortness of breath, and cough for five days was positive and had moderate COVID-19 pneumonia in thorax tomography and had serious clinical and radiological improvement after pulsed methylprednisolone and convalescent plasma therapy in the early period.",
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"fulltext": "\n==== Front\nPan Afr Med J\nPan Afr Med J\nPAMJ\nThe Pan African Medical Journal\n1937-8688\nThe African Field Epidemiology Network\n\nPAMJ-38-273\n10.11604/pamj.2021.38.273.28577\nCase Report\nSuccessful pulsed methylprednisolone and convalescent plasma treatment in a case of a renal transplant recipient with COVID-19 positive pneumonia: a case report\nBayrak Muharrem 1&https://orcid.org/0000-0003-2760-4181\n\nÇadirci Kenan 1https://orcid.org/0000-0002-2765-4288\n\n1 Department of Internal Medicine, Erzurum Regional Training and Research Hospital, Health Sciences University, Erzurum, Turkey\nCorresponding author: Muharrem Bayrak, Department of Internal Medicine, Erzurum Regional Training and Research Hospital, Health Sciences University, Erzurum, Turkey. muhabayrak@hotmail.com\n16 3 2021\n2021\n38 27325 2 2021\n02 3 2021\nCopyright: Muharrem Bayrak et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ The Pan African Medical Journal (ISSN: 1937-8688). This is an Open Access article distributed under the terms of the Creative Commons Attribution International 4.0 License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nCoronavirus 2019 disease (COVID-19) is a deadly disease that was first seen in Wuhan, China, and primarily affects the respiratory system, but also has different systemic involvements. It has caused 89 million cases and 1.9 million deaths worldwide. COVID-19 positive renal transplant recipients have a higher mortality rate than COVID-19 patients in the normal population. There is no specific treatment and follow-up protocol for COVID-19 infection in transplant recipients. COVID-19 treatment and immunosuppressive therapy choices are controversial. Recently, pulse steroid therapies have been used in cases with severe COVID-19 pneumonia. Convalescent plasma therapy is used limitedly in COVID-19 patients. Our 49-year-old male patient has been a recipient of a renal transplant from a cadaver for 6 years. We aimed to make an additional contribution by presenting our patient to the literature whose COVID-19 PCR-RT test performed in the emergency department due to the complaints of fever, shortness of breath, and cough for five days was positive and had moderate COVID-19 pneumonia in thorax tomography and had serious clinical and radiological improvement after pulsed methylprednisolone and convalescent plasma therapy in the early period.\n\nCOVID-19\nrenal transplantation\nmethylprednisolone\nconvalescent plasma\ncase report\n==== Body\nIntroduction\n\nCoronavirus 2019 disease (COVID-19) is a deadly disease that was first seen in Wuhan, China, primarily involving the respiratory system with different systemic involvements [1,2]. It caused 89 million cases and 1.9 million deaths worldwide [3]. The risk of viral infection and mortality due to chronic immunosuppressive therapy in renal transplant recipients with COVID-19 infection is higher than in the normal population. The severity and duration of infection and prognosis may be worse due to immunosuppression [4,5]. There is no specialized treatment follow-up protocol in immunosuppressive therapy and infection treatment in COVID-19 renal transplant recipients [6]. Corticosteroid therapy is frequently used in patients hospitalized with COVID-19 infection. Recently, high-dose steroid treatments are used in patients with severe COVID-19 pneumonia [7,8]. Although there is no clear protocol for methylprednisolone treatment in the treatment of COVID-19 infection in renal transplant recipients, it is used effectively [9]. Although convalescent plasma therapy is a potentially effective treatment in the treatment of COVID-19, its difficulty in obtaining it and its use according to indications may cause problems for treatment. Convalescent plasma therapy was used in the treatment of COVID-19 infection successfully in the renal transplant recipient, using a donor who had previously had COVID-19 infection [10,11]. In our case, after the diagnosis of moderate COVID-19 pneumonia was made in the renal transplant recipient, we obtained a successful clinical and radiological response in our patient with severe clinical complaints with pulse methylprednisolone and convalescent plasma therapy in the early period. Since there is no clear follow-up and treatment protocol in the treatment of COVID-19 in renal transplant recipients, we think that we contribute to the literature by presenting our experience in our case.\n\nPatient and observation\n\nA 50-year-old male patient was followed up for 14 years with a diagnosis of chronic glomerulonephritis. He had hemodialysis for 8 years as a result of end-stage renal failure due to this disease. A renal transplant operation with a kidney taken from a cadaver donor has been performed for the last 6 years. Serological tests for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV) before transplant were reported as negative. Our case had type 2 diabetes mellitus for 5 years and hypertension for 9 years.\n\nHe was using medication as mycophenolate mofetil (500 mg/day), cyclosporine (100 mg/day), prednisolone (5mg/day), insulin glargine 18 units, acetylsalicylic acid (100mg/day), pantoprazole (40 mg/day), valsartan 50 mg/day. Fever that started in the last five days was 38.6°C, pulse 98/min, respiratory rate 24/min, blood pressure 142/95 mm Hg, and oxygen saturation was measured by pulse oximetry 88%. On physical examination, there were rales in respiratory sounds in the lower lobes of both lungs. In our case, it is seen that the COVID-19 PCR-RT test performed as a result of these complaints is positive, and thoracic tomography shows consolidated areas of peripherally located ground glass density and crazy paving findings, which are evident in the lower lobe basal segments in both lungs (Figure 1). He was admitted to the infection service because of moderate COVID-19 pneumonia on thoracic tomography. Laboratory findings on the first day in the service were hemoglobin 14.8 g/dL (14.1-17.8), white blood cell (WBC) 7.2x103 (3.91-10.9 x103), platelet (PLT) 101x103 (152-383x103), neutrophil 62.2% (40-74%), lymphocyte count 0.42 x103 μL (1.21-3.77x103 μL), serum creatine: 1.36 (0.7-1.7 mg/dl), urea: 36 (9-23 mg/dl), glomerular filtration rate (GFR) 60.6 ml/min C-reactive protein (CRP) 116.2 mg/L (0-5 mg / L), D-dimer 1544 mgL (0-500 mgL), procalcitonin 0.04 ng/ml (0-0.05 ng/ml), fibrinogen 224 mg/dL (200-400 mg/dL), ferritin 1650 ng/ml (22-232 ng/ml), AST 55 IU/L (0-40 IU/L), ALT 65 U/L (7-40 U/L), lactate dehydrogenase (LDH) 594 U/L (230-500 U/L), albumin 4.2 mg/dl (3.2-4.8 g/dl), glycated hemoglobin level (HbA1c) 9.1, cyclosporine blood level 88 ng/ml, arterial blood gas: pH: 7.39, PO22 88.4 PCO2: 34.1 HCO323.2 BE: -2 SpO2: 88. H1N1 and other viral serological markers were negative. Mycophenolate mofetil and prednol were discontinued, and cyclosporine was started to be given at half dose. Favipiravir 2x1600 mg loading and 2x600 mg maintenance (10 days), 3-4 lt/min oxygen therapy with a nasal cannula, subcutaneous 40 mg/day enoxaparin, acetyl cysteine 900 mg/day, meropenem 1 g every 12 hours, intravenous treatment was initiated. Since our patient had high CRP values, low oxygen saturation, and moderate involvement in thoracic tomography, methylprednisolone 250 mg/day, a 1-hour intravenous infusion was given for 3 days. After 3 days of pulse methylprednisolone treatment, 40 mg/day methylprednisolone maintenance treatment was continued in our patient.\n\nFigure 1 thoracic tomography findings before and after treatment\n\nOur patient's CRP and lymphocyte count were followed up (Figure 2). On the 4th day in the hospital, 200 ml of convalescent plasma taken from a donor with a previous COVID-19 infection, and a sufficient antibody level was given intravenously for 3 days. No complications occurred during convalescent plasma and pulse steroid therapy. Blood, sugar, and blood pressure arterioles were monitored, intensive insulin therapy was initiated. In our case, no growth was detected in blood, urine, and throat cultures. On the 10th day of the treatment of our patient, antiviral treatment was discontinued, methylprednisolone treatment was reduced to 20 mg/day. In the control thoracic tomography, a minimal ground-glass opacity is observed in the lower lobes of both lungs (Figure 1). In the laboratory, HB: 14.2 g/dL, WBC 8.3x103, PLT 202x103, neutrophil 58.4%, lymphocyte count 0.78 x103μL, serum creatine: 1.04, urea: 21, GFR 83.9. ml/min, CRP 7.1 mg/L, D-dimer 614 mgL, procalcitonin 0.06 ng/ml, ferritin 1004 ng/ml, oxygen saturation 98%. As a result of clinical and radiological improvement in the clinical follow-up of our case, normalization of vital signs, and improvement of oxygen saturation, the treatment before admission to the service was restarted, and he was discharged with subcutaneous 40 mg/day enoxaparin added as anticoagulant treatment.\n\nFigure 2 treatment process during the days of the patient's hospitalization\n\nDiscussion\n\nThe incidence of COVID-19 infection in renal transplant recipients is gradually increasing. The T cells immune system is suppressed due to the long-term immunosuppressive agents used by renal transplant recipients. In some case series, acute renal injury and mortality rates have been observed more frequently than in the general population [12]. Our case had similar symptoms, such as cough, shortness of breath, and fever, similar to the literature [13]. There are no proven algorithms in antiviral and immunosuppressive treatment management in COVID-19 infection in renal transplant recipients. Oseltamivir, remdesivir, hydroxychloroquine, lopinavir/ritonavir, and favipiravir treatments were used in studies in COVID-19 positive renal transplant recipients. No definitive efficacy of antiviral treatments has been proven in the treatment of COVID-19. Favipiravir treatment was used in our case and no side effects were observed during the treatment process. Mycophenolate mofetil treatment was discontinued until the viral infection was controlled, cyclosporine dose was halved. There is no proven protocol in the literature regarding the immunosuppressive agents used by renal transplant recipients during the treatment of COVID-19 infection. It is known that mycophenolate mofetil increases the progression in viral infections because of inhibiting T and B lymphocyte activation and proliferation, whereas cyclosporine does not have such an effect on T lymphocytes [14].\n\nMycophenolate mofetil treatment was discontinued to prevent the progression of COVID-19 viral pneumonia. The frequency of bacterial pneumonia due to chronic immunosuppression has increased in renal transplant recipients, therefore, meropenem, a broad-spectrum antibiotic, was chosen for the initial treatment of our case [15]. In the treatment of COVID-19 infection in renal transplant recipients, steroid therapy is used for treatment to prevent inflammation and adrenal insufficiency. Methylprednisolone treatment has been used at different doses in case series [16]. Pulse methylprednisolone therapy is an outstanding treatment option in patients with COVID-19 infection in severe clinical cases, cytokine storm, and macrophage-activation syndrome. In our case, because of hyperinflammation due to high CRP values, decreased oxygen saturation, moderate viral pneumonia on thoracic tomography, lymphopenia, high D-dimer and ferritin, pulsed methylprednisolone treatment was applied as aggressive treatment. Ruiz-Irastorza et al. [17] successfully applied pulse methylprednisolone therapy in the second week of treatment in a patient with COVID-19 positive renal transplant recipient due to high CRP values and severe viral pneumonia. In our case, unlike this case, the existing hyperinflammation was prevented by applying pulse steroid therapy in the early period. Also, we think that the cytokine storm, severe lung damage, and the need for intensive care in our patient were prevented by early treatment. Sauñe PM et al. [8] applied 500 mg/day 3-day pulse methylprednisolone treatment in the renal transplant recipient patient due to cytokine storm in the late period after the cytokine storm developed and a positive clinical response was obtained. In our case, clinical deterioration was prevented by applying it in an earlier period.\n\nConvalescent plasma therapy has limited use in COVID-19 patients due to the difficulty in finding ABO-compatible plasma and various contraindications. In the COVID-19 case series in China, CRP decreases in the early period and clinical improvement in oxygen saturation were observed in patients who received convalescent plasma [18,19]. In the study of Jiang J et al. [11], a 70-year-old patient with a poor prognosis who has been a recipient of a renal transplant for 10 years had positive clinical results. Our case is a younger patient. Although the CRP values were higher, oxygen saturation was lower, and in our case, using high-dose methylprednisolone and administering convalescent plasma for 3 days made the difference between the two cases. In both cases, the 4th day of treatment and the early use were similar.\n\nConclusion\n\nWe applied pulse methylprednisolone and convalescent treatment as an aggressive treatment due to moderate COVID-19 pneumonia, high CRP, D-dimer, ferritin level in the renal transplant recipient candidate and since there is no contraindication in the early period before complications as cytokine storm, macrophage activation syndrome and acute respiratory stress syndrome developed in the patient. Renal transplant recipient patients have unproven and different treatment options for COVID-19 infection. We aimed to make an additional contribution to the current literature considering that the early stage methylprednisolone and convalescent plasma treatment we used in our case could be an outstanding treatment in this regard.\n\nCompeting interests\n\nThe authors declare no competing interests.\n\nAuthors' contributions\n\nMB managed the patient. MB, KC drafted the manuscript and performed literature search, and also performed manuscript review and editing. All authors contributed to the writing of the manuscript and approved the manuscript for publication.\n\nCite this article: Muharrem Bayrak et al. Successful pulsed methylprednisolone and convalescent plasma treatment in a case of a renal transplant recipient with COVID-19 positive pneumonia: a case report. Pan African Medical Journal. 2021;38(273). 10.11604/pamj.2021.38.273.28577\n==== Refs\n1 Ning L Liu L Li W Liu H Wang J Yao Z et al Novel coronavirus (SARS-CoV-2) infection in a renal transplant recipient: case report Am J Transplant 2020 7 20 7 1864 1868 32277555\n2 Dirim AB Demir E Ucar AR Garayeva N Safak S Oto OA et al Fatal SARS-CoV-2 infection in a renal transplant recipient CEN Case Rep 2020 11 9 4 409 412 32564306\n3 Hopkins J Johns Hopkins Coronavirus Resource Center COVID-19 Case Tracker 2020\n4 Hilbrands LB Duivenvoorden R Vart P Franssen CF Hemmelder MH Jager KJ et al COVID-19-related mortality in kidney transplant and dialysis patients: results of the ERACODA collaboration Nephrol Dial Transplant 2020 11 1 35 11 1973 1983 33151337\n5 Zhu L Gong N Liu B Lu X Chen D Chen S et al Coronavirus disease 2019 pneumonia in immunosuppressed renal transplant recipients: a summary of 10 confirmed cases in Wuhan, China Eur Urol 2020 6 77 6 748 754 32317180\n6 Tanaka R Kakuta Y Tsutahara K Nakagawa M Ichimaru N Sakaguchi K et al Successful recovery from coronavirus disease 2019 in a living kidney transplant recipient using low-dose methylprednisolone IJU case reports 2020 4 1 22 4\n7 Chen Q Song Y Wang L Zhang Y Han L Liu J et al Corticosteroids treatment in severe patients with COVID-19: a propensity score matching study Expert Rev Respir Med 2021 2 1 1 10\n8 Sauñe PM Bryce-Alberti M Portmann-Baracco AS Accinelli RA Methylprednisolone pulse therapy: an alternative management of severe COVID-19 Respiratory Medicine Case Reports 2020 31 101221 32995261\n9 Zhu L Xu X Ma K Yang J Guan H Chen S et al Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression Am J Transplant 2020 7 20 7 1859 1863 32181990\n10 Bloch EM Shoham S Casadevall A Sachais BS Shaz B Winters JL et al Deployment of convalescent plasma for the prevention and treatment of COVID-19 J Clin Invest 2020 6 1 130 6 2757 2765 32254064\n11 Jiang J Miao Y Zhao Y Lu X Zhou P Zhou X et al Convalescent plasma therapy: helpful treatment of COVID-19 in a kidney transplant recipient presenting with severe clinical manifestations and complex complications Clin Transplant 2020 9 34 9 e14025 32602952\n12 Akalin E Azzi Y Bartash R Seethamraju H Parides M Hemmige V et al COVID-19 and kidney transplantation N Engl J Med 2020 6 18 382 25 2475 2477 32329975\n13 Devresse A Belkhir L Vo B Ghaye B Scohy A Kabamba B et al COVID-19 infection in kidney transplant recipients: a single-center case series of 22 cases from Belgium Kidney Med 2020 2 4 459 66 32775986\n14 Allison AC Eugui EM Preferential suppression of lymphocyte proliferation by mycophenolic acid and predicted long-term effects of mycophenolate mofetil in transplantation Transplant Proc 1994 12 26 6 3205 10 7998117\n15 Chang GC Wu CL Pan SH Yang TY Chin CS Yang YC et al The diagnosis of pneumonia in renal transplant recipients using invasive and noninvasive procedures Chest 2004 125 2 541 7 14769736\n16 Viana LA Cristelli MP Ficher KN Rezende JT Villanueva LA Santos DW et al Kidney transplantation in patients with SARS-CoV-2 infection: a case series report Transplantation 2021 1 1 105 1 e1 e3 33350628\n17 Ruiz-Irastorza G Pijoan JI Bereciartua E Dunder S Dominguez J Garcia-Escudero P et al Second week methyl-prednisolone pulses improve prognosis in patients with severe coronavirus disease 2019 pneumonia: an observational comparative study using routine care data PloS one 2020 15 9 e0239401 32960899\n18 Duan K Liu B Li C Zhang H Yu T Qu J et al The feasibility of convalescent plasma therapy in severe COVID-19 patients: a pilot study MedRxiv 2020\n19 Chen L Xiong J Bao L Shi Y Convalescent plasma as a potential therapy for COVID-19 Lancet Infect Dis 2020 20 4 398 400 32113510\n\n",
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"abstract": "Graft rejection (GR) is a poorly understood complication of hematopoietic cell transplant (HCT). GR risk factors are well published, but there are no reliable biomarkers or therapies known. Fever is the most common symptom of GR, but no study has evaluated fever kinetics as a diagnostic marker of GR. The objectives of this study were to identify mechanisms, biomarkers, and potential therapies for GR after HCT. Chemokine ligand 9 (CXCL9), B-cell activating factor (BAFF), and complement markers (sC5b-9, C3a, and C5a) were measured in 7 patients with GR and compared with 15 HCT controls. All patients had a diagnosis of aplastic anemia, Fanconi anemia, or genetically undefined chromosomal fragility syndrome. All patients with GR were febrile during GR; therefore, control patients who underwent HCT were matched for diagnosis and early fevers after HCT. Patients withh GR had significantly higher CXCL9, BAFF, and sC5b-9 at the time of fever and GR compared with control patients who underwent HCT at the time of fever. The maximum fever was significantly higher and occurred significantly later in the transplant course in patients with GR compared with febrile HCT controls. These data support the use of CXCL9, BAFF, sC5b-9, and fever kinetics as GR markers. Two patients with GR underwent a second HCT that was complicated by high fevers. Both patients received interferon and complement blockers during their second HCT, and both preserved their graft. These laboratory and clinical findings support larger studies to evaluate the safety and efficacy of interferon, complement, and BAFF inhibitors for the prevention and treatment of GR after HCT.",
"affiliations": "Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.;Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.;Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.;Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.;Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.;Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.;Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.;Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.",
"authors": "Sabulski|Anthony|A|0000-0002-3652-0003;Myers|Kasiani C|KC|0000-0002-5528-4405;Bleesing|Jack J|JJ|;Duell|Alexandra|A|;Lane|Adam|A|;Teusink-Cross|Ashley|A|;Davies|Stella M|SM|;Jodele|Sonata|S|",
"chemical_list": "D015415:Biomarkers",
"country": "United States",
"delete": false,
"doi": "10.1182/bloodadvances.2021005231",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2473-9529",
"issue": "5(22)",
"journal": "Blood advances",
"keywords": null,
"medline_ta": "Blood Adv",
"mesh_terms": "D015415:Biomarkers; D005199:Fanconi Anemia; D006084:Graft Rejection; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D019172:Transplantation Conditioning",
"nlm_unique_id": "101698425",
"other_id": null,
"pages": "4594-4604",
"pmc": null,
"pmid": "34614507",
"pubdate": "2021-11-23",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Graft rejection markers in children undergoing hematopoietic cell transplant for bone marrow failure.",
"title_normalized": "graft rejection markers in children undergoing hematopoietic cell transplant for bone marrow failure"
} | [
{
"companynumb": "US-OTSUKA-2021_044903",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": "3",
"dr... |
{
"abstract": "A 49-year-old female patient presented with acute-on-chronic chest pain. She was diagnosed with multiple systemic thromboemboli, including myocardial infarctions, bilateral chronic pulmonary emboli, ischaemic stroke, deep venous thrombosis and superficial thrombophlebitis. She had a background of sickle cell trait. Cardiac magnetic resonance showed bilateral superior vena cava (SVC). The right-sided SVC (RSVC) was joined by the right upper pulmonary vein and drained anomalously into the left atrium. This caused a small volume right to left shunt. The persistent left SVC drained into the right atrium (RA) via a dilated coronary sinus. The overall clinical impression was recurrent paradoxical emboli due to anomalous venous anatomy with a thrombophilia secondary to sickle cell trait. In the normal embryo, the right common cardinal vein develops to become the RSVC, which drains into the RA by term.",
"affiliations": "Intensive Care Unit, West Hertfordshire Hospitals NHS Trust, Watford, UK maria.karavassilis@nhs.net.;Stroke Medicine, West Hertfordshire Hospitals NHS Trust, Watford, Hertfordshire, UK.;Cardiology, West Hertfordshire Hospitals NHS Trust, Watford, UK.",
"authors": "Karavassilis|Maria Elizabeth|ME|;Haji-Coll|Michael|M|;Keenan|Niall G|NG|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-237401",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(2)",
"journal": "BMJ case reports",
"keywords": "clinical diagnostic tests; haematology (incl blood transfusion); radiology; radiology (diagnostics); venous thromboembolism",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D004452:Echocardiography; D019320:Embolism, Paradoxical; D005260:Female; D006801:Humans; D000083242:Ischemic Stroke; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009203:Myocardial Infarction; D000083402:Persistent Left Superior Vena Cava; D011655:Pulmonary Embolism; D011667:Pulmonary Veins; D012008:Recurrence; D012805:Sickle Cell Trait; D019851:Thrombophilia; D013924:Thrombophlebitis; D054079:Vascular Malformations; D020246:Venous Thrombosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33526519",
"pubdate": "2021-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": null,
"title": "Multiple thromboembolic events associated with bilateral superior vena cava and anomalous drainage into the left atrium.",
"title_normalized": "multiple thromboembolic events associated with bilateral superior vena cava and anomalous drainage into the left atrium"
} | [
{
"companynumb": "GB-MYLANLABS-2021M1049912",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BISOPROLOL"
},
"drugadditional": "3",
... |
{
"abstract": "The reports of chemoradiotherapy for anal squamous cell carcinoma with Crohn's disease are few. Severe toxicity related to radiotherapy is concerned in patients with inflammatory bowel disease. We report a case of chemoradiotherapy for locally advanced fistula-related perianal squamous cell carcinoma in a patient with long-standing Crohn's disease which was controlled by a maintenance therapy. The patient completed standard chemoradiotherapy using intensity-modulated radiotherapy without severe toxicity, and achieved complete remission. Standard chemoradiotherapy using intensity-modulated radiotherapy may be feasible and effective treatment for this population when Crohn's disease is controlled.",
"affiliations": "Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.;Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.;Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.;Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.;Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.;Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.;Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.;Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.",
"authors": "Sakanaka|Katsuyuki|K|0000-0002-1590-0250;Fujii|Kota|K|;Hirashima|Hideaki|H|;Mukumoto|Nobutaka|N|;Inoo|Hiroyuki|H|;Narukami|Ryo|R|;Sakai|Yoshiharu|Y|;Mizowaki|Takashi|T|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-021-00497-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-3183",
"issue": "10(4)",
"journal": "International cancer conference journal",
"keywords": "Chemoradiotherapy; Crohn’s disease; Fistula-unrelated perianal squamous cell carcinoma",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "305-311",
"pmc": null,
"pmid": "34567943",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": "1248701;19826882;10826422;23154075;25853748;22379406;18430910;28293746;25564345;26889506",
"title": "Chemoradiotherapy for fistula-related perianal squamous cell carcinoma with Crohn's disease.",
"title_normalized": "chemoradiotherapy for fistula related perianal squamous cell carcinoma with crohn s disease"
} | [
{
"companynumb": "JP-MLMSERVICE-20211019-3166568-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": nul... |
{
"abstract": "Low-level BK polyomavirus (BKPyV) shedding is seen in at least 10% of seropositive immunocompetent adults. Moreover, BKPyV infection is highly prevalent amongst immunocompromised populations, yet little is known on its relationship with malignancy. We studied a female patient with BKPyV-associated and donor-derived de novo high-grade sarcomatoid urothelial carcinoma developed 8 years after kidney transplantation from a male donor. Through whole-genome sequencing, we discovered integration of genotype IV BKPyV genome into the non-coding RNA (ncRNA) intronic region of human chromosome 18. The two breakpoints in the virus genome were located at the non-coding control region (NCCR) and large T antigen (TAg) coding region, respectively. Nevertheless, the TAg was overexpressed. We, therefore, inferred that the BKPyV was clonally integrated into the human genome in the form of concatemers, facilitating the expression of the TAg. The patient presented with multiorgan metastases, which were reduced in size and number throughout the body after removal of the graft and cessation of immunosuppressants. The few remaining lesions located in the liver were identified, through biopsy to be necrotic tumor tissue with TAg detected; additionally, genomic sequencing of the liver mass found Y chromosome. In conclusion, we propose that integration of the BKPyV genome is closely related to oncogenesis in this patient; while oncogenesis occurred when host immunity was impaired, recovery of the patient's native immunity effectively curbed viral replication and eliminated the metastatic lesions.",
"affiliations": "Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.;Organ Transplant Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.;The Second Clinical Medical School, Southern Medical University, Guangzhou 510515, China.;Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.;Organ Transplant Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.;Organ Transplant Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.;Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.;Department of Information Analysis, Vazyme Biotech Co.,Ltd., Nanjing 210000, China.;Department of Pathology, Southern Medical University, Guangzhou 510515, China.;Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.;Department of Organ Transplantation, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.;State Key Laboratory of Virology, CAS Center for Excellence in Brain Science and Intelligence Technology, Wuhan Institute of Virology, Wuhan, China.;Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.;Departments of Pathology and Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, U.S.A.;Organ Transplant Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China miaoyunecho@126.com.",
"authors": "Fu|Fangxiang|F|;Deng|Wenfeng|W|;Yu|Siyuan|S|;Liu|Yanna|Y|;Yu|Lixin|L|;Liu|Rumin|R|;Lang|Jiping|J|;Geng|Dianxiang|D|;Geng|Jian|J|;Li|Jiangtao|J|;Huang|Gang|G|;Luo|Minhua|M|;Xiong|Fu|F|;Wu|Chin-Lee|CL|;Miao|Yun|Y|",
"chemical_list": "D004279:DNA, Viral",
"country": "England",
"delete": false,
"doi": "10.1042/CS20180443",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0143-5221",
"issue": "132(16)",
"journal": "Clinical science (London, England : 1979)",
"keywords": "BK polyomavirus; Carcinoma; Transplantation",
"medline_ta": "Clin Sci (Lond)",
"mesh_terms": "D001739:BK Virus; D002292:Carcinoma, Renal Cell; D002472:Cell Transformation, Viral; D002887:Chromosomes, Human, Pair 18; D004279:DNA, Viral; D005260:Female; D016679:Genome, Viral; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007680:Kidney Neoplasms; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D027601:Polyomavirus Infections; D014019:Tissue Donors",
"nlm_unique_id": "7905731",
"other_id": null,
"pages": "1753-1763",
"pmc": null,
"pmid": "30026258",
"pubdate": "2018-08-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Occurrence and regression of BK polyomavirus associated carcinoma: a clinical and next-generation sequencing study.",
"title_normalized": "occurrence and regression of bk polyomavirus associated carcinoma a clinical and next generation sequencing study"
} | [
{
"companynumb": "CN-MYLANLABS-2018M1072876",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "... |
{
"abstract": "It is difficult to diagnose an acute abdomen condition in people with spinal cord injury due to abnormal sensation below the injured level and multiple co-morbidities. These issues can mislead the exact diagnosis and delay proper treatment.\n\n\n\nA 57-year-old male with C4 AIS C tetraplegia developed nausea and vomiting, abdominal distension and feeding intolerance. Serum electrolytes indicated severe hyponatremia. A provisional diagnosis of pseudo-gut obstruction was made. After the failure of 48 h of conservative treatment with a nasogastric and rectal tube, abdominal CT was performed and revealed sigmoid volvulus.\n\n\n\nDue to the inconclusive clinical features and lack of subjective complaints, early use of CT scan or MRI is preferable in people with SCI who are suspected of an emergency intra-abdominal condition.",
"affiliations": "Department of Rehabilitation Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. umedicus@hotmail.com.;Department of Rehabilitation Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.",
"authors": "Pattanakuhar|Sintip|S|;Kovindha|Apichana|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/s41394-020-0305-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2058-6124",
"issue": "6(1)",
"journal": "Spinal cord series and cases",
"keywords": null,
"medline_ta": "Spinal Cord Ser Cases",
"mesh_terms": "D000208:Acute Disease; D012809:Colon, Sigmoid; D006801:Humans; D045822:Intestinal Volvulus; D008297:Male; D008875:Middle Aged; D011782:Quadriplegia; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101680856",
"other_id": null,
"pages": "53",
"pmc": null,
"pmid": "32601285",
"pubdate": "2020-06-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22457863;8337003;20236153;6981707",
"title": "Colonic obstruction in a tetraplegic patient: a common symptom from an uncommon cause.",
"title_normalized": "colonic obstruction in a tetraplegic patient a common symptom from an uncommon cause"
} | [
{
"companynumb": "TH-CADILA HEALTHCARE LIMITED-TH-ZYDUS-054135",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugaddition... |
{
"abstract": "OBJECTIVE\nThe aims of this study were to compare the application of three geriatric medication screening tools to the Beers Criteria alone for potentially inappropriate medication quantification and to determine feasibility of a pharmacist-led polypharmacy assessment in a geriatric oncology clinic.\n\n\nMETHODS\nAdult patients with cancer aged 65 and older underwent a comprehensive geriatric assessment. A polypharmacy assessment was completed by a pharmacist and included a review of all drug therapies. Potentially inappropriate medications were screened using the Beers Criteria, Screening Tool to Alert doctors to Right Treatment/Screening Tool of Older Persons' Prescriptions, and the Medication Appropriateness Index. Deprescribing occurred after discussion with the pharmacist, geriatric oncologist, patient, and caregiver.\n\n\nRESULTS\nData were collected for 26 patients. The mean number of medications was 12. The Beers Criteria alone identified 38 potentially inappropriate medications compared to 119 potentially inappropriate medications with the three-tool assessment; a mean of 5 potentially inappropriate medications were identified per patient. After the application of the three-tool assessment, 73% of potentially inappropriate medications identified were deprescribed, resulting in a mean of 3 medications deprescribed per patient. Approximately two thirds of patients reported a reduction in symptoms after the deprescribing intervention. Healthcare expenditures of $4282.27 per patient were potentially avoided as a result of deprescribing.\n\n\nCONCLUSIONS\nOur three-tool assessment identified three times more potentially inappropriate medications than the Beers Criteria alone. Pharmacist-led deprescribing interventions are feasible and may lead to improved patient outcomes and cost savings. This three-tool assessment process should be incorporated into interdisciplinary assessments of older patients with cancer and validated in future studies.",
"affiliations": "Department of Pharmacy, University of Virginia Health System, Charlottesville, VA, USA. Amw6az@virginia.edu.;Department of Pharmacy, University of Virginia Health System, Charlottesville, VA, USA.;Department of Pharmacy, University of Virginia Health System, Charlottesville, VA, USA.;Division of Hematology/Oncology, University of Rochester Medical Center, Rochester, NY, USA.;Division of Hematology/Oncology, University of Rochester Medical Center, Rochester, NY, USA.",
"authors": "Whitman|Andrew|A|http://orcid.org/0000-0002-1646-0699;DeGregory|Kathlene|K|;Morris|Amy|A|;Mohile|Supriya|S|;Ramsdale|Erika|E|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-018-4281-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "26(12)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "Deprescribing; Geriatric oncology; Polypharmacy; Potentially inappropriate medications",
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000069340:Deprescriptions; D005260:Female; D015577:Geriatric Assessment; D006801:Humans; D057970:Inappropriate Prescribing; D008297:Male; D009369:Neoplasms; D010595:Pharmacists; D010865:Pilot Projects; D019338:Polypharmacy; D000067561:Potentially Inappropriate Medication List",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "4105-4113",
"pmc": null,
"pmid": "29869294",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": "25800766;26961585;16567597;25799203;26449548;23912674;24975044;26998708;25798731;26361160;25798575;23305190;21731193;26822776;27151653;27737436;20133536;19030900;21741307;26668713;29760253;26733578",
"title": "Pharmacist-led medication assessment and deprescribing intervention for older adults with cancer and polypharmacy: a pilot study.",
"title_normalized": "pharmacist led medication assessment and deprescribing intervention for older adults with cancer and polypharmacy a pilot study"
} | [
{
"companynumb": "US-RECORDATI RARE DISEASES INC.-US-R13005-18-00289",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLORAZEPATE DIPOTASSIUM"
},
... |
{
"abstract": "Membranoproliferative glomerulonephritis (MPGN) is a rare cause of glomerulopathy in children. Recently, a new classification based on immunohistological features has been established. Infections and anomalies in complement-regulating genes, leading to alternative complement pathway activation, are suspected to trigger the disease. Nevertheless, little is known about optimal treatment and outcome in children with immune-complex-MPGN (IC-MPGN) and C3-glomerulopathy (C3G).\n\n\n\nThe method used is retrospective analysis of clinical, histological, and genetic characteristics of 14 pediatric patients with MPGN in two medical centers.\n\n\n\nMean age of the patients was 10.6 ± 4.5 years. Patients were grouped into C3G (n = 6) and IC-MPGN (n = 8). One patient showed a likely pathogenic variant in the CFHR5 gene. All 10 patients had risk polymorphisms in complement-regulating genes. Most patients were treated with ACE inhibition, steroids, and mycophenolate mofetil. Three patients with C3G received eculizumab. Median follow-up was 2.3 years. After 1 year of disease, three patients (two C3G, one IC-MPGN) reached complete, five patients partial (three IC-MPGN, two C3G), and five patients no remission (four IC-MPGN, one C3G). One patient progressed to end-stage renal disease (ESRD) 6 years after disease onset.\n\n\n\nIC-MPGN and C3G are rare disorders in children. Most patients have signs of complement activation associated with risk polymorphisms or likely pathogenic variants in complement-regulating genes. Steroids and mycophenolate mofetil seem to be effective and for some patients, eculizumab might be a treatment option. Outcome is heterogeneous and precise differentiation between IC-MPGN and C3G is still pending.",
"affiliations": "Department of Pediatric Pulmonology, Immunology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. johannes-benjamin.holle@charite.de.;Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Pediatrics and Adolescent Medicine, Pediatric Nephrology, Ulm University Medical Center, Ulm, Germany.;Department of Pediatrics and Adolescent Medicine, Pediatric Nephrology, Ulm University Medical Center, Ulm, Germany.;Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany.",
"authors": "Holle|Johannes|J|0000-0001-8032-4096;Berenberg-Goßler|Lena|L|;Wu|Kaiyin|K|;Beringer|Ortraud|O|;Kropp|Florian|F|;Müller|Dominik|D|;Thumfart|Julia|J|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D003176:Complement C3; D003169:Complement Inactivator Proteins; D005938:Glucocorticoids; C546931:THBD protein, human; D018180:Thrombomodulin; C481642:eculizumab; D009173:Mycophenolic Acid",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-018-4034-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "33(12)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "C3-Glomerulopathy; Children; Complement system; Eculizumab; MPGN",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D000293:Adolescent; D000806:Angiotensin-Converting Enzyme Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D003176:Complement C3; D003169:Complement Inactivator Proteins; D003170:Complement Pathway, Alternative; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D015432:Glomerulonephritis, Membranoproliferative; D005938:Glucocorticoids; D006801:Humans; D007676:Kidney Failure, Chronic; D007678:Kidney Glomerulus; D008297:Male; D009173:Mycophenolic Acid; D063868:Patient Outcome Assessment; D012074:Remission Induction; D012189:Retrospective Studies; D018180:Thrombomodulin; D016896:Treatment Outcome",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "2289-2298",
"pmc": null,
"pmid": "30238151",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": "24178974;22435382;22435371;22403278;20852386;12960213;26283675;26032627;9554862;29329521;17396113;26316621;16299065;26895476;25447133;29326307;27056062;23318699;22456601;22168663;23689905;28236143;21269585;24172683;29310824;25524631;25986912;22105967;27467768;24799308;25859752;19158356;21839367;14583443;24536001;18971369;24799307;27402056",
"title": "Outcome of membranoproliferative glomerulonephritis and C3-glomerulopathy in children and adolescents.",
"title_normalized": "outcome of membranoproliferative glomerulonephritis and c3 glomerulopathy in children and adolescents"
} | [
{
"companynumb": "PHHY2018DE107400",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Mycobacterial infection in an organ transplant recipient is a diagnostic and therapeutic challenge. Diagnosis is often delayed, resulting in significant morbidity. Anti-microbial chemotherapy needs careful selection to prevent potentially significant complications, such as organ rejection and dose-related toxicities. We present the case of a 61-year-old Caucasian male kidney transplant recipient with chronic tenosynovitis of the left wrist. Histological findings of the synovial biopsy revealed multinucleated giant cell epithelioid granuloma. Culture of synovial fluid grew Mycobacterium kansasii. Treatment with rifampicin, ethambutol, and clarithromycin proved curative, but the patient developed irreversible ethambutol-related optic neuritis.",
"affiliations": "Department of Renal Medicine, Broomfield Hospital, Mid Essex Hospitals, NHS Trust, Chelmsford, UK. anthony.chan@meht.nhs.uk",
"authors": "Chan|A|A|;Findlay|A|A|;Abeygunasekara|S|S|",
"chemical_list": "D004977:Ethambutol; D017291:Clarithromycin; D012293:Rifampin",
"country": "Denmark",
"delete": false,
"doi": "10.1111/j.1399-3062.2012.00768.x",
"fulltext": null,
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"issn_linking": "1398-2273",
"issue": "14(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": null,
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D017291:Clarithromycin; D004977:Ethambutol; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D019909:Mycobacterium kansasii; D009902:Optic Neuritis; D012293:Rifampin; D013717:Tenosynovitis; D014953:Wrist",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "E44-9",
"pmc": null,
"pmid": "22822725",
"pubdate": "2012-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of wrist tenosynovitis caused by Mycobacterium kansasii in a renal transplant recipient.",
"title_normalized": "a case of wrist tenosynovitis caused by mycobacterium kansasii in a renal transplant recipient"
} | [
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"abstract": "Mycobacterium tuberculosis infection in patients with cystic fibrosis (CF) is rare. We report a 22-year-old CF patient with high fever, dyspnea and weight loss that progressively worsened over 2 weeks before admission. The patient suffered from liver cirrhosis, was colonized with Pseudomonas aeruginosa and had been repeatedly hospitalized for pulmonary infections. The patient was treated initially as for an exacerbation of P. aeruginosa infection, but tuberculosis (TBC) was suspected due to lack of improvement. A CT of the chest revealed enlarged bilateral cavities in the upper and middle lobes. A tuberculin skin test was positive, and M. tuberculosis nucleic acid was isolated from sputum samples. After receiving first-line anti-TBC drugs for 1 month, the patient's condition continued to worsen so molecular drug susceptibility testing was performed. Multidrug-resistant TBC was discovered, leading to a change in regimen. The patient was treated with ethionamide, moxifloxacin, linezolid, amikacin, imipenem/cilastatin and rifabutin and showed a remarkable clinical improvement. Although nontuberculous mycobacteria are more common in CF, the possibility of TBC should not be ignored. In that setting, early suspicion of infection due to resistant M. tuberculosis can be life saving.",
"affiliations": "Adult Cystic Fibrosis Unit, Pulmonary Department, Aristotle University of Thessaloniki, G. Papanikolaou Hospital, Thessaloniki, Greece.",
"authors": "Manika|K|K|;Giouleka|P|P|;Zarogoulidis|K|K|;Kioumis|I|I|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000338846",
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"issn_linking": "0025-7931",
"issue": "85(4)",
"journal": "Respiration; international review of thoracic diseases",
"keywords": null,
"medline_ta": "Respiration",
"mesh_terms": "D000995:Antitubercular Agents; D003550:Cystic Fibrosis; D005260:Female; D006801:Humans; D018088:Tuberculosis, Multidrug-Resistant; D014397:Tuberculosis, Pulmonary; D055815:Young Adult",
"nlm_unique_id": "0137356",
"other_id": null,
"pages": "350-3",
"pmc": null,
"pmid": "22869452",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multidrug-resistant tuberculosis in an adult with cystic fibrosis.",
"title_normalized": "multidrug resistant tuberculosis in an adult with cystic fibrosis"
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"abstract": "It is currently recommended that hydroxychloroquine (HCQ) be maintained during pregnancy in patients with systemic lupus erythematosus. Recent data suggest that this Toll-like receptor inhibitor may also reduce the recurrence rate of anti-SSA/Ro associated congenital heart block (CHB). This case report describes a unique situation in which a CHB-afflicted, HCQ-exposed pregnancy was electively terminated. The heart did not reveal any characteristic features of cardiotoxicity, providing further evidence supporting the safety of foetal exposure to HCQ.",
"affiliations": "Paediatric Cardiology, New York Medical College, USA.;Paediatric Cardiology, Children's and Women's Physicians of Westchester LLP, Norwalk, CT, USA.;Pathology, Johns Hopkins Medicine, Baltimore, MD, USA.;Medicine, Division of Rheumatology, New York University School of Medicine, New York, USA.;Medicine, Division of Rheumatology, New York University School of Medicine, New York, USA.;Medicine, Division of Rheumatology, New York University School of Medicine, New York, NY, USA. jill.buyon@nyumc.org.",
"authors": "Friedman|Deborah|D|;Lovig|Leif|L|;Halushka|Marc|M|;Clancy|Robert M|RM|;Izmirly|Peter M|PM|;Buyon|Jill P|JP|",
"chemical_list": "D018501:Antirheumatic Agents; D006886:Hydroxychloroquine",
"country": "Italy",
"delete": false,
"doi": null,
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"issn_linking": "0392-856X",
"issue": "35(5)",
"journal": "Clinical and experimental rheumatology",
"keywords": null,
"medline_ta": "Clin Exp Rheumatol",
"mesh_terms": "D000032:Abortion, Therapeutic; D000328:Adult; D018501:Antirheumatic Agents; D001344:Autopsy; D066126:Cardiotoxicity; D005260:Female; D005318:Fetal Heart; D006327:Heart Block; D006331:Heart Diseases; D006801:Humans; D006886:Hydroxychloroquine; D008180:Lupus Erythematosus, Systemic; D011247:Pregnancy; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8308521",
"other_id": null,
"pages": "857-859",
"pmc": null,
"pmid": "28598777",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18061791;22308531;20089705;24062937;19790064;23635029;17075810;20447951;11508435;16804295;21969015;25456525;14613284;22626746",
"title": "No histologic evidence of foetal cardiotoxicity following exposure to maternal hydroxychloroquine.",
"title_normalized": "no histologic evidence of foetal cardiotoxicity following exposure to maternal hydroxychloroquine"
} | [
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"companynumb": "US-MYLANLABS-2017M1069683",
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{
"abstract": "BACKGROUND\nNephrocalcinosis is often asymptomatic but can manifest with renal colic or hematuria. There is no reported association between nephrocalcinosis and renal vascular malformations, which may also be a source of hematuria. We herein present a case of a patient with hematuria related to nephrocalcinosis and renal papillary varicosities. These varicosities were diagnosed and successfully treated with flexible ureteroscopy and laser fulguration.\n\n\nMETHODS\nA 24-year-old female with a history of epilepsy (on zonisamide), recent uncomplicated pregnancy, and new diagnosis of nephrocalcinosis presented with right flank pain and intermittent gross hematuria. Imaging revealed intermittent right sided hydronephrosis. A cystoscopy identified hematuria from the right ureteral orifice. Diagnostic flexible ureteroscopy revealed numerous intrapapillary renal stones and varicose veins of several renal papillae. A 200 μm holmium laser fiber was used to unroof these stones and fulgurate the varicosities with resolution of her symptoms for several months. She later presented with left-sided symptoms and underwent left ureteroscopy with similar findings and identical successful treatment.\n\n\nCONCLUSIONS\nUnilateral hematuria from discrete vascular lesions of the renal collecting system may be obscured by other benign co-existing conditions, such as nephrocalcinosis and nephrolithiasis. Although a simultaneous presentation is rare, flexible ureteroscopy with laser fulguration offers an ideal diagnostic and therapeutic modality for these concurrent conditions if symptoms arise.",
"affiliations": "University of Minnesota, 420 Delaware St. S. E., MMC 394, Minneapolis, MN, 55455, USA. cleve169@umn.edu.;University of Minnesota, 420 Delaware St. S. E., MMC 394, Minneapolis, MN, 55455, USA.",
"authors": "Cleveland|Brent|B|http://orcid.org/0000-0002-7563-8741;Borofsky|Michael|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12894-021-00931-3",
"fulltext": "\n==== Front\nBMC Urol\nBMC Urol\nBMC Urology\n1471-2490\nBioMed Central London\n\n931\n10.1186/s12894-021-00931-3\nCase Report\nSymptomatic renal papillary varicosities and medullary nephrocalcinosis\nhttp://orcid.org/0000-0002-7563-8741\nCleveland Brent cleve169@umn.edu\n\nBorofsky Michael mborofsk@umn.edu\n\ngrid.17635.36 0000000419368657 University of Minnesota, 420 Delaware St. S. E., MMC 394, Minneapolis, MN 55455 USA\n29 11 2021\n29 11 2021\n2021\n21 16427 10 2021\n23 11 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nNephrocalcinosis is often asymptomatic but can manifest with renal colic or hematuria. There is no reported association between nephrocalcinosis and renal vascular malformations, which may also be a source of hematuria. We herein present a case of a patient with hematuria related to nephrocalcinosis and renal papillary varicosities. These varicosities were diagnosed and successfully treated with flexible ureteroscopy and laser fulguration.\n\nCase presentation\n\nA 24-year-old female with a history of epilepsy (on zonisamide), recent uncomplicated pregnancy, and new diagnosis of nephrocalcinosis presented with right flank pain and intermittent gross hematuria. Imaging revealed intermittent right sided hydronephrosis. A cystoscopy identified hematuria from the right ureteral orifice. Diagnostic flexible ureteroscopy revealed numerous intrapapillary renal stones and varicose veins of several renal papillae. A 200 μm holmium laser fiber was used to unroof these stones and fulgurate the varicosities with resolution of her symptoms for several months. She later presented with left-sided symptoms and underwent left ureteroscopy with similar findings and identical successful treatment.\n\nConclusion\n\nUnilateral hematuria from discrete vascular lesions of the renal collecting system may be obscured by other benign co-existing conditions, such as nephrocalcinosis and nephrolithiasis. Although a simultaneous presentation is rare, flexible ureteroscopy with laser fulguration offers an ideal diagnostic and therapeutic modality for these concurrent conditions if symptoms arise.\n\nKeywords\n\nRenal papillary varicosity\nRenal vascular malformation\nNephrocalcinosis\nEssential hematuria\nLaser fulguration\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nNephrocalcinosis describes a condition in which calcium oxalate or calcium phosphate deposition occurs within the renal parenchyma. It is often asymptomatic and discovered incidentally on radiographic imaging. When symptoms do occur, they often include renal colic from associated nephrolithiasis or extrusion of calcium deposits into the collecting system, both of which can result in hematuria [1].\n\nThere is no reported association between nephrocalcinosis and renal vascular malformations. Although rare bilateral cases have been reported, generally these malformations are unilateral sources of hematuria. When diagnosed endoscopically, these vascular abnormalities have been classified as either discrete or diffuse lesions. Benign discrete lesions include renal hemangioma, minute venous rupture, or previously unidentified renal calculi. Although varices of the renal papillae have been categorized with MVR, there is a paucity of literature describing this unique clinical entity and its management. After obtaining informed voluntary consent from the patient, herein we describe a case of the incidental diagnosis and successful treatment of symptomatic varicosities of renal papillae in the setting of medullary nephrocalcinosis and recent pregnancy.\n\nCase presentation\n\nA 24-year-old female with a history of epilepsy (on zonisamide) and an uncomplicated pregnancy with spontaneous vaginal delivery 1 week prior presented with right flank pain and intermittent gross hematuria. Her work-up was concerning for pyelonephritis, and CT imaging revealed right hydronephrosis as well as findings consistent with medullary nephrocalcinosis. The hydronephrosis was suspected to be secondary to her recent pregnancy; however, due to concern for possible urosepsis she underwent multiple attempts at renal decompression, including placement of 2 ureteral stents and a percutaneous nephrostomy tube, all which were dislodged. Of note, during the second ureteral stent placement, right distal ureteroscopy was performed and identified blood clot within the right ureter. She was treated with culture directed antibiotics but re-presented to a tertiary center with recurrent fevers. Repeat CT imaging demonstrated persistent right hydronephrosis. Ultimately, she declined another surgical intervention and elected for conservative management with additional antibiotics.\n\nShe was later seen on an outpatient basis at which time she reported intermittent right flank pain and gross hematuria, including string-like clots suspicious for upper tract bleeding. Physical exam revealed inconsistent right CVA tenderness. Initially, a renal ultrasound demonstrated resolution of her right hydronephrosis. Over the course of several months she visited the hospital several times for these symptoms. During one such visit, repeat CT imaging showed recurrent right hydronephrosis and proximal hydroureter suggesting new obstruction. It also demonstrated stable bilateral focal nephrocalcinosis in the right upper and mid poles as well as the left lower pole (Fig. 1). Laboratory work-up included normal serum creatinine (1.02 mg/dL), bicarbonate (25 mmol/L), calcium (8.7 mmol/L), and intact parathyroid hormone (22 pg/mL). Urinalysis confirmed gross hematuria with > 182 RBC per high power field. A urine culture was negative for significant pathogenic bacterial growth. A 24-h urine collection revealed borderline low urine volume (1.89 L), normocalciuria (154 mg/day), hypocitraturia (103 mg/day), hyperoxaluria (48 mg/day), hypernatriuria (253 mmol/day), and elevated urine pH (6.9). Her zonisamide was identified as a potential contributing factor to her nephrocalcinosis, as it has been known to be associated with pharmacologically induced renal tubular acidosis, a pathophysiology capable of causing nephrocalcinosis and stone formation. The patient’s Neurologist therefore transitioned her to lamotrigine for her history of epilepsy.Fig. 1 Coronal CT image demonstrating patient’s focal nephrocalcinosis prior to treatment\n\nAfter discussion of further diagnostic and management options, the patient elected for diagnostic right ureteroscopy. Her cystoscopy was unremarkable. Right retrograde pyelogram confirmed mild right hydronephrosis but showed no filling defects. Right ureteroscopy identified no ureteral lesions but did reveal numerous intrapapillary renal stones in the upper and mid poles of the right kidney with associated varicose veins of the renal papillae (Fig. 2). A 11/13 Fr 36 cm ureteral access sheath was placed under fluoroscopic guidance. A 200 μm holmium laser fiber was introduced and on the settings of 0.8 J and 8 Hz several embedded stones estimated to be < 2 mm in size were unroofed from the papillae. Next, using the laser settings of 0.4 J and 40 Hz on a long pulse mode the varicose veins were laser fulgurated (Fig. 2). Finally, a 6 Fr × 26 cm double J ureteral stent was placed on the right. She was observed overnight to monitor for hematuria. Her ureteral stent was dislodged overnight. She experienced no clinically significant bleeding. Her pre-operative and post-operative hemoglobin values were 12.7 and 12.2, respectively. She was discharged home the day after her surgery.Fig. 2 Intra-operative photo renal papillary varices before (left) and after (right) laser fulguration\n\nThe patient was seen virtually for follow up 6 weeks later at which point she reported intermittent passage of tiny stones and complete resolution of her hematuria. A repeat renal ultrasound 9 weeks post-operatively demonstrated no hydronephrosis. A stone composition analysis revealed her renal stones were 10% calcium oxalate and 90% calcium phosphate.\n\nShe returned with left flank pain and gross hematuria about 10 weeks after her right sided treatment. CT imaging revealed a left ureteral stone and nonobstructing left renal calculi. Cystoscopy revealed isolated hematuria from the left ureteral orifice and a left sided ureteral stent was placed. She was transferred to a tertiary center where she underwent left diagnostic ureteroscopy. Nearly identical findings of embedded stones and papillary varices were discovered on the left. These were treated with laser unroofing and fulguration, respectively, with resolution of her symptoms once again.\n\nDiscussion and conclusion\n\nVaricose veins of the renal papillae have previously been described as the underlying etiology of chronic unilateral hematuria. Historically, diagnosis of such entities required radical or partial nephrectomy with subsequent pathologic examination. With the advent of endoscopic urology techniques, namely ureteroscopy, both the diagnosis and treatment of chronic unilateral hematuria was advanced such that the urologist might identify the source of bleeding in vivo. Thus, the categorization of diffuse and discrete lesions could be made more easily. Amongst the discrete lesions are MVR, which has been used as a catch-all term encompassing renal papillary varicosities. Not only was diagnosis advanced with modern endourologic techniques, but treatment was also revolutionized as surgical resection gave way to electrode fulguration and most recently laser ablation. Endoscopic techniques, predominantly flexible ureteroscopy with fulguration or laser ablation, have been shown to resolve 93% of cases of chronic unilateral hematuria with only a 10% rate of recurrence [2].\n\nNo prior case reports have demonstrated an association between nephrocalcinosis and renal papillary varicosities. Unique to this patient are the use of zonisamide and recent pregnancy prior to symptom onset. The underlying cause of renal stone formation related to zonisamide use is the inhibition of carbonic anhydrase, which leads to a renal tubular acidosis; however, rates of renal calculi formation with zonisamide are lower compared to those of other anti-epileptics, like topiramate and acetazolamide [3]. Pregnancy is known to cause renal physiologic changes that both promote renal calculi formation, such as hypercalciuria, but also counter-act it, like an increase in total urinary volume. But pregnancy also leads to systemic and renal vasodilatory changes. During pregnancy hormones such as RAAS, relaxin, and progesterone are all upregulated leading to vasodilatory effects and increased circulating blood volume [4]. This vasodilation could conceivably promote the development of renal papillary varices. The combination of these dilated blood vessels and inflammation from eroding renal calculi may explain the new onset and continuation of gross hematuria following her pregnancy.\n\nRenal papillary varicose veins are an underlying cause of chronic unilateral hematuria. On one hand, work-up for discrete vascular lesions of the renal collecting system such as varices may be obscured by other benign co-existing conditions, such as nephrocalcinosis and nephrolithiasis in this case. On the other hand, a confluence of these conditions may in fact be the source of the patient’s symptoms. Regardless, flexible ureteroscopy with laser fulguration offers an ideal diagnostic and therapeutic modality for symptomatic renal papillary varicosities.\n\nAbbreviations\n\nCVA Costovertebral angle\n\nCT Computed tomography\n\nFr French\n\nMVR Minute venous rupture\n\nRAAS Renin-angiotensin-aldosterone system\n\nRBC Red blood cells\n\nAcknowledgements\n\nNot applicable.\n\nAuthors' contributions\n\nBC and MB conceived of the case report, performed the operation, and drafted the manuscript. MB was involved in postoperative follow-up. Both authors read and approved the final manuscript.\n\nFunding\n\nThere were no sources of funding for this study.\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 consent was obtained from the patient for publication of this study.\n\nCompeting interests\n\nBrent Cleveland—none; Michael Borofsky—paid consultant for Boston Scientific and Auris Health. Member of the data safety and monitoring board for Urotronic.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Oliveira B Kleta R Bockenhauer D Genetic, pathophysiological, and clinical aspects of nephrocalcinosis Am J Physiol Renal Physiol 2016 311 1243 1252 10.1152/ajprenal.00211.2016\n2. Tanimoto R Kumon H Bagley DH Development of endoscopic diagnosis and treatment for chronic unilateral hematuria: 35 years experience J Endourol 2017 31 1 76 80 10.1089/end.2016.0747\n3. Jion YI Raff A Grosberg BM The risk and management of kidney stones from the use of topiramate and zonisamide in migraine and idiopathic intracranial hypertension Headache 2015 55 161 166 10.1111/head.12480 25486999\n4. Cheung KL Lafayette RA Renal physiology of pregnancy Adv Chronic Kidney Dis 2013 20 3 209 214 10.1053/j.ackd.2013.01.012 23928384\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2490",
"issue": "21(1)",
"journal": "BMC urology",
"keywords": "Case report; Essential hematuria; Laser fulguration; Nephrocalcinosis; Renal papillary varicosity; Renal vascular malformation",
"medline_ta": "BMC Urol",
"mesh_terms": null,
"nlm_unique_id": "100968571",
"other_id": null,
"pages": "164",
"pmc": null,
"pmid": "34844581",
"pubdate": "2021-11-29",
"publication_types": "D016428:Journal Article",
"references": "23928384;25486999;27605580;28322594",
"title": "Symptomatic renal papillary varicosities and medullary nephrocalcinosis.",
"title_normalized": "symptomatic renal papillary varicosities and medullary nephrocalcinosis"
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"abstract": "BACKGROUND\nWe present a case wherein diabetic ketoacidosis (DKA) was treated with a large amount of sodium bicarbonate and potassium chloride, resulting in the development of osmotic demyelination syndrome (ODS).\n\n\nMETHODS\nOur patient was a 29-year-old male with a history of post-surgical repair for ventricular septal defect. Upon arrival, the patient's Glasgow Coma Scale (GCS) score was E2M4V3. Laboratory examinations revealed leukocytosis, severe metabolic acidosis, hypokalemia, and hyperglycemia. His consciousness status and hemodynamics improved after resuscitation (GCS: E3M6Ve). However, they declined at the 40th hour of admission and dropped to GCS E2M2Ve. Magnetic resonance imaging revealed multifocal abnormal signal intensity changes in the whole brain stem. The diagnosis of type 1 diabetes mellitus was made during the hospitalization period. The patient exhibited improved consciousness status after 17-day medical care at the ICU.\n\n\nCONCLUSIONS\nWe recommend that in the case of DKA, the correction of hypokalemia should be prioritized during treatment. Sodium bicarbonate infusion should be reserved for pH < 6.9. In addition, close monitoring of the serum sodium level and prompt actions to lower it if it exceeds the threshold may be necessary.",
"affiliations": "Division of Critical Care, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.;Division of Critical Care, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.;Division of Critical Care, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.;Division of Critical Care, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan. garykou@gmail.com.",
"authors": "Hsieh|Hui-Chi|HC|;Wu|Shin-Hwar|SH|;Chiu|Chun-Ching|CC|;Ko|Keng-Chu|KC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s13300-019-0592-8",
"fulltext": "\n==== Front\nDiabetes Ther\nDiabetes Ther\nDiabetes Therapy\n1869-6953\n1869-6961\nSpringer Healthcare Cheshire\n\n30843157\n592\n10.1007/s13300-019-0592-8\nCase Report\nExcessive Sodium Bicarbonate Infusion May Result in Osmotic Demyelination Syndrome During Treatment of Diabetic Ketoacidosis: A Case Report\nHsieh Hui-Chi 1\nWu Shin-Hwar 1\nChiu Chun-Ching 12\nKo Keng-Chu garykou@gmail.com\n\n13\n1 0000 0004 0572 7372 grid.413814.b Division of Critical Care, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan\n2 0000 0004 0572 7372 grid.413814.b Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan\n3 0000 0004 0572 7372 grid.413814.b Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan\n6 3 2019\n6 3 2019\n4 2019\n10 2 765771\n28 1 2019\n© The Author(s) 2019\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\nIntroduction\n\nWe present a case wherein diabetic ketoacidosis (DKA) was treated with a large amount of sodium bicarbonate and potassium chloride, resulting in the development of osmotic demyelination syndrome (ODS).\n\nCase presentation\n\nOur patient was a 29-year-old male with a history of post-surgical repair for ventricular septal defect. Upon arrival, the patient’s Glasgow Coma Scale (GCS) score was E2M4V3. Laboratory examinations revealed leukocytosis, severe metabolic acidosis, hypokalemia, and hyperglycemia. His consciousness status and hemodynamics improved after resuscitation (GCS: E3M6Ve). However, they declined at the 40th hour of admission and dropped to GCS E2M2Ve. Magnetic resonance imaging revealed multifocal abnormal signal intensity changes in the whole brain stem. The diagnosis of type 1 diabetes mellitus was made during the hospitalization period. The patient exhibited improved consciousness status after 17-day medical care at the ICU.\n\nConclusions\n\nWe recommend that in the case of DKA, the correction of hypokalemia should be prioritized during treatment. Sodium bicarbonate infusion should be reserved for pH < 6.9. In addition, close monitoring of the serum sodium level and prompt actions to lower it if it exceeds the threshold may be necessary.\n\nKeywords\n\nCase report\nDiabetic ketoacidosis\nHypernatremia\nOsmotic demyelination syndrome\nSodium bicarbonate\nissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\n\nCentral pontine myelinolysis (CPM) was first described in 1959 by Adams et al. [1]. It is also known as osmotic demyelination syndrome (ODS), which includes CPM and extrapontine myelinolysis (EPM) [2]. The clinical presentation of ODS includes various neurologic symptoms including consciousness disturbance, flaccid quadriplegia, dysarthria, and dysphagia [2]. This neurologic disorder has often been associated with overly corrected hyponatremia [3]; however, other factors such as alcoholism [4], malnutrition [5], and electrolyte disturbance [4, 6] have also been described.\n\nThe pathogenesis of ODS is poorly understood [2]. However, a possible hypothesis is that the glial cells are swollen during chronic hyponatremia, and treatment with hypertonic saline creates a hypertonic state and causes shrinkage of cells. Simultaneously, substances such as cytokines and immunoglobins were released, triggering oligodendrocyte degeneration and ultimately myelin destruction [2].\n\nDiabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are diabetic emergencies that often cause electrolyte and osmolality changes, which are theoretically compatible with the etiologies of ODS. Previously, ODS was documented as the initial presentation of DKA [7]. However, osmotic fluids, such as sodium bicarbonate and potassium chloride, used in the treatment of DKA may also provide similar effects to hypertonic saline. Herein, we present a case wherein DKA was treated with a large amount of sodium bicarbonate and potassium chloride, which resulted in the development of ODS.\n\nCase presentation\n\nA 29-year-old male with a history of post-surgical repair for ventricular septal defect (VSD) contacted the emergency department of a branch hospital of Changhua Christian Hospital because of dyspnea and altered consciousness for 3 days. Symptoms of poor response to stimulations and lethargy occurred gradually. No medications or street drugs were administered. Upon arrival, the patient’s Glasgow Coma Scale (GCS) score was reported as E2M4V3; furthermore, hypotension (80/39 mmHg) and hypothermia (34.5 °C) were noted. Laboratory examinations revealed leukocytosis (15,000/μl), severe metabolic acidosis (pH: 7.04, PCO2: 11.2 mmHg, HCO3−: 3.1 mmol/l), hypokalemia (2.0 mmol/l), and hyperglycemia (646 mg/dl). Serum sodium level was 138 mmol/l unadjusted and 148 mmol/l after adjustment according to the formula of an increase of 1.6 mmol/l per 100 mg/dl of serum glucose.\n\nInitially, four ampules of sodium bicarbonate (7%, 20 ml each ampule) and one ampule of potassium chloride (20 meq) were administered. The patient was admitted to the ICU because of unstable hemodynamics. Insulin was continuously infused, and intubation was performed because of persistent hypotension and altered consciousness. Large amounts of isotonic and hypertonic intravenous fluids were administered for resuscitation (2500 ml 0.9% normal saline, 2000 ml 6% hydroxyethyl starch fluid, and 4000 ml Ringer’s solution for 24-h duration). In addition, norepinephrine and epinephrine were continuously infused. Severe hypokalemia was reported, and multiple ventricular premature complexes (VPCs) were witnessed. In total, 440 meq of potassium chloride was administered. Notably, his consciousness status (GCS: E3M6Ve) and hemodynamics improved following the resuscitation. Sequential blood sampling results are presented in Fig. 1.Fig. 1 Sequential blood sampling of the patient. a Serum sodium (Na) level. b Serum potassium (K) level. The horizontal axis represents hours after the emergency room visit. The units of Na and K are mmol/l. The Na results were corrected by the formula of an increase of 1.6 mmol/l per 100 mg/dl of serum glucose\n\nHowever, the patient’s consciousness status declined at the 40th hour of admission (GCS: E2M2Ve). Accordingly, emergent brain computed tomography was performed, and he was transferred to the medical center for magnetic resonance imaging (MRI) evaluation.\n\nMRI results revealed multifocal abnormal signal intensity changes in the whole brain stem; these lesions involved the lower midbrain, whole pons, and upper medulla oblongata. The lesions presented as faint signal on the apparent diffusion coefficient (ADC) map and brightened up on diffusion-weighted images(DWI), fluid-attenuated inversion recovery(FLAIR), and T2WI MRI images. Based on these findings, ODS was established (Fig. 2). Later, type 1 diabetes mellitus was diagnosed during the hospitalization period.Fig. 2 a–c T2-weighted fluid-attenuated inversion recovery magnetic resonance imaging (MRI) images. d–f Diffusion-weighted magnetic resonance imaging shows multifocal abnormal signal intensity change in the whole brain stem; these lesions involve the parts from the lower midbrain and whole pons to the upper medulla oblonganta\n\nThe patient exhibited improved consciousness status following 17-day medical care at the ICU; nonetheless, he was ventilator dependent and subsequently was placed in a respiratory care unit for another 25 days. Although the ventilator was gradually weaned, the patient still needed assistance and rehabilitation at the time of discharge from the hospital. The case report was approved by the institutional review board committee of Changhua Christian Hospital (reference no. 181114). Informed consent was obtained from the individual participant for being included in the study. Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.\n\nDiscussion and conclusion\n\nSeveral case reports have described the relationship between hyperglycemia and ODS [3, 8, 9]. In one such case report [8], a type 2 diabetic and cirrhotic patient presented with several neurologic symptoms following ingestion of large amounts of sugar-containing foods and was diagnosed with ODS [8]. During admission, the patient had serum sodium levels in the range of 133–144 mmol/l. The authors concluded that ODS resulted from sudden hyperglycemia. In another instance [3], a patient presented with a serum glucose level of 106 mmol/l (1908 mg/dl) that declined to 60 mmol/l (1080 mg/dl) in 6 h. The serum sodium level simultaneously elevated from 135 to 159 mmol/l. Both cases did not report hyponatremia but displayed abrupt serum osmolality changes.\n\nTreatment of DKA involves the administration of intravenous fluids, potassium supplements, and insulin [10]. A systematic review concluded that bicarbonate therapy provided no clinical advantages in the management of DKA [11]. A report suggested that bicarbonate infusion can be administered if the serum pH is < 6.9 [10 12] to justify the deleterious effect of acidemia. However, another review conducted in 2011 stated the absence of sufficient evidence to support the therapy [11]. In addition, once administered, sodium bicarbonate infusion was initially recommended at the dose of 100 mmol and later at a dose of 20 mmol for every 2 h until the serum pH was > 7.0 [12]. Furthermore, some side effects of bicarbonate therapy have been reported, including cerebral edema [13], hypokalemia, and paradoxical central nervous system acidosis [12].\n\nA case report on the association between rapid sodium bicarbonate supplement and ODS has been published [14], but not on the DKA status. The case patient, who was later diagnosed with renal tubular acidosis, was intravenously administered 480 meq sodium bicarbonate; consequently, the patient’s serum sodium increased from 142.8 to 172.8 mmol/l. The symptoms of ODS developed 6 days following the treatment.\n\nHypokalemia has been reported in association with ODS at various serum sodium levels [15, 16, 17]. Lohr et al. reported a series of cases and suggested hypokalemia to be associated with the development of ODS and correction of hypokalemia prior to the rectification of hyponatremia [15]. Koul et al. reported a case of severe hyponatremia and hypokalemia, but the correction speed of the serum sodium level did not exceed the recommendations (< 8 mmol/l in 24 h) [16]. In 2003, Sugimoto et al. reported a case of anorexia nervosa with a normal serum sodium level (140 mmol/l) and hypokalemia (2.8 mmol/l) [17]. Fluctuation of the serum potassium level was documented.\n\nThe underlying mechanism through which serum hypokalemia influences the development of ODS is still unclear. Lohr et al. proposed a theory suggesting that a decreased NaK-ATPase level during hypokalemia predisposes the cell to osmotic stress injury [15].\n\nIn our case, there were several possible insults related to ODS: (1) development of DKA and dehydration; (2) a large quantity of sodium supplement (including sodium bicarbonate), which exceeded the suggested doses and enormous amounts of hypertonic fluid resuscitation; (3) serum hypokalemia, followed by a large volume of potassium chloride infusion. Whether the DKA status or sodium supplement was the main cause of ODS remains unclear. The DKA status may have caused cell shrinkage, as mentioned above. However, although the patient had altered consciousness at the time of presentation, his consciousness status improved subsequently. The initial resuscitation may have helped in enhancing tissue perfusion and subsequently the consciousness level. Hence, it is more likely that ODS developed during the following hospital courses. A large amount of osmotic electrolyte supplementation may have played a causative role.\n\nWe often encounter severe metabolic acidosis status in the emergency room setting or ICU, and sodium bicarbonate infusion is considered an important initial treatment to correct the acid-base status. In our case, a total of 30 ampules of sodium bicarbonate was administered over a 16-h period. The sodium content of these fluids was 510 meq, which was equal to that of 1 l of 3% sodium chloride. Frequent VPCs and hypotension also interfered with the clinician’s decision. First-line clinicians may attribute this status to severe hypokalemia and acidosis and liberally prescribe sodium bicarbonate and potassium supplements, with the expectation of correcting the electrolyte disturbance as early as possible. However, osmotic changes caused by sodium bicarbonate and potassium chloride remain unaddressed.\n\nIt is widely known that ODS is often linked to the rapid correction of hyponatremia, and intensive monitoring of the serum sodium level has been suggested for ODS [18, 19]. Nevertheless, in the clinical setting of DKA, only potassium monitoring has been highlighted [12]. Our case implies that not only potassium but also sodium levels must be monitored carefully in the first few hours of resuscitation and that clinicians should be aware of the possibility of a rapid increase in the serum sodium level. In life-threatening conditions, potassium supplements should primarily be administered as indicated by a previous report [12]. The use of sodium bicarbonate should be refrained until the serum pH decreases to < 6.9.\n\nDKA with concurrent hypokalemia, arrhythmia, and unstable hemodynamics could be quite challenging for clinicians. The correction of hypokalemia should receive priority during treatments. Sodium bicarbonate infusion should be reserved for pH < 6.9. Close monitoring of the serum sodium level and prompt actions to lower it if it exceeds the threshold may be necessary.\n\nAcknowledgements\n\nWe thank the participants of the study.\n\nFunding\n\nNo funding or sponsorship was received for this study or publication of this article. The article processing charges were funded by the authors.\n\nAuthors\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nAuthors' contributions\n\nHCH was involved in patient care, writing, imaging, and laboratory data gathering. KCK was involved in writing and giving academic suggestions regarding nephrology, including hyponatremia and its management. SHW was involved in patient care and data gathering and suggestions of clinical problems encountered. CCC was involved in suggestions for the discussion, neurologic consultation, and image interpretation.\n\nDisclosures\n\nHui-Chi Hsieh, Shin-Hwar Wu, Chun-Ching Chiu, and Keng-Chu Ko have nothing to disclose.\n\nCompliance with Ethics Guidelines\n\nThe case report was approved by the institutional review board committee of Changhua Christian Hospital. The reference no. is 181114. Informed consent was obtained from the individual participant for being included in the study. Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.\n\nData Availability\n\nThe data that support the findings of this case were kept confidential for patient privacy.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\n\nEnhanced Digital Features\n\nTo view enhanced digital features for this article go to 10.6084/m9.figshare.7770347.\n==== Refs\nReferences\n\n1. Adams RD Victor M Mancall EL Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholic and malnourished patients AMA Arch Neurol Psychiatry. 1959 81 154 172 10.1001/archneurpsyc.1959.02340140020004 13616772\n2. Dagur G Khan SA Current concepts in pontine myelinolysis: review of literature Transl Biomed 2015 6 4\n3. O'Malley G Moran C Draman MS King T Smith D Central pontine myelinolysis complicating treatment of the hyperglycaemic hyperosmolar state Ann Clin Biochem. 2008 45 440 443 10.1258/acb.2008.007171 18583636\n4. Bähr M Sommer N Petersen D Wiethölter H Dichgans J Central pontine myelinolysis associated with low potassium levels in alcoholism J Neurol. 1990 237 275 276 10.1007/BF00314635 2391553\n5. King J Rosner M Osmotic demyelination syndrome Am J Med Sci. 2010 339 561 567 10.1097/MAJ.0b013e3181d3cd78 20453633\n6. Turnbull J Lumsden D Siddiqui A Lin J Lim M Osmotic demyelination syndrome associated with hypophosphataemia: 2 cases and a review of literature Acta Paediatr. 2013 102 e164 e168 10.1111/apa.12143 23278861\n7. Rodríguez-Velver KV Soto-Garcia AJ Zapata-Rivera MA Montes-Villarreal J Villarreal-Pérez JZ Rodríguez-Gutiérrez R Osmotic demyelination syndrome as the initial manifestation of a hyperosmolar hyperglycemic state Case Rep Neurol Med. 2014 2014 1 5 10.1155/2014/381480\n8. Pliquett RU Noll A Ibe R Katz A Ackmann C Schreiber A Hyperglycemia-related central pontine demyelinization after a binge-eating attack in a patient with type-2 diabetes: a case report BMC Endocr Disord. 2018 18 18 10.1186/s12902-018-0245-3 29530008\n9. Burns J Kosa S Wijdicks E Central pontine myelinolysis in a patient with hyperosmolar hyperglycemia and consistently normal serum sodium Neurocrit Care. 2009 11 251 254 10.1007/s12028-009-9241-9 19565358\n10. Umpierrez G Korytkowski M Diabetic emergencies—ketoacidosis, hyperglycaemic hyperosmolar state and hypoglycaemia Nat Rev Endocrinol. 2016 12 222 232 10.1038/nrendo.2016.15 26893262\n11. Chua H Schneider A Bellomo R Bicarbonate in diabetic ketoacidosis—a systematic review Ann Intensive Care. 2011 1 1 12 10.1186/2110-5820-1-23 21906322\n12. Kitabchi A Umpierrez G Miles J Fisher J Hyperglycemic crises in adult patients with diabetes Diabetes Care 2009 32 1335 1343 10.2337/dc09-9032 19564476\n13. Glaser N Barnett P McCaslin I Nelson D Trainor J Louie J Risk factors for cerebral edema in children with diabetic ketoacidosis. The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics N Engl J Med 2001 344 264 9 10.1056/NEJM200101253440404 11172153\n14. Chang KY Lee IH Kim GJ Cho K Park HS Kim HW Plasma exchange successfully treats central pontine myelinolysis after acute hypernatremia from intravenous sodium bicarbonate therapy BMC Nephrol. 2014 15 56 10.1186/1471-2369-15-56 24708786\n15. Lohr J Osmotic demyelination syndrome following correction of hyponatremia: association with hypokalemia Am J Med. 1994 96 408 413 10.1016/0002-9343(94)90166-X 8192171\n16. Koul PA Khan UH Jan RA Shah S Qadri AB Wani B Osmotic demyelination syndrome following slow correction of hyponatremia: possible role of hypokalemia Indian J Crit Care Med. 2013 2013 17 231 233\n17. Sugimoto T Murata T Omori M Wada Y Central pontine myelinolysis associated with hypokalaemia in anorexia nervosa J Neurol Neurosurg Psychiatry. 2003 74 353 355 10.1136/jnnp.74.3.353 12588925\n18. Spasovski G Vanholder R Allolio B Annane D Ball S Bichet D Clinical practice guideline on diagnosis and treatment of hyponatraemia Eur J Endocrinol. 2014 170 G1 47 10.1530/EJE-13-1020 24569125\n19. Verbalis JG Goldsmith SR Greenberg A Korzelius C Schrier RW Sterns RH Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations Am J Med. 2013 126 S1 42 10.1016/j.amjmed.2013.07.006 24074529\n\n",
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"issue": "10(2)",
"journal": "Diabetes therapy : research, treatment and education of diabetes and related disorders",
"keywords": "Case report; Diabetic ketoacidosis; Hypernatremia; Osmotic demyelination syndrome; Sodium bicarbonate",
"medline_ta": "Diabetes Ther",
"mesh_terms": null,
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"pages": "765-771",
"pmc": null,
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"pubdate": "2019-04",
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"title": "Excessive Sodium Bicarbonate Infusion May Result in Osmotic Demyelination Syndrome During Treatment of Diabetic Ketoacidosis: A Case Report.",
"title_normalized": "excessive sodium bicarbonate infusion may result in osmotic demyelination syndrome during treatment of diabetic ketoacidosis a case report"
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"abstract": "To evaluate the renoprotective effects of canagliflozin, we assessed the albuminuria-lowering effect in Japanese type 2 diabetes patients with chronic kidney disease (CKD).\n\n\n\nIn this prospective, open-label, parallel-group study, type 2 diabetes patients with CKD were randomized to receive either oral canagliflozin (100 mg/day) or usual care (control group) for 52 weeks. Endpoints included changes in urinary albumin-to-creatinine ratio (UACR), other urinary biomarkers, laboratory parameters, and adverse events.\n\n\n\nBoth groups included 20 patients in the analysis. Mean changes in UACR was -83 (-266 to -31) mg/gCr and 27 (-11 to 131) mg/gCr, in the canagliflozin and control groups, respectively ( p = 0.004). Urinary liver-type free acid binding protein, N-acetyl-β-d-glucosaminidase, and β2-microglobulin levels were also significantly decreased in the canagliflozin group, but not in the control group. Mean change in estimated glomerular filtration rate at the end of the study was 0.7 and -3.4 mL/min/1.73 m2 in the canagliflozin and control group, respectively ( p = 0.024). Canagliflozin treatment led to improvement of glycaemic control and reduction in body weight, blood pressure, and liver transaminase. There were no adverse events associated with canagliflozin.\n\n\n\nCanagliflozin was associated with slower progression of kidney disease and reduction in albuminuria and tubulointerstitial markers in diabetes patients with CKD.",
"affiliations": "Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.",
"authors": "Takashima|Hiroyuki|H|;Yoshida|Yoshinori|Y|;Nagura|Chinami|C|;Furukawa|Tetsuya|T|;Tei|Ritsukou|R|;Maruyama|Takashi|T|;Maruyama|Noriaki|N|;Abe|Masanori|M|0000-0002-9156-5415",
"chemical_list": "D015415:Biomarkers; D001786:Blood Glucose; C493319:FABP1 protein, human; D050556:Fatty Acid-Binding Proteins; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D001613:beta 2-Microglobulin; D000068896:Canagliflozin; D000118:Acetylglucosaminidase",
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"issue": "15(5)",
"journal": "Diabetes & vascular disease research",
"keywords": "Albuminuria; canagliflozin; chronic kidney disease; type 2 diabetes",
"medline_ta": "Diab Vasc Dis Res",
"mesh_terms": "D000118:Acetylglucosaminidase; D000368:Aged; D000419:Albuminuria; D015415:Biomarkers; D001786:Blood Glucose; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2; D003928:Diabetic Nephropathies; D018450:Disease Progression; D050556:Fatty Acid-Binding Proteins; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007004:Hypoglycemic Agents; D007564:Japan; D007668:Kidney; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013997:Time Factors; D016896:Treatment Outcome; D001613:beta 2-Microglobulin",
"nlm_unique_id": "101234011",
"other_id": null,
"pages": "469-472",
"pmc": null,
"pmid": "29923427",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Renoprotective effects of canagliflozin, a sodium glucose cotransporter 2 inhibitor, in type 2 diabetes patients with chronic kidney disease: A randomized open-label prospective trial.",
"title_normalized": "renoprotective effects of canagliflozin a sodium glucose cotransporter 2 inhibitor in type 2 diabetes patients with chronic kidney disease a randomized open label prospective trial"
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"abstract": "OBJECTIVE\nAcute pulmonary edema is a rare complication in women with preeclampsia especially at advanced maternal age. We aimed to determine the cardiovascular hemodynamics in advanced maternal age women who developed acute pulmonary edema and preeclampsia.\n\n\nMETHODS\nRetrospective cohort study of women aged over 45 years giving birth at single university affiliated tertiary medical center which developed acute pulmonary edema due to severe preeclampsia. Clinical features were identified in order to predict and potentially prevent this severe complication of pregnancy.\n\n\nMETHODS\nAdvanced maternal age women who developed acute pulmonary edema due to preeclampsia.\n\n\nRESULTS\nOverall, during the study period 90,540 women delivered in our hospital, of them, 540 women (0.6%) above the age of 45 years gave birth. Of those, 67 women (12.4%) had preeclampsia in which 4 women (6%) were complicated with acute pulmonary edema. The common clinical relevant characteristics for all four women were: preterm delivery by cesarean section for preeclampsia with severe features, non-restrictive fluid management around the time of delivery, post-partum pain control medication with non-steroidal anti-inflammatory drug, blood pressure stabilization with oral labetalol and a sudden hemodynamic deterioration to hypertensive crisis and pulmonary edema between post-operative days 4-9.\n\n\nCONCLUSIONS\nAlthough the precise trigger for the sudden presentation of acute pulmonary edema remains unknown, we suggest that there is a multi-factorial combination of etiologies that are common to women of advanced maternal age and women with preeclampsia that could have contributed to the development of pulmonary edema.",
"affiliations": "Lis Hospital for Women, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: maya3000@gmail.com.;Lis Hospital for Women, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Division of Anesthesia and Critical Care and Pain, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Cardiology Division, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Lis Hospital for Women, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Lis Hospital for Women, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Lis Hospital for Women, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"authors": "Ram|Maya|M|;Anteby|Matan|M|;Weiniger|Carolyn F|CF|;Havakuk|Ofer|O|;Gilboa|Itamar|I|;Shenhav|Michael|M|;Yogev|Yariv|Y|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.1016/j.preghy.2021.05.019",
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"issn_linking": "2210-7789",
"issue": "25()",
"journal": "Pregnancy hypertension",
"keywords": "Advanced maternal age; Endothelial dysfunction; Hypertensive crisis; Preeclampsia; Pulmonary edema",
"medline_ta": "Pregnancy Hypertens",
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"pages": "150-155",
"pmc": null,
"pmid": "34144403",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Acute pulmonary edema due to severe preeclampsia in advanced maternal age women.",
"title_normalized": "acute pulmonary edema due to severe preeclampsia in advanced maternal age women"
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"companynumb": "IL-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-335772",
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"activesubstancename": "AMLODIPINE BESYLATE"
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"abstract": "The real-world data for the effectiveness and safety of sofosbuvir/ledipasvir (SOF/LDV) with or without ribavirin (RBV) in patients with hepatitis C virus genotype 1 (HCV-1) infection remain limited in Taiwan.\n\n\n\nA total of 273 chronic HCV-1 patients receiving 8, 12, or 24 weeks of SOF/LDV with or without RBV were enrolled. The sustained virologic response rate at week 12 off-therapy (SVR12) by evaluable population (EP) and per-protocol population (PP) were assessed for effectiveness. The treatment discontinuation rate due to adverse events (AEs) and serious AE rate were assessed for safety. Baseline patient characteristics and on-treatment HCV viral kinetics associated with SVR12 were analyzed.\n\n\n\nThe SVR12 rates by EP and PP analyses were 96.7% (95% confidence interval [CI]: 93.9%-98.3%) and 97.5% (95% CI: 94.8%-98.8%), respectively. The rates of treatment discontinuation due to AE and serious AE were 0.4% and 4.4%, respectively. Seven patients with true virologic failure were relapsers. In 2 patients who were lost-to follow-up, one expired at treatment week 3 due to pneumonia which was considered not related to treatment, and one declined follow-up at off-therapy week 4. The SVR12 rates were comparable in terms of baseline patient characteristics and viral decline at week 4 of treatment.\n\n\n\nSOF/LDV with or without RBV for 8-24 weeks is well tolerated and achieves a high SVR12 rate in patients with HCV-1 infection in Taiwan.",
"affiliations": "Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.",
"authors": "Liu|Chen-Hua|CH|;Liu|Chun-Jen|CJ|;Su|Tung-Hung|TH|;Yang|Hung-Chih|HC|;Hong|Chun-Ming|CM|;Tseng|Tai-Chung|TC|;Chen|Pei-Jer|PJ|;Chen|Ding-Shinn|DS|;Kao|Jia-Horng|JH|0000-0002-2442-7952",
"chemical_list": "D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; C000595958:ledipasvir, sofosbuvir drug combination; D012254:Ribavirin; D014542:Uridine Monophosphate; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0209299",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0209299PONE-D-18-31141Research ArticleBiology and life sciencesOrganismsVirusesRNA virusesFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensFlavivirusesHepacivirusHepatitis C virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesOrganismsVirusesViral pathogensFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensHepatitis virusesHepatitis C virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensHepatitis virusesHepatitis C virusBiology and life sciencesOrganismsVirusesViral pathogensHepatitis virusesHepatitis C virusMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesCirrhosisBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesInfectious DiseasesCo-InfectionsMedicine and Health SciencesSurgical and Invasive Medical ProceduresDigestive System ProceduresLiver TransplantationMedicine and Health SciencesSurgical and Invasive Medical ProceduresTransplantationOrgan TransplantationLiver TransplantationBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensHepatitis virusesHepatitis B virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensHepatitis virusesHepatitis B virusBiology and life sciencesOrganismsVirusesViral pathogensHepatitis virusesHepatitis B virusMedicine and Health SciencesOncologyCancers and NeoplasmsCarcinomasHepatocellular CarcinomaMedicine and Health SciencesOncologyCancers and NeoplasmsGastrointestinal TumorsHepatocellular CarcinomaMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesHepatocellular CarcinomaMedicine and Health SciencesSurgical and Invasive Medical ProceduresTransplantationOrgan TransplantationRenal TransplantationMedicine and Health SciencesSurgical and Invasive Medical ProceduresUrinary System ProceduresRenal TransplantationReal-world effectiveness and safety of sofosbuvir and ledipasvir with or without ribavirin for patients with hepatitis C virus genotype 1 infection in Taiwan SOF/LDV for HCV-1 in TaiwanLiu Chen-Hua ConceptualizationData curationFormal analysisInvestigationMethodologyWriting – original draftWriting – review & editing123Liu Chun-Jen Data curationInvestigationWriting – review & editing124Su Tung-Hung Data curationInvestigationWriting – review & editing12Yang Hung-Chih Data curationInvestigationWriting – review & editing125Hong Chun-Ming Data curationInvestigationWriting – review & editing1Tseng Tai-Chung Data curationInvestigationWriting – review & editing12Chen Pei-Jer Data curationInvestigationWriting – review & editing124Chen Ding-Shinn Data curationInvestigationWriting – review & editing126http://orcid.org/0000-0002-2442-7952Kao Jia-Horng ConceptualizationData curationFormal analysisInvestigationMethodologyProject administrationSupervisionWriting – original draftWriting – review & editing124*1 \nDepartment of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan2 \nHepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan3 \nDepartment of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliou, Taiwan4 \nGraduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan5 \nDepartment of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan6 \nGenomics Research Center, Academia Sinica, Taipei, TaiwanKanda Tatsuo EditorNihon University School of Medicine, JAPANCompeting Interests: Chen-Hua Liu: advisory board for Abbvie, Gilead Science, Merck Sharp & Dohme; speaker’s bureau for Abbott, Abbvie, Gilead Science, Merck Sharp & Dohme; research grant from Abbvie, Gilead Science, Merck Sharp & Dohme. Jia- Horng Kao: advisory board for Abbott, Abbvie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche; speaker’s bureau for Abbott, Abbvie, Bayer, Bristol-Myers Squibb, Gilead Science, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche. Ding-Shinn Chen: advisory board for Abbvie, Gilead Science, GlaxoSmithKline, Merck Sharp & Dohme, Novartis. Pei-Jer Chen: advisory board for Abbvie, Novartis, Roche. All other authors declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.\n\n* E-mail: kaojh@ntu.edu.tw21 12 2018 2018 13 12 e020929928 10 2018 3 12 2018 © 2018 Liu et al2018Liu et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nThe real-world data for the effectiveness and safety of sofosbuvir/ledipasvir (SOF/LDV) with or without ribavirin (RBV) in patients with hepatitis C virus genotype 1 (HCV-1) infection remain limited in Taiwan.\n\nMethods\nA total of 273 chronic HCV-1 patients receiving 8, 12, or 24 weeks of SOF/LDV with or without RBV were enrolled. The sustained virologic response rate at week 12 off-therapy (SVR12) by evaluable population (EP) and per-protocol population (PP) were assessed for effectiveness. The treatment discontinuation rate due to adverse events (AEs) and serious AE rate were assessed for safety. Baseline patient characteristics and on-treatment HCV viral kinetics associated with SVR12 were analyzed.\n\nResults\nThe SVR12 rates by EP and PP analyses were 96.7% (95% confidence interval [CI]: 93.9%-98.3%) and 97.5% (95% CI: 94.8%-98.8%), respectively. The rates of treatment discontinuation due to AE and serious AE were 0.4% and 4.4%, respectively. Seven patients with true virologic failure were relapsers. In 2 patients who were lost-to follow-up, one expired at treatment week 3 due to pneumonia which was considered not related to treatment, and one declined follow-up at off-therapy week 4. The SVR12 rates were comparable in terms of baseline patient characteristics and viral decline at week 4 of treatment.\n\nConclusions\nSOF/LDV with or without RBV for 8–24 weeks is well tolerated and achieves a high SVR12 rate in patients with HCV-1 infection in Taiwan.\n\nThe authors received no specific funding for this work. Data AvailabilityAll relevant data are within the manuscript and its Supporting Information file.Data Availability\nAll relevant data are within the manuscript and its Supporting Information file.\n==== Body\nIntroduction\nHepatitis C virus (HCV) infection is a challenging health problem which affects approximately 71.1 million people worldwide [1]. Over a period of 20–30 years, about 20% of chronic HCV-infected patients will evolve to cirrhosis which may progress to hepatic decompensation and hepatocellular carcinoma (HCC) [2,3]. Apart from the liver-related morbidity and mortality, HCV infection may also induce extra-hepatic manifestations which adversely affects the patients’ health outcome and quality of life [4]. On the other hand, the prognosis is improved once patients achieve sustained virologic response (SVR) following anti-HCV agents [5–8]. Currently, HCV genotype 1 (HCV-1) infection is predominant around the world [9]. Compared to patients with non-HCV-1 infection, those with HCV-1 infection have an increased risk of cirrhosis and HCC [10,11]. Therefore, an effective and safe HCV treatment strategy, particularly for patients with HCV-1infection, is mandatory.\n\nThe introduction of interferon (IFN)-free direct acting antiviral agents (DAAs) has revolutionized the care of HCV infection. Sofosbuvir (SOF) is a pyrimidine nucleotide analogue that inhibits the HCV non-structural protein 5B (NS5B) ribonucleic acid (RNA)-dependent RNA polymerase. After intra-hepatic metabolism, the active uridine triphosphate form is incorporated to HCV RNA by NS5B polymerase and acts as the chain terminator [12]. Clinically, SOF is administered once-daily with pangenotypic potency, excellent tolerability, high genetic barriers to drug resistance, and few potential drug-drug interactions (DDIs). Currently, SOF can be used with ledipasvir (LDV) as a formula of fixed-dose combination which is active against HCV-1, 4, 5 or 6 infection. The efficacy and safety of SOF/LDV with or without RBV for 8–24 weeks for ordinary HCV-1 patients are excellent in phase III trials [13–16]. Furthermore, the therapeutic profiles remain excellent among patients with human immunodeficiency virus (HIV) coinfection, decompensated cirrhosis, or organ transplantation [17–21]. Therefore, SOF/LDV-based regimens for HCV-1 patients are appealing to most health care providers.\n\nRegarding to the real-world effectiveness and safety of SOF/LDV with or without RBV for HCV-1 patients, data from Western and Eastern countries showed that the SVR rates ranged from 92%-98% and most patients tolerated the treatment well [22–26]. On the basis of these encouraging results, we aimed to evaluate the real-world performance of SOF/LDV with or without RBV for HCV-1 patients in Taiwan.\n\nMaterials and methods\nPatients\nBetween April 2015 and August 2017, HCV-1 infected patients who received SOF/LDV for 8, 12 or 24 weeks with or without ribavirin (RBV) were retrospectively enrolled at the National Taiwan University Hospital (NTUH) and NTUH Yun-Lin Branch. All patients were aged ≥ 20 years and had chronic HCV infection, defined as detectable HCV antibody (anti-HCV; Abbott HCV EIA 2.0, Abbott Laboratories, Abbott Park, Illinois, USA) and quantifiable serum HCV RNA (Cobas TaqMan HCV Test v2.0, Roche Diagnostics GmbH, Mannheim, Germany, lower limit of detection [LLOD]: 15 IU/mL) for ≥ 6 months. Patients who had non-HCV-1 infection, had prior DAA exposure, had active HCC, had estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2, received treatment regimens outside the guideline recommendation, or refused to provide written informed consent were excluded from the study [27–29]. The study was approved by the NTUH Research Ethics Committee (201205058RIC) and was conducted in accordance with the principles of Declaration of Helsinki and the International Conference on Harmonization for Good Clinical Practice. All patients provided written informed consent before the study.\n\nStudy design\nBaseline patient demographics, hemogram, serum biochemical data (albumin, total bilirubin, aspartate aminotransferase [AST], alanine aminotransferase [ALT], creatinine, eGFR, as calculated by modification of diet in renal disease (MDRD) equation, anti-HCV, hepatitis B virus (HBV) surface antigen (Abbott Architect HBsAg qualitative assay, Abbott Laboratories, Abbott Park, Illinois, USA), HCV RNA, HCV genotype (Abbott RealTime HCV Genotype II, Abbott Laboratories, Abbott Park, Illinois, USA) and anti-HIV (Abbott Architect HIV Ag/Ab Combo, Abbott Laboratories, Abbott Park, Illinois, USA) were collected [30]. The status of cirrhosis was determined by liver biopsy, clinical signs of portal hypertension, imaging studies, AST-to-platelet ratio index (ARPI) with a cutoff value of > 2.0 or liver stiffness measurement (LSM, FibroScan, Echosens, Paris, France) with a cutoff value of > 12.5 kPa when appropriate [31,32]. The stage of cirrhosis was graded by Child-Pugh score. Baseline serum HBV DNA (Cobas AmpliPrep/Cobas Taqman HBV test v.2.0, Roche Diagnostics GmbH, Mannheim, Germany, LLOD: 20 IU/mL) or HIV RNA (Cobas AmpliPrep/Cobas Taqman HIV-1 test v.2.0, Roche Diagnostics GmbH, Mannheim, Germany, LLOD: 20 copies/mL) level was determined for patients with HBV or HIV coinfection [33].\n\nPatients received fixed-dose combination of SOF/LDV (400mg/90mg, Harvoni, Gilead Sciences, Carrigtohill, Co. Cork, Ireland) 1 tablet per day for 8, 12 or 24 weeks. Treatment-naïve, non-cirrhotic patients with baseline HCV RNA level < 6,000,000 IU/mL can receive 8 or 12 weeks of SOF/LDV treatment. Patients with compensated cirrhosis (Child-Pugh A) can receive 12 weeks of SOF/LDV with or without weight-based RBV (Robatrol, 200 mg capsule, Genovate Biotechnology Co. Ltd., Hsinchu, Taiwan; 1,200 mg per day if the body weight ≥ 75 kg; 1,000 mg per day if the body weight < 75 kg) or 24 weeks of SOF/LDV at the discretion of the physicians. Patients who had decompensated cirrhosis (Child-Pugh B or C) or had undergone liver transplantation can receive 12 weeks of SOF/LDV with weight-based RBV or 24 weeks of SOF/LDV. For patients with baseline eGFR between 30–50 mL/min/1.73m2, the RBV was adjusted to 200 mg/400 mg per day at alternative dosage.\n\nEffectiveness\nPatients received on-treatment serum HCV RNA monitoring at week 4 and at the end of treatment (EOT). Furthermore, they received off-therapy serum HCV RNA testing at week 12 to assess SVR12. Patients were considered failure to achieve SVR12 if they lacked SVR12 data. We adopted two different endpoints for effectiveness: the evaluable population (EP) which assessed the SVR12 for patients who received at least one dosage of treatment, and the per-protocol population (PP) which assessed the SVR12 by excluding non-SVR12 patients due to non-virologic failure.\n\nSafety\nThe rate of treatment completion was assessed for all patients. The reasons for patients who prematurely discontinued treatment or were lost-to follow-up were assessed through the chart review. The on-treatment constitutional and laboratory adverse events (AEs), and serious AEs were also evaluated. In patients who were seropositive for HBsAg, serum HBV DNA levels were evaluated after the initiation of DAA treatment. HBV reactivation was defined as the presence of HBV DNA level ≥ LLOD in patients with baseline HBV DNA level < LLOD, or increase of HBV DNA level > 1 log10 IU/mL in patients with baseline HBV DNA level ≥ LLOD [34]. HBV-associated hepatitis was defined as HBV reactivation and hepatitis flare presenting with ALT increase ≥ 3 times baseline and > 100 U/L [35].\n\nStatistical analysis\nAll analyses were performed using Statistical Program for Social Sciences (SPSS Statistics Version 23.0, IBM Corp., Armonk, New York, USA). The baseline characteristics were shown in median (range) and numbers (percentages) when appropriate. The rates of antiviral response were shown in numbers (percentages) with 95% confidence interval (CI) and the AE rates were shown in numbers (percentages). The stratified analysis of SVR12 by EP analysis for baseline characteristics and week 4 viral decline were assessed and shown in percentages with 95% CI.\n\nResults\nPatient characteristics\nOf 320 HCV-infected patients receiving SOF/LDV with or without RBV, 47 were excluded from the study because of non-HCV-1 infection, prior DAA exposure, active HCC, eGFR < 30 mL/min/1.73m2, receiving antiviral regimens not recommended by guidelines, or refusal to provide informed consent. The remaining 273 patients were eligible for the analysis (Fig 1). Table 1 shows the baseline patient characteristics. One hundred twenty-seven (46.5%) patients were male and 182 (66.7%) were treatment-naïve. Nine (3.3%) and 13 (4.8%) patients had HBV and HIV coinfection, respectively. Twenty-six (9.5%) and 13 (4.8%) patients underwent liver and renal transplantation, respectively. Among the 88 (32.2%) patients receiving RBV, all received treatment for 12 weeks, including 25 who underwent liver transplantation (one with decompensated cirrhosis), 25 with decompensated cirrhosis (one who underwent liver transplantation), and 39 with compensated cirrhosis (37 with prior IFN-based treatment). All patients who underwent renal transplantation were treatment-naïve and received SOF/LDV for 12 weeks. One decompensated cirrhotic, one treatment-naïve compensated cirrhotic, and one liver transplantation patients received SOF/LDV for 24 weeks. With regard to HCV subgenotype distribution, 21 (7.7%), 242 (88.6%) and 10 (3.7) patients had HCV-1a, HCV-1b, and unsubtypable HCV-1 infections. One hundred thirty-eight (50.5%) patients were non-cirrhotic. Among the 135 cirrhotic patients, 109 (80.7) and 26 (19.3%) of them had compensated and decompensated cirrhosis, respectively. Seven (77.8%) and 12 (92.3%) patients with HBV or HIV coinfection had baseline undetectable serum HBV DNA or HIV RNA.\n\n10.1371/journal.pone.0209299.g001Fig 1 Study flow.\n10.1371/journal.pone.0209299.t001Table 1 Baseline patient characteristics.\nCharacteristics*\tPatient (N = 273)\t\nAge, year, median (range)\t64 (29–86)\t\nAge ≥ 60 years\t188 (68.9)\t\nMale\t127 (46.5)\t\nTreatment-naive\t182 (66.7)\t\nHBV coinfection\t9 (3.3)\t\nHIV coinfection\t13 (4.8)\t\nPrior history of HCC\t57 (20.9)\t\nLiver transplantation\t26 (9.5)\t\nRenal transplantation\t13 (4.8)\t\nTreatment duration, week\t\t\n 8 weeks\t5 (1.8)\t\n 12 weeks\t265 (97.1)\t\n 24 weeks\t3 (1.1)\t\nRBV usage\t88 (32.2)\t\nHemoglobin, g/dL, median (range)\t13.5 (7.7–17.6)\t\nWhite cell count, 109\ncells/L, median (range)\t4.9 (1.9–12.5)\t\nPlatelet count, 109\ncells/L, median (range)\t136 (33–433)\t\nAlbumin, g/dL, median (range)\t4.1 (2.1–5.0)\t\nTotal bilirubin, mg/dL, median (range)\t0.8 (0.3–8.8)\t\nAST, ULN, median (range)\t1.7 (0.3–8.5)\t\nALT, ULN, median (range)\t1.7 (0.3–10.6)\t\nCreatinine, mg/dL, median (range)\t0.8 (0.4–2.1)\t\neGFR, mL/min/1.73m2, median (range)\n†\t84 (32–186)\t\neGFR < 60 mL/min/1.73m2\n†\t52 (19.0)\t\nHCV RNA, log10\nIU/mL, median (range)\t6.17 (2.85–7.69)\t\nHCV RNA > 6,000,000 IU/mL\t48 (17.6)\t\nHCV genotype\t\t\n 1a\t21 (7.7)\t\n 1b\t242 (88.6)\t\n 1‡\t10 (3.7)\t\nCirrhosis\t\t\n Absent\t138 (50.5)\t\n Present\t135 (49.5)\t\n Child-Pugh A\t109 (80.7)\t\n Child-Pugh B and C\t26 (19.3)\t\nHBV: hepatitis B virus; HIV: human immunodeficiency virus; HCC: hepatocellular carcinoma; RBV: ribavirin; AST: aspartate aminotransferase; ALT: alanine aminotransferase; ULN: upper limit of normal; eGFR: estimated glomerular filtration rate.\n\n* Values are numbers (percentages) unless otherwise indicated.\n\n† eGFR was calculated by MDRD equation.\n\n‡ Failed subtyping for major genotyping.\n\nEffectiveness\nOf the 272 patients with available HCV RNA data at week 4 of treatment, 218 (80.2%) of them had undetectable serum HCV RNA. All 272 (100%) patients with available HCV RNA data had undetectable HCV RNA at EOT. One Child-Pugh C cirrhotic patient receiving SOF/LDV with RBV died at treatment week 3 did not receive HCV RNA testing at week 4 and EOT. The overall SVR12 rates were 96.7% (264 of 273 patients; 95% CI: 93.9%-98.3%) by EP analysis, and 97.5% (264 of 271 patients; 95% CI: 94.8%-98.8%) by PP analysis (Table 2).\n\n10.1371/journal.pone.0209299.t002Table 2 Virologic responses.\nHCV RNA < LLOD\tPatient (N = 273)\t\nn/N (%)\t95% CI\t\nDuring treatment\t\t\t\n Week 4*\t218/272 (80.2)\t75.0–84.5\t\n EOT*\t272/272 (100)\t98.6–100\t\nAfter treatment\t\t\t\n SVR12 (EP)†\t264/273 (96.7)\t93.9–98.3\t\n SVR12 (PP)‡\t264/271 (97.5)\t94.8–98.8\t\nReason for non-SVR12, n\t\t\t\n Relapse\t7\t\t\n Lost to follow-up\t2\t\t\n During treatment\t1\t\t\n After treatment\t1\t\t\nLLOD: lower limit of detection; EOT: end-of-treatment; EP: evaluate population; PP: per-protocol population; CI: confidence interval.\n\n* One patient who expired at treatment week 3 did not have week 4 and EOT HCV RNA data.\n\n† Patients who received at least one dosage of treatment were included in the analysis.\n\n‡ Patients with non-virologic failure were excluded from the analysis.\n\nAmong patients who failed to achieved SVR12, 7 (2.6%) were relapsers and 2 (0.7%) were lost to follow-up. Among the relapser, 5 (71.4%) were female, 6 (85.7%) were treatment-naïve, 4 (57.1%) had cirrhosis and all received SOF/LDV with or without RBV for 12 weeks. In 2 patients who were lost to follow-up, one died of pneumonia at treatment week 3, and the other one declined follow-up at post-treatment week 4 (S1 Table).\n\nStratified analysis of patient characteristics predictive of SVR12\nTable 3 shows the stratified SVR12 rates of SOF/LDV with or without RBV by baseline characteristics and week 4 treatment response. The SVR12 rates were comparable with regard to age at a cut-off value of 60 years, sex, prior IFN exposure, HBV or HIV coinfection, liver or renal transplantation, scheduled treatment duration, use of RBV, eGFR at a cut-off value of 60 mL/min/1.73m2, baseline HCV viral load at a cut-off value of 6,000,000 IU/mL, HCV genotype, cirrhosis and week 4 viral decline. The SVR12 rates for patients with HCV-1a, HCV-1b, and unsubtypable HCV-1 infections were 90.5% (95% CI: 71.1%-97.4%), 97.9% (95% CI: 95.3%-99.1%), and 80.0% (95% CI: 49.0%-94.3%), respectively. Among the cirrhotic patients, the SVR12 rates for those with compensated and decompensated cirrhosis were 97.3% (95% CI: 92.2%-99.1%) and 88.5% (95% CI: 71.0%-96.0%), respectively.\n\n10.1371/journal.pone.0209299.t003Table 3 SVR12 according to baseline patient characteristics and on-treatment HCV viral decline.\nCharacteristics\tPatient (N = 273)\t\nPatient No.\tSVR12 (%)\t95% CI\t\nAge, years\t\t\t\t\n < 60\t85\t94.1\t87.0–97.5\t\n ≥ 60\t188\t97.9\t94.7–99.2\t\nSex\t\t\t\t\n Female\t146\t96.6\t92.2–98.5\t\n Male\t127\t96.9\t92.2–98.8\t\nTreatment experience\t\t\t\t\n Naïve\t182\t96.7\t93.0–98.5\t\n Experienced\t91\t96.7\t90.8–98.9\t\nHBV coinfection\t\t\t\t\n Absent\t264\t96.6\t93.7–98.2\t\n Present\t9\t100\t70.1–100\t\nHIV coinfection\t\t\t\t\n Absent\t260\t96.5\t93.6–98.2\t\n Present\t13\t100\t77.2–100\t\nPrior HCC history\t\t\t\t\n Absent\t216\t96.8\t93.5–98.4\t\n Present\t57\t96.5\t88.1–99.0\t\nLiver transplantation\t\t\t\t\n No\t247\t96.4\t93.2–98.1\t\n Yes\t26\t100\t87.1–100\t\nRenal transplantation\t\t\t\t\n No\t260\t96.5\t93.6–98.2\t\n Yes\t13\t100\t77.2–100\t\nTreatment duration, week\t\t\t\t\n 8\t5\t100\t56.6–100\t\n 12\t265\t96.6\t93.7–98.2\t\n 24\t3\t100\t43.9–100\t\nRBV usage\t\t\t\t\n No\t185\t97.3\t93.8–98.8\t\n Yes\t88\t95.5\t88.9–98.2\t\neGFR, mL/min/1.73m2\t\t\t\t\n < 60\t52\t98.1\t89.9–99.7\t\n ≥ 60\t221\t96.4\t93.0–98.2\t\nHCV RNA, IU/mL\t\t\t\t\n < 6,000,000\t225\t96.4\t93.1–98.2\t\n ≥ 6,000,000\t48\t97.9\t89.1–99.6\t\nHCV genotype\t\t\t\t\n 1a\t21\t90.5\t71.1–97.4\t\n 1b\t242\t97.9\t95.3–99.1\t\n 1\t10\t80.0\t49.0–94.3\t\nCirrhosis\t\t\t\t\n Absent\t138\t97.8\t93.8–99.3\t\n Present\t135\t95.6\t90.7–98.0\t\n Child-Pugh A\t109\t97.3\t92.2–99.1\t\n Child-Pugh B and C\t26\t88.5\t71.0–96.0\t\nWeek 4 HCV RNA < LLOD*\t\t\t\t\n No\t54\t94.4\t84.9–98.1\t\n Yes\t218\t97.7\t94.8–99.0\t\nNA: not assessed.\n\n* One patient who expired at treatment week 3 did not have week 4 HCV RNA data.\n\nIn patients who were treatment-naïve, non-cirrhotic and had baseline HCV RNA level < 6,000,000 IU/mL, the SVR12 rates were 100% (95% CI: 56.6%-100%) and 98.7% (95% CI: 92.8%-99.8%) for patients receiving 8 and 12 weeks of SOF/LDV. The SVR12 rates of SOF/LDV for 12 weeks in compensated cirrhotic patients who were treatment-naïve and treatment-experienced were 96.5% (95% CI: 88.1%-99.0%) and 100% (95% CI: 61.0%-100%), respectively. Furthermore, the SVR12 rates of SOF/LDV with RBV for 12 weeks in compensated cirrhotic patients who were treatment-naïve and treatment-experienced were 100% (95% CI: 61.0%-100%) and 97.4% (95% CI: 86.8%-99.6%), respectively. In patients with decompensated cirrhosis, the SVR12 rates of SOF/LDV with RBV for 12 weeks and SOF/LDV for 24 weeks were 88% (95% CI: 70.0%-95.8%) and 100% (95% CI: 20.7%-100%), respectively (Table 4).\n\n10.1371/journal.pone.0209299.t004Table 4 SVR12 in patients of specific interest.\nPatients of specific interest*\tPatient No.\tSVR12 (%)\t95% CI\t\nTreatment-naïve, non-cirrhotic, & baseline HCV RNA level < 6,000,000 IU/mL\t\n SOF/LDV, 8 weeks\t5\t100\t56.6–100\t\n SOF/LDV, 12 weeks\t75\t98.7\t92.8–99.8\t\nTreatment-naïve, Child-Pugh A cirrhotic\t\n SOF/LDV, 12 weeks\t57\t96.5\t88.1–99.0\t\n SOF/LDV with RBV, 12 weeks\t6\t100\t61.0–100\t\n SOF/LDV, 24 weeks\t1\t100\t20.7–5100\t\nTreatment-experienced, Child-Pugh A cirrhotic\t\n SOF/LDV, 12 weeks\t6\t100\t61.0–100\t\n SOF/LDV with RBV, 12 weeks\t39\t97.4\t86.8–99.6\t\nChild-Pugh B or C cirrhotic\t\n SOF/LDV with RBV, 12 weeks\t25\t88\t70.0–95.8\t\n SOF/LDV, 24 weeks\t1\t100\t20.7–100\t\n* Patients receiving liver or renal transplantation were not included in the analysis.\n\nSafety\nTwo hundred seventy-two (99.6%) patients completed the scheduled treatment. One treatment-naïve Child-Pugh C cirrhotic patients receiving SOF/LDV with RBV died at treatment week 3 due to pneumonia, which was not related to treatment. Twelve (4.4%) patients experienced on-treatment serious AEs, and none were considered related to DAA treatment. The rates and severity of hematological and hepatic AEs were generally low and mild in grade. The common AEs with event rates ≥ 10% included fatigue (27.1%), headache (20.5%), nausea (17.9%) and insomnia (13.9%) (Table 5). The rates for serious AE, fatigue, hemoglobin level < 10 g/dL, and elevated total bilirubin level were higher in patients with decompensated cirrhosis than those with no cirrhosis and with compensated cirrhosis. Among the 9 patients with HBV coinfection, 2 (22.2%) experienced HBV reactivation after treatment, but none had HBV-associated hepatitis that needed anti-HBV treatment.\n\n10.1371/journal.pone.0209299.t005Table 5 Safety summary.\nVariable, n (%)\tAll patient (N = 273)\tNo cirrhosis (n = 138)\tChild-Pugh A cirrhosis (n = 109)\tChild-Pugh B/C cirrhosis (n = 26)\t\nSerious adverse event\t12 (4.4)\t1 (0.7)\t5 (4.6)\t6 (23.1)\t\n Pneumonia\t1 (0.4)\t0 (0)\t0 (0)\t1 (3.8)\t\n Spontaneous bacterial peritonitis\t3 (1.1)\t0 (0)\t0 (0)\t3 (11.5)\t\n Variceal bleeding\t2 (0.7)\t0 (0)\t1 (0.9)\t1 (3.8)\t\n Hepatocellular carcinoma\t4 (1.5)\t0 (0)\t3 (2.8)\t1 (3.8)\t\n Herpes zoster\t1 (0.4)\t0 (0)\t1 (0.9)\t0 (0)\t\n Duodenal ulcer bleeding\t1 (0.4)\t1 (0.7)\t0 (0)\t0 (0)\t\nDiscontinuation due to adverse event*\t1 (0.4)\t0 (0)\t0 (0)\t1 (3.8)\t\nDeath*\t1 (0.4)\t0 (0)\t0 (0)\t1 (3.8)\t\nAdverse event in ≥ 10% of patients\t\t\t\t\t\n Fatigue\t74 (27.1)\t30 (21.7)\t32 (29.4)\t12 (46.2)\t\n Headache\t56 (20.5)\t28 (20.3)\t22 (20.2)\t6 (23.1)\t\n Nausea\t49 (17.9)\t22 (15.9)\t21 (19.3)\t6 (23.1)\t\n Insomnia\t38 (13.9)\t18 (13.0)\t15 (13.8)\t5 (19.2)\t\nLaboratory adverse event\t\t\t\t\t\n Hemoglobin\t\t\t\t\t\n 8.0–10.0 g/dL\t21 (7.7)\t1 (0.7)\t14 (12.8)\t6 (23.1)\t\n < 8.0 g/dL\t4 (1.5)\t0 (0)\t3 (2.8)\t1 (3.8)\t\n White blood cell count\t\t\t\t\t\n 2.0–3.0 x 109 cells/L\t7 (2.6)\t0 (0)\t5 (4.6)\t2 (7.7)\t\n < 2.0 x 109 cells/L\t2 (0.7)\t0 (0)\t1 (0.9)\t1 (3.8)\t\n Platelet count\t\t\t\t\t\n 50–75 x 109 cells/L\t46 (16.8)\t3 (2.2)\t24 (22.0)\t19 (73.1)\t\n < 50 x 109 cells/L\t10 (3.7)\t0 (0)\t4 (3.7)\t6 (19.2)\t\n Total bilirubin\t\t\t\t\t\n 1.5–3.0 x ULN\t21 (7.7)\t2 (1.4)\t11 (10.1)\t8 (30.8)\t\n > 3.0 x ULN\t9 (3.3)\t0 (0)\t4 (3.7)\t5 (19.2)\t\n ALT\t\t\t\t\t\n 3–5 x ULN\t6 (2.2)\t3 (2.2)\t2 (1.8)\t1 (3.8)\t\n > 5x ULN\t2 (0.7)\t1 (0.7)\t1 (0.9)\t0 (0)\t\n eGFR\t\t\t\t\t\n 15–30 mL/min/1.73m2\t3 (1.1)\t0 (0)\t2 (1.8)\t1 (3.8)\t\n < 15 mL/min/1.73m2\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t\n* One patient expired due to pneumonia at treatment week 3, which was considered not related to DAA treatment.\n\nDiscussion\nCompared to protease inhibitor (PI)-containing HCV DAA regimens for HCV-1 infection, the PI-free SOF/LDV regimen has lower pill burden, fewer potential drug-drug interactions (DDIs), and can be applied to decompensated cirrhotic patients [36–38]. Therefore, treatment by SOF/LDV with or without RBV is appealing to most health care providers in the management of HCV-1 infection.\n\nOur real-world study which enrolled a heterogeneous group of HCV-1 patients showed that the SVR12 rates by EP and PP analyses in patients receiving SOF/LDV with or without RBV for 8–24 weeks were excellent (96.7% and 97.5%, respectively) and were comparable to the response rates in clinical trials and real-world studies [13,14,15,17–20,23–26]. Furthermore, 99.6% of our patients completed the scheduled treatment and 4.4% of them experienced on-treatment serious AEs, which were also comparable to the pooled safety analysis for patients receiving SOF/LDV with or without RBV for 8–24 weeks in ION studies [16]. Only one decompensated cirrhotic patient prematurely discontinued treatment due to pneumonia, which was considered not related to SOF/LDV. The rates of common constitutional AEs, including fatigue, headache, nausea, and insomnia were also in line with the ION reports [16]. However, patients with decompensated cirrhosis tended to have higher risks of serious AE, fatigue, anemia and hyperbilirubinemia than those with no cirrhosis and with compensated cirrhosis, implying that the treating physicians should be alert to the clinical presentations in patients with decompensated cirrhosis to secure the safety profiles [18,19]. Based on the excellent safety and effectiveness in our study, applying SOF/LDV with or without RBV may serve as an ideal regimen for HCV-1 infection.\n\nIn terms of patient characteristics, our study showed that the SVR12 rates were similar regardless of age, sex, prior treatment experience, HBV or HIV coinfection, prior HCC history, HCV viral load, eGFR level or week 4 viral decline [17,39–41]. The SVR12 rate in compensated cirrhotic patients was also comparable to non-cirrhotic patients [13,14]. Furthermore, the SVR12 rate in decompensated cirrhotic patients was 88.5% (95% CI: 71.0%-96%) and was comparable to the reports in SOLAR-1 and SOLAR-2 studies [18,19]. Patients with decompensated cirrhosis had lower SVR12 rate than patients with no cirrhosis or with compensated cirrhosis, probably due to lower drug delivery, altered drug metabolism, and impaired immune response in these patients [42–44]. Applying velpatasvir (VEL), which exhibits a higher genetic barrier to N55A resistance associated substitutions (RASs) than LDV, in combination with SOF and RBV for 12 weeks, or treating patients following liver transplantation, may improve the clinical outcome in decompensated cirrhotic patients [18,19,32,45]. Although there were no statistical differences, the SVR12 rate in patients with HCV-1a infection were numerically lower than that with HCV-1b infection, which may be reasoned by the greater loss of response rates for HCV-1a patients receiving SOF/LDV than for HCV-1b patients in the presence of NS5A RASs [46].\n\nAmong our HCV-1 patients receiving liver transplantation, 25 patients were treated by SOF/LDV with RBV for 12 weeks and one were treated by SOF/LDV for 24 weeks. All of them achieved SVR12, implying that the effectiveness of SOF/LDV-based therapies remained excellent in this special population [18,19]. In contrast, 13 HCV-1 patients receiving renal transplantation were treated by SOF/LDV for 12 weeks and all achieved SVR12, implying that RBV-free SOF/LDV regimen can be applied to patients receiving non-liver solid organ transplantation [20,21,47].\n\nIn ION-3 and real-world studies, treatment-naïve, non-cirrhotic HCV-1 patients with baseline HCV RNA < 6,000,000 IU/mL can receive SOF/LDV for 8 weeks without compromising the treatment responses [15,48]. All 5 (100%) patients and 74 of 75 (98.7%) patients who met such criteria achieved SVR12 by 8 and 12 weeks of SOF/LDV, respectively. In treatment-naïve, compensated cirrhotic HCV-1 patients, our study showed that adding RBV to SOF/LDV for 12 week or extending SOF/LDV treatment to 24 weeks did not benefit the SVR12 rates, compared to SOF/LDV for 12 weeks [49]. In contrast to Western studies, our data were in line with Asian reports indicating that there was no benefit to improve the SVR12 rate by adding RBV to SOF/LDV for 12 weeks in treatment-experienced, compensated cirrhotic HCV-1 patients [50,51]. Further studies are needed to explore the potential mechanisms for such discrepancies.\n\nAmong the 9 patients with HBV coinfection, the risks of HBV reactivation and the HBV-related hepatitis after DAA treatment were 22.2% and 0%, which were comparable to the report in a meta-analysis enrolling 242 HBV-coinfected patients [52]. Although there were no apparent clinical events related to HBV reactivation in our study, watchful surveillance of HBV activity is still needed to detect and treat potential complications related to HBV reactivation at the earliest stage.\n\nAlthough we confirmed that SOF/LDV with or without RBV had excellent safety and effectiveness for HCV-1 patients in Taiwan, several limitations existed in our study. First, the numbers of patients receiving SOF/LDV for 8 or 24 weeks were small and more data are needed to confirm the overall performance in patients of specific interests. Second, HCV-6 patients may potentially be misclassified to unsubtypable HCV-1 patients by Abbott RealTime HCV Genotype II testing, which might affect the SVR12 rate in our study [53]. Third, we did not evaluate the effects baseline NS5A RASs on the treatment responses in our patients, particularly for HCV-1a patients.\n\nIn summary, SOF/LDV with or without RBV for 8–24 weeks is well tolerated and achieves a high SVR12 rate in HCV-1 infection, which may improve the care of such patients in Taiwan.\n\nSupporting information\nS1 Table Summary of patients who did not achieve SVR12.\n(DOCX)\n\nClick here for additional data file.\n\n The authors thank Hui-Ju Lin and Pin-Chin Huang for clinical data management; the 7th Core Lab of National Taiwan University Hospital and the 1st Common Laboratory of National Taiwan University Hospital, Yun-Lin Branch for instrumental and technical support.\n==== Refs\nReferences\n1 Polaris Observatory HCV Collaborators . Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study . Lancet Gastroenterol Hepatol . 2017 ;2 : 161 –176 . 10.1016/S2468-1253(16)30181-9 \n28404132 \n2 Kao JH . 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Open Forum Infect Dis . 2017 ;4 : ofx028 \n10.1093/ofid/ofx028 \n28480296 \n35 Terrault NA , Lok ASF , McMahon BJ , Chang KM , Hwang JP , Jonas MM , et al\nUpdate on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance . Hepatology . 2018 ;67 : 1560 –1599 . 10.1002/hep.29800 \n29405329 \n36 Liu CH , Liu CJ , Su TH , Yang HC , Hong CM , Tseng TC , et al\nReal-world effectiveness and safety of paritaprevir/ritonavir, ombitasvir, and dasabuvir with or without ribavirin for patients with chronic hepatitis C virus genotype 1b infection in Taiwan . J Gastroenterol Hepatol . 2018 ;33 : 710 –717 . 10.1111/jgh.13912 \n28762541 \n37 Liu CH , Yu ML , Peng CY , Hsieh TY , Huang YH , Su WW , et al\nComorbidities, concomitant medications, and potential drug-drug interactions with interferon-free direct-acting antiviral agents in hepatitis C patients in Taiwan . Aliment Pharmacol Ther . 2018 ;48 : 1290 –1300 . 10.1111/apt.15011 \n30362139 \n38 Liu CH , Huang YJ , Yang SS , Chang CH , Yang SS , Sun HY , et al\nGeneric sofosbuvir-based interferon-free direct acting antiviral agents for patients with chronic hepatitis C virus infection: a real-world multicenter observational study . Sci Rep . 2018 ;8 : 13699 \n10.1038/s41598-018-32060-7 \n30209349 \n39 Liu CJ , Chuang WL , Sheen IS , Wang HY , Chen CY , Tseng KC , et al\nEfficacy of ledipasvir and sofosbuvir treatment of HCV infection in patients coinfected with HBV . Gastroenterology . 2018 ;154 : 989 –997 . 10.1053/j.gastro.2017.11.011 \n29174546 \n40 Maasoumy B , Vermehren J , Welker MW , Bremer B , Perner D , Höner Zu Siederdissen C , et al\nClinical value of on-treatment HCV RNA levels during different sofosbuvir-based antiviral regimens . J Hepatol . 2016 ;65 : 473 –482 . 10.1016/j.jhep.2016.04.006 \n27085252 \n41 Fourati S , Guedj J , Chevaliez S , Nguyen THT , Roudot-Thoraval F , Ruiz I , et al\nViral kinetics analysis and virological characterization of treatment failures in patients with chronic hepatitis C treated with sofosbuvir and an NS5A inhibitor . Aliment Pharmacol Ther . 2018 ;47 : 665 –673 . 10.1111/apt.14478 \n29271114 \n42 Al Marzooqi SH , Feld JJ . Sorting out cirrhosis: mechanisms of non-response to hepatitis C therapy . Liver Int . 2015 ;35 : 1923 –1933 . 10.1111/liv.12861 \n25939775 \n43 Serti E , Chepa-Lotrea X , Kim YJ , Keane M , Fryzek N , Liang TJ , et al\nSuccessful interferon-free therapy of chronic hepatitis C virus infection normalizes natural killer cell function . Gastroenterology . 2015 ;149 : 190 –200.e2 . 10.1053/j.gastro.2015.03.004 \n25754160 \n44 Serti E , Park H , Keane M , O’Keefe AC , Rivera E , Liang TJ , et al\nRapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNα . Gut . 2017 ;66 : 724 –735 . 10.1136/gutjnl-2015-310033 \n26733671 \n45 Curry MP , O’Leary JG , Bzowej N , Muir AJ , Korenblat KM , Fenkel JM , et al\nSofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis . N Engl J Med . 2015 ;373 : 2618 –2628 . 10.1056/NEJMoa1512614 \n26569658 \n46 Zeuzem S , Mizokami M , Pianko S , Mangia A , Han KH , Martin R , et al\nNS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: prevalence and effect on treatment outcome . J Hepatol . 2017 ;66 : 910 –918 . 10.1016/j.jhep.2017.01.007 \n28108232 \n47 D’Ambrosio R , Aghemo A , Rossetti V , Carrinola R , Colombo M . Sofosbuvir-based regimens for the treatment of hepatitis C virus in patients who underwent lung transplant: case series and review of the literature . Liver Int . 2016 ;36 : 1585 –1589 . 10.1111/liv.13203 \n27429162 \n48 Kowdley KV , Sundaram V , Jeon CY , Qureshi K , Latt NL , Sahota A , et al\nEight weeks of ledipasvir/sofosbuvir is effective for selected patients with genotype 1 hepatitis C virus infection . Hepatology . 2017 ;65 : 1094 –1103 . 10.1002/hep.29005 \n28027579 \n49 Reddy KR , Bourlière M , Sulkowski M , Omata M , Zeuzem S , Feld JJ , et al\nLedipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: An integrated safety and efficacy analysis . Hepatology . 2015 ;62 : 79 –86 . 10.1002/hep.27826 \n25846144 \n50 Mizokami M , Yokosuka O , Takehara T , Sakamoto N , Korenaga M , Mochizuki H , et al\nLedipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial . Lancet Infect Dis . 2015 ;15 : 645 –653 . 10.1016/S1473-3099(15)70099-X \n25863559 \n51 Chuang WL , Chien RN , Peng CY , Chang TT , Lo GH , Sheen IS , et al\nLedipasvir/sofosbuvir fixed-dose combination tablet in Taiwanese patients with chronic genotype 1 hepatitis C virus . J Gastroenterol Hepatol . 2016 ;31 : 1323 –1329 . 10.1111/jgh.13305 \n26841930 \n52 Mücke MM , Backus LI , Mücke VT , Coppola N , Preda CM , Yeh ML , et al\nHepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C: a systematic review and meta-analysis . Lancet Gastroenterol Hepatol . 2018 ;3 : 172 –180 . 10.1016/S2468-1253(18)30002-5 \n29371017 \n53 Mallory MA , Lucic D , Ebbert MT , Cloherty GA , Toolsie D , Hillyard DR . Evaluation of the Abbott RealTime HCV genotype II plus RUO (PLUS) assay with reference to core and NS5B sequencing . J Clin Virol . 2017 ;90 : 26 –31 . 10.1016/j.jcv.2017.03.007 \n28324789\n\n",
"fulltext_license": "CC BY",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents; D001562:Benzimidazoles; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005449:Fluorenes; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012254:Ribavirin; D012449:Safety; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response; D013624:Taiwan; D016896:Treatment Outcome; D014542:Uridine Monophosphate",
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"pmid": "30576344",
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"title": "Real-world effectiveness and safety of sofosbuvir and ledipasvir with or without ribavirin for patients with hepatitis C virus genotype 1 infection in Taiwan.",
"title_normalized": "real world effectiveness and safety of sofosbuvir and ledipasvir with or without ribavirin for patients with hepatitis c virus genotype 1 infection in taiwan"
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"abstract": "A 54-year-old female with dermatomyositis treated with cyclosporine and methylprednisolone presented with multiple subcutaneous nodules on her upper and lower extremities on December 2011. The number of lesions gradually increased. She had a history of surgical intervention such as debridement, skin graft of right lower leg due to trauma and subsequent bacterial infection on August 2011. Culture from a skin lesion on June 2012 confirmed Mycobacterium chelonae, which was susceptible to clarithromycin (CAM). We started treatment with CAM, imipenem/cilastatin (IPM/CS) and tobramycin (TOB) for 2 weeks. Then CAM monotherapy was continued, however CAM was discontinued because of liver dysfunction. In September 2012 new nodular lesions were observed on the left arm and right leg. We administrated azithromycin, IPM/CS and TOB. Subcutaneous nodules were partially improved, but new lesions appeared on her right leg. A culture of skin lesion yielded M. chelonae, which was highly resistant to CAM and IPM/CS. Based on the sensitivity test, moxifloxacin was used. However, there was no significant improvement in her skin lesions, so we started thermal therapy on day 57 after admission. She showed an excellent response to thermal therapy, and there has been no recurrence.",
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"authors": "Yoshimoto|Akira|A|;Nakamura-Uchiyama|Fukumi|F|;Sato|Masatoshi|M|;Fukumori|Tatsuya|T|;Yamada|Yutaka|Y|;Hishiya|Naokuni|N|;Shiraishi|Naotaka|N|;Ogawa|Taku|T|;Uno|Kenji|K|;Kasahara|Kei|K|;Maeda|Koichi|K|;Konishi|Mitsuru|M|;Yoshikawa|Masahide|M|;Mikasa|Keiichi|K|",
"chemical_list": null,
"country": "Japan",
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"doi": "10.11150/kansenshogakuzasshi.89.410",
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"issn_linking": "0387-5911",
"issue": "89(3)",
"journal": "Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases",
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"medline_ta": "Kansenshogaku Zasshi",
"mesh_terms": "D005260:Female; D006358:Hot Temperature; D006801:Humans; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D016926:Mycobacterium chelonae; D012874:Skin Diseases, Infectious",
"nlm_unique_id": "0236671",
"other_id": null,
"pages": "410-5",
"pmc": null,
"pmid": "26552135",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A Case of Disseminated Cutaneous Mycobacterium chelonae Infection Successfully Improved with Thermal Therapy.",
"title_normalized": "a case of disseminated cutaneous mycobacterium chelonae infection successfully improved with thermal therapy"
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{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-108207",
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{
"abstract": "Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis and psoriatic arthritis. Japanese patients aged 20 years or more with moderate to severe plaque psoriasis and/or psoriatic arthritis were double-blindly randomized 1:1 to tofacitinib 5 or 10 mg b.i.d. for 16 weeks, open-label 10 mg b.i.d. for 4 weeks, then variable 5 or 10 mg b.i.d. to Week 52. Primary end-points at Week 16 were the proportion of patients achieving at least a 75% reduction in Psoriasis Area and Severity Index (PASI75) and Physician's Global Assessment of \"clear\" or \"almost clear\" (PGA response) for psoriasis, and 20% or more improvement in American College of Rheumatology criteria (ACR20) for patients with psoriatic arthritis. Safety was assessed throughout. Eighty-seven patients met eligibility criteria for moderate to severe plaque psoriasis (5 mg b.i.d., n = 43; 10 mg b.i.d., n = 44), 12 met eligibility criteria for psoriatic arthritis (5 mg b.i.d., n = 4; 10 mg b.i.d., n = 8) including five who met both criteria (10 mg b.i.d.). At Week 16, 62.8% and 72.7% of patients achieved PASI75 with tofacitinib 5 and 10 mg b.i.d., respectively; 67.4% and 68.2% achieved PGA responses; all patients with psoriatic arthritis achieved ACR20. Responses were maintained through Week 52. Adverse events occurred in 83% of patients through Week 52, including four (4.3%) serious adverse events and three (3.2%) serious infections (all herpes zoster). No malignancies, cardiovascular events or deaths occurred. Tofacitinib (both doses) demonstrated efficacy in patients with moderate to severe plaque psoriasis and/or psoriatic arthritis through 52 weeks; safety findings were generally consistent with prior studies.",
"affiliations": "Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.;Department of Dermatology, Tokyo Teishin Hospital, Tokyo, Japan.;Department of Dermatology, NTT Medical Center Tokyo, Tokyo, Japan.;Department of Dermatology, Fukuoka University Faculty of Medicine, Fukuoka, Japan.;Department of Dermatology, Nippon Medical School, Tokyo, Japan.;Pfizer Japan Inc., Tokyo, Japan.;Pfizer Japan Inc., Tokyo, Japan.;Pfizer Japan Inc., Tokyo, Japan.;Pfizer Japan Inc., Tokyo, Japan.;Department of Dermatology, Jichi Medical University, Tochigi, Japan.",
"authors": "Asahina|Akihiko|A|;Etoh|Takafumi|T|;Igarashi|Atsuyuki|A|;Imafuku|Shinichi|S|;Saeki|Hidehisa|H|;Shibasaki|Yoshiyuki|Y|;Tomochika|Yukiko|Y|;Toyoizumi|Shigeyuki|S|;Nagaoka|Makoto|M|;Ohtsuki|Mamitaro|M|;|||",
"chemical_list": "D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib",
"country": "England",
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"doi": "10.1111/1346-8138.13258",
"fulltext": "\n==== Front\nJ DermatolJ. Dermatol10.1111/(ISSN)1346-8138JDEThe Journal of Dermatology0385-24071346-8138John Wiley and Sons Inc. Hoboken 10.1111/1346-8138.13258JDE13258Original ArticleOriginal ArticlesOral tofacitinib efficacy, safety and tolerability in Japanese patients with moderate to severe plaque psoriasis and psoriatic arthritis: A randomized, double‐blind, phase 3 study A. Asahina et al.Asahina Akihiko \n1\nEtoh Takafumi \n2\nIgarashi Atsuyuki \n3\nImafuku Shinichi \n4\nSaeki Hidehisa \n5\nShibasaki Yoshiyuki \n6\nTomochika Yukiko \n6\nToyoizumi Shigeyuki \n6\nNagaoka Makoto \n6\nOhtsuki Mamitaro \n7\nthe study investigators \n†\n1 Department of DermatologyThe Jikei University School of MedicineTokyoJapan2 Department of DermatologyTokyo Teishin HospitalTokyoJapan3 Department of DermatologyNTT Medical Center TokyoTokyoJapan4 Department of DermatologyFukuoka University Faculty of MedicineFukuokaJapan5 Department of DermatologyNippon Medical SchoolTokyoJapan6 Pfizer Japan Inc.TokyoJapan7 Department of DermatologyJichi Medical UniversityTochigiJapan* Correspondence: Akihiko Asahina, M.D., Ph.D., Department of Dermatology, The Jikei University School of Medicine, 3‐25‐8 Nishi‐Shimbashi, Minato‐ku, Tokyo 105‐8461, Japan. Email: asahina-tky@umin.ac.jp† A list of principal investigators is provided in the supporting information.\n\n15 2 2016 8 2016 43 8 10.1111/jde.2016.43.issue-8869 880 07 10 2015 10 11 2015 © 2016 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nTofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis and psoriatic arthritis. Japanese patients aged 20 years or more with moderate to severe plaque psoriasis and/or psoriatic arthritis were double‐blindly randomized 1:1 to tofacitinib 5 or 10 mg b.i.d. for 16 weeks, open‐label 10 mg b.i.d. for 4 weeks, then variable 5 or 10 mg b.i.d. to Week 52. Primary end‐points at Week 16 were the proportion of patients achieving at least a 75% reduction in Psoriasis Area and Severity Index (PASI75) and Physician's Global Assessment of “clear” or “almost clear” (PGA response) for psoriasis, and 20% or more improvement in American College of Rheumatology criteria (ACR20) for patients with psoriatic arthritis. Safety was assessed throughout. Eighty‐seven patients met eligibility criteria for moderate to severe plaque psoriasis (5 mg b.i.d., n = 43; 10 mg b.i.d., n = 44), 12 met eligibility criteria for psoriatic arthritis (5 mg b.i.d., n = 4; 10 mg b.i.d., n = 8) including five who met both criteria (10 mg b.i.d.). At Week 16, 62.8% and 72.7% of patients achieved PASI75 with tofacitinib 5 and 10 mg b.i.d., respectively; 67.4% and 68.2% achieved PGA responses; all patients with psoriatic arthritis achieved ACR20. Responses were maintained through Week 52. Adverse events occurred in 83% of patients through Week 52, including four (4.3%) serious adverse events and three (3.2%) serious infections (all herpes zoster). No malignancies, cardiovascular events or deaths occurred. Tofacitinib (both doses) demonstrated efficacy in patients with moderate to severe plaque psoriasis and/or psoriatic arthritis through 52 weeks; safety findings were generally consistent with prior studies.\n\nJapankinase inhibitorplaque psoriasispsoriatic arthritistofacitinibPfizer Inc. source-schema-version-number2.0component-idjde13258cover-dateAugust 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.5 mode:remove_FC converted:18.10.2016\n==== Body\nIntroduction\nPsoriasis is a chronic, immune‐mediated disease, characterized by prominent skin lesions, and affects 0.1–3% of the global population.1, 2 Psoriasis can cause significant impairment to quality of life (QoL)3 and requires long‐term treatment. The prevalence of psoriasis in the Japanese population is estimated to be lower (0.3%)4 than in countries with a mostly Caucasian population (up to 3.6%).5, 6, 7 However, more than 400 000 patients with psoriasis have been recently identified in Japan.4 The most common type of psoriasis is plaque psoriasis, with a prevalence of nearly 90% among patients with psoriasis in Japan.8\n\n\nPsoriatic arthritis is an inflammatory arthropathy associated with psoriasis. Its prevalence was estimated to be approximately 3% in Japanese patients with psoriasis,8 but the most recent survey indicates an even higher prevalence of 14.3%.9\n\n\nTreatment options for Japanese patients with moderate to severe psoriasis include oral systemic therapies, such as cyclosporin and etretinate, as well as phototherapy. Four injectable biologic agents, adalimumab, infliximab, ustekinumab and recently secukinumab, have each demonstrated considerable efficacy in this patient population,10, 11, 12, 13 and are approved in Japan for moderate to severe psoriasis following an inadequate response to systemic therapy.14 However, all of these treatments have limitations in addition to their clinical benefit. Long‐term use of systemic therapies is limited by safety considerations, including organ toxicity, infection and malignancy,15, 16 and teratogenicity with systemic retinoids, such as etretinate.17 Phototherapy is associated with increased risk of skin malignancies,18, 19 while some patients do not respond to phototherapy or have disease recurrence, and multiple office visits are required. The efficacy of biologic therapies may diminish over time owing in part to immunogenicity and use is restricted by parenteral administration.20, 21 Given the potentially serious toxicities associated with long‐term use of orally available systemic therapies and phototherapy and the drawbacks of biologic therapy, benefit : risk and patient preference need to be considered for each individual patient with psoriasis.22 Furthermore, patient dissatisfaction with available treatments is common in psoriasis, and both physician and patient perspectives should be considered in disease management.23, 24 Consequently, there is a need for new therapies for moderate to severe psoriasis, especially p.o. administrated therapies that offer sustained efficacy and manageable long‐term safety, as oral treatment options are currently limited and patients with psoriasis have reported that injections required with biologics are burdensome.25\n\n\nTofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis and psoriatic arthritis. Phase 2 and 3 studies have demonstrated tofacitinib efficacy with a manageable safety profile.26, 27, 28, 29 Here, we present results from a 52‐week, phase 3 study conducted at Japanese centers evaluating the efficacy, safety and tolerability of oral tofacitinib for the treatment of Japanese patients with moderate to severe plaque psoriasis (psoriasis vulgaris) and/or psoriatic arthritis. In addition, this study is the first to report outcomes with tofacitinib treatment for psoriatic arthritis in Japanese patients.\n\nMethods\nPatients\nPatients were aged 20 years or older. Patients with moderate to severe plaque psoriasis were required to have a diagnosis of plaque‐type psoriasis for 12 months or more prior to baseline, a Psoriasis Area and Severity Index (PASI) score of 12 or more, a Physician's Global Assessment (PGA) of 3 (moderate) or 4 (severe) (on a 5‐point scale), and an affected body surface area of 10% or more, at baseline. Patients with psoriatic arthritis were required to have a diagnosis of psoriatic arthritis 6 months or more prior to baseline, meet the Classification Criteria for Psoriatic Arthritis,30 have active arthritis as defined as three or more tender/painful joints (68‐joint count) and three or more swollen joints (66‐joint count) and active plaque psoriasis with a qualifying lesion of 2 cm or more in diameter confirmed by a dermatologist. Patients were to be considered candidates for systemic therapy or phototherapy for psoriasis (either treatment‐naive or ‐experienced). Exclusion criteria included evidence of active, latent or inadequately treated Mycobacterium tuberculosis infection, non‐plaque forms or drug‐induced psoriasis, other skin conditions that would interfere with psoriasis evaluation, inability to discontinue systemic, topical or phototherapies, concomitant oral or injectable corticosteroids, a history of disseminated herpes zoster or disseminated herpes simplex or recurrent localized dermatomal herpes zoster, a history of infection requiring hospitalization or parenteral microbial therapy (or other infection deemed clinically significant) within 6 months of baseline, a history or symptoms of any lymphoproliferative disorders, or a history of malignancies except for adequately treated or excised non‐metastatic basal cell or squamous cell skin cancer or cervical carcinoma in situ without recurrence for 3 years. Patients with psoriatic arthritis were excluded if they had a history of another autoimmune rheumatic disease, fibromyalgia or rheumatic inflammatory disease aside from psoriatic arthritis, unless agreed with the sponsor.\n\nWashout periods for prior medications were 7 days or more or five half‐lives (whichever was longer) prior to first dose of study drug. A washout period of 2 weeks or more was applied for topical medications and ultraviolet B phototherapy, 4 weeks or more for etanercept, psoralen plus ultraviolet A therapy and non‐biologic systemic therapies, 8 weeks or more for adalimumab and infliximab, 10 weeks or more for golimumab, and 12 weeks or more for ustekinumab, tocilizumab and investigational/experimental agents. Topical hydrocortisone/hydrocortisone acetate of 1% or less were allowed (after 16 weeks for scalp), as were tar and salicylic acid preparations for the scalp.\n\nThe study was conducted in compliance with the ethical principles of the Declaration of Helsinki, and in accordance with the International Conference on Harmonization Good Clinical Practice guidelines. The study protocol was approved by the Institutional Review Boards and/or Independent Ethics Committees at each investigational center. All patients provided written informed consent at the first screening visit and before initiation of any washout period of prior medications.\n\nStudy design and treatment\nThis was a 52‐week, phase 3, multisite, randomized, double‐blind study conducted in 16 centers in Japan (clinicaltrials.gov NCT01519089; Pfizer protocol A3921137). The study comprised an initial 16‐week, double‐blind period, in which patients were randomized to tofacitinib 5 or 10 mg b.i.d. At Week 16, all patients received open‐label tofacitinib 10 mg b.i.d. for 4 weeks, after which the dose could be adjusted to tofacitinib 5 or 10 mg b.i.d. at the investigator's discretion, to Week 52 (Fig. 1). The visit window at Week 52 had a 7‐day allowance, so patients could receive tofacitinib up to Week 53 (day 372). A follow‐up visit was performed 2–4 weeks after the patient's last dose.\n\nFigure 1 Study design. †Stratified by type of psoriasis at randomization. BL, baseline; FU, follow‐up.\n\nPatients were randomized 1:1 to tofacitinib 5 or 10 mg b.i.d. using a computer‐generated randomization schedule; patients were registered by the investigator in a central randomized management system, and a stratification factor of psoriatic arthritis was employed.\n\nTofacitinib was supplied as 5 mg tablets with a corresponding matching placebo. Patients and study staff were unable to determine from the packaging which treatment group the patient was assigned to. Patients, investigators, study teams, the contract research organization and the sponsor remained blinded throughout the study period.\n\nStudy assessments\nThe primary efficacy end‐points at Week 16 for plaque psoriasis were the proportion of patients achieving at least a 75% reduction in PASI score (PASI75) from baseline at Week 16 and the proportion of patients achieving a PGA response of “clear” or “almost clear”. The primary efficacy end‐point at Week 16 for psoriatic arthritis was the proportion of patients with 20% or more improvement in American College of Rheumatology criteria (ACR20), calculated as a 20% or more improvement in tender/painful and swollen joint counts and improvements in three of Patient Global Assessment of arthritis, PGA of arthritis, patient pain assessment, Health Assessment Questionnaire–Disability Index and an acute‐phase reactant.\n\nSecondary end‐points in plaque psoriasis included PASI75 and 90% or more improvement in PASI from baseline (PASI90) through Week 52, and the proportion of patients with PASI of 125% or more of baseline score at any time point. Nail Psoriasis Severity Index (NAPSI) score,31 change from baseline in NAPSI and patient‐reported outcomes (PRO) were also measured through Week 52. PRO included the Itch Severity Item (ISI), a single‐item, horizontal numeric rating scale to assess itching due to psoriasis with response options ranging from 0 (no itching) to 10 (worst possible itching) and the Dermatology Life Quality Index (DLQI), a 10‐item questionnaire that assesses the impact of chronic skin conditions on health‐related QoL (HRQoL).32 For psoriatic arthritis, ACR20, 50 and 70 were measured through Week 52.\n\nSafety assessments\nSafety was assessed according to the incidence and severity of treatment‐emergent adverse events (AEs), clinical laboratory abnormalities, physical examination changes, vital sign abnormalities and electrocardiogram (ECG) changes for all patients who received one or more dose of study drug (safety analysis set; SAS). Serious AEs were defined as those resulting in death, were life‐threatening, required hospitalization or prolongation of existing hospitalization, led to persistent or significant disability, or resulted in congenital abnormalities. Serious infections were defined as treated infections requiring parenteral antimicrobial therapy or hospitalization, or met other criteria for a serious AE. Patients with serious infections were discontinued from the study. Cardiovascular and opportunistic infection events were adjudicated by a prospectively defined, sponsor‐independent, masked safety event adjudication committee. All biopsies of potentially malignant tumors were confirmed by a central laboratory pathologist over‐read of local histology data. Pooled data for psoriasis and psoriatic arthritis are presented for Weeks 0–16 by treatment group, and for all tofacitinib‐treated patients through Week 52.\n\nStatistical analyses\nThe treatment groups (tofacitinib 5 mg b.i.d. and 10 mg b.i.d.) were defined based on the initial tofacitinib dose received during Weeks 0–16. The full analysis set included all randomized patients who received one or more dose of study drug. No formal statistical hypotheses were tested to investigate efficacy and safety between treatment groups; although there was statistical testing applied at a significance level of 0.05 (two‐sided), statistical analysis was descriptive in nature. A sample size of 88 patients was chosen to allow 80% probability to observe a positive point estimate of a difference between treatment groups (10 mg b.i.d. to 5 mg b.i.d.) in PASI75 and PGA end‐points at Week 16. Of these 88 patients, the target number of patients with psoriatic arthritis was 10, with five expected responders based on data on tofacitinib in rheumatoid arthritis (RA) clinical studies. For primary end‐points, response rates were calculated. Missing values were treated as non‐responders (non‐responder imputation).\n\nSecondary end‐points involving binary data were summarized as for the primary end‐points, above. For continuous data, descriptive statistics were calculated.\n\nResults\nPatient disposition and demographics\nBetween March and December 2012, 95 patients were randomized and 94 treated with tofacitinib 5 and 10 mg b.i.d. (Fig. 2). Of these, 87 (91.6%) had moderate to severe plaque psoriasis and 12 (12.6%) had active psoriatic arthritis. Five of these 12 patients also had a diagnosis of moderate to severe plaque psoriasis (all in tofacitinib 10 mg b.i.d. group); these patients were included in both the plaque psoriasis and psoriatic arthritis populations. Eighteen patients with plaque psoriasis and four with psoriatic arthritis discontinued from the study (Fig. 2). Mean [SD] age was 48.7 [11.5] years, 83.0% were male, and the mean [SD] body mass index was 24.0 [4.1] kg/m2. Baseline demographics were similar across groups (Table 1). Patients with plaque psoriasis had a longer duration of disease than those with psoriatic arthritis. Patients with psoriatic arthritis in the tofacitinib 10 mg b.i.d. group had a higher mean proportion of body surface area affected by psoriasis compared with those in the tofacitinib 5 mg b.i.d. group, likely due to the five patients in the 10 mg b.i.d. group who also had psoriasis.\n\nFigure 2 Patient disposition. †Five patients in the tofacitinib 10 mg b.i.d. group had both plaque psoriasis and psoriatic arthritis. AEs, adverse events; FAS, full analysis set; SAS, safety analysis set.\n\nTable 1 Baseline demographics and disease characteristics\n\n\tPlaque psoriasis\tPsoriatic arthritis\t\nTofacitinib 5 mg b.i.d. (n = 43)\tTofacitinib 10 mg b.i.d. (n = 44)\tTofacitinib 5 mg b.i.d. (n = 4)\tTofacitinib 10 mg b.i.d. (n = 8)\t\nMean age, years (range)\t50.9 (28–72)\t46.6 (28–69)\t51.0 (41–64)\t48.5 (43–59)\t\nMale, n (%)\t35 (81.4)\t36 (81.8)\t4 (100)\t7 (87.5)\t\nMean weight, kg (SD)\t67.0 (13.3)\t66.6 (13.6)\t76.4 (13.9)\t74.4 (18.4)\t\nMean BMI, kg/m2 (SD)\t23.8 (4.0)\t23.6 (4.0)\t26.4 (4.5)\t25.7 (5.0)\t\nMean duration of disease, years (SD)\t13.4 (10.5)\t13.9 (8.2)\t4.0 (3.1)\t7.5 (6.5)\t\nMean PASI score (SD)\t26.9 (11.3)\t26.7 (11.8)\t6.7 (2.2)\t15.2 (12.6)\t\nPGA, n (%)\t\nAlmost clear\t0\t0\t1 (25.0)\t2 (25.0)\t\nMild\t0\t0\t1 (25.0)\t0\t\nModerate\t34 (79.1)\t37 (84.1)\t2 (50.0)\t6 (75.0)\t\nSevere\t9 (20.9)\t7 (15.9)\t0\t0\t\nTotal % psoriatic BSA, mean (SD)\t43.0 (21.3)\t43.1 (23.6)\t6.8 (1.9)\t24.3 (22.8)\t\nNail psoriasis, n (%)\t30 (69.8)\t29 (65.9)\t2 (50.0)\t5 (62.5)\t\nPsoriatic arthritis, n (%)\t0\t5 (11.4)†\n\t4 (100)\t8 (100)\t\nTender/painful joint count, mean (SD)\tNA\tNA\t15.0 (9.3)\t15.0 (11.9)\t\nSwollen joint count, mean (SD)\tNA\tNA\t7.8 (7.6)\t10.1 (4.9)\t\nDLQI total score, mean (SD)\t11.3 (6.3)\t8.6 (5.9)\t5.0 (2.8)\t7.8 (3.1)\t\nFAS\tTofacitinib 5 mg b.i.d. (n = 47)\t\tTofacitinib 10 mg b.i.d. (n = 47)\t\t\nMean NAPSI score (SD)‡\n\t29.3 (20.8)\t\t24.3 (17.8)\t\t\nMean ISI score (SD)\t6.0 (2.7)\t\t5.3 (2.9)\t\t\nMean DLQI score (SD)\t10.7 (6.3)\t\t8.4 (5.8)\t\t\nSAS\tTofacitinib 5 mg b.i.d. (n = 47)\t\tTofacitinib 10 mg b.i.d. (n = 47)\t\t\nPrior therapies, n (%)\t\nTopical\t47 (100)\t\t47 (100)\t\t\nBiologics§\n\t6 (12.8)\t\t9 (19.1)\t\t\nNon‐biologics¶\n\t30 (63.8)\t\t30 (63.8)\t\t\nInadequate response or intolerance to TNFi\t4 (8.5)\t\t4 (8.5)\t\t\nInadequate response or intolerance to MTX, cyclosporin, etretinate or phototherapy\t21 (44.7)\t\t24 (51.1)\t\t\nConcomitant therapies used by ≥5% of patients in any group, n (%)\t\nHydrocortisone in Eurax lotion\t4 (8.5)\t\t5 (10.6)\t\t\nFexofenadine hydrochloride\t3 (6.4)\t\t4 (8.5)\t\t\nBetamethasone butyrate propionate\t2 (4.3)\t\t4 (8.5)\t\t\nLevocetirizine dihydrochloride\t1 (2.1)\t\t4 (8.5)\t\t\nCelecoxib\t0\t\t4 (8.5)\t\t\nTotal\t13 (27.7)\t\t20 (42.6)\t\t\n\n†These five patients had both plaque psoriasis and psoriatic arthritis and were included in both populations. ‡\nn = 34 for tofacitinib 5 mg b.i.d. and n = 31 for tofacitinib 10 mg b.i.d. (patient numbers differed from those with nail psoriasis according to plaque psoriasis and psoriatic arthritis, as patients diagnosed with both psoriasis and psoriatic arthritis were included in both population groups). §Irrespective of previous use of conventional systemic or phototherapy. ¶Including conventional systemic or phototherapy. BMI, body mass index; BSA, body surface area; DLQI, Dermatology Life Quality Index; FAS, full analysis set; ISI, Itch Severity Item; MTX, methotrexate; NA, not applicable; NAPSI, Nail Psoriasis Severity Index; SAS, safety analysis set; SD, standard deviation; TNFi, tumor necrosis factor inhibitor.\n\nJohn Wiley & Sons, LtdBetween Weeks 20 and 52, 8/47 patients initially assigned tofacitinib 5 mg b.i.d. and 11/42 patients initially assigned 10 mg b.i.d. underwent dose changes from the 10 mg b.i.d. dose given during Weeks 16 to 20. Most patients initially assigned to tofacitinib 5 mg b.i.d. were exposed to 10 mg b.i.d. from Weeks 20 to 52. Therefore, formal comparisons between initial dose groups after Week 16 were not appropriate. From Weeks 20 to 52 the median (inter‐quartile range) daily doses received by patients initially assigned to 5 and 10 mg b.i.d. were 19.8 (18.4, 19.9) mg and 19.7 (17.6, 19.9) mg, respectively.\n\nEfficacy\nAt Week 16, with tofacitinib 5 and 10 mg b.i.d., 27 (62.8%, standard error; SE 7.4) and 32 (72.7%; SE 6.7) patients with plaque psoriasis, respectively, achieved a PASI75 response, and 29 [67.4%; SE 7.1] and 30 [68.2%; 7.0] patients achieved a PGA response (Table 2).\n\nTable 2 Clinical responses at Week 16 (double‐blind period; NRI)†\n\n\n\tTofacitinib 5 mg b.i.d., n (%) (SE)\tTofacitinib 10 mg b.i.d., n (%) (SE)\t\nModerate to severe plaque psoriasis population\t\nn = 43\t\nn = 44\t\nPASI75\t27 (62.8) (7.4)\t32 (72.7) (6.7)\t\nPASI90\t16 (37.2) (7.4)\t24 (54.5) (7.5)\t\nPGA response\t29 (67.4) (7.1)\t30 (68.2) (7.0)\t\nPsoriatic arthritis population\t\nn = 4\t\nn = 8\t\nACR20\t4 (100) (0)\t8 (100) (0)\t\nACR50\t3 (75.0) (21.7)\t7 (87.5) (11.7)\t\nACR70\t2 (50) (25.0)\t5 (62.5) (17.1)\t\n\n†No statistically significant difference was observed between dose groups for any end‐point at Week 16. ACR, American College of Rheumatology response criteria; NRI, non‐responder imputation; PASI, Psoriasis Area and Severity Index; PGA, Physician's Global Assessment; SE, standard error.\n\nJohn Wiley & Sons, LtdClinical response rates increased throughout time during the double‐blind period (Fig. 3); although responses with tofacitinib 10 mg b.i.d. appeared higher than with 5 mg b.i.d., actual differences between the doses were relatively small and the only statistically significant difference between doses was observed at Week 4 with PASI75. Response rates of PASI75 in the tofacitinib 5 mg b.i.d. group increased from 27/43 (62.8%; SE 7.4) at Week 16 to 29/43 (67.4%; SE 7.1) at Week 20 upon advancement to 10 mg b.i.d., and response rates remained stable from Week 20 to 52. In patients who achieved a PASI75 response at Week 16 with tofacitinib 10 mg b.i.d., 20/32 (62.5%; SE 8.6) maintained their response to Week 52. Similarly, 18/30 (60.0%; SE 8.9) patients initially assigned tofacitinib 10 mg b.i.d. maintained their Week 16 PGA response to Week 52. Upon treatment cessation, response rates dropped for all measures during the follow‐up period (Fig. 3).\n\nFigure 3 Proportion of patients with moderate to severe plaque psoriasis achieving (a) PASI75, (b) PASI90 and (c) PGA response of “clear” or “almost clear” over time, according to initially randomized dose group (NRI). *P < 0.05 versus tofacitinib 5 mg b.i.d.; FU, follow‐up; NRI, non‐responder imputation; PASI, Psoriasis Area and Severity Index; PGA, Physician's Global Assessment; SE, standard error.\n\nAll 12 patients with psoriatic arthritis achieved an ACR20 response at Week 16, and at least half achieved ACR50 or ACR70 (Table 2). Responses were maintained with tofacitinib treatment through Week 52 and dropped upon treatment cessation (Fig. 4). However, small patient numbers meant that SE were wide.\n\nFigure 4 Proportion of patients with psoriatic arthritis who achieved (a) ACR20, (b) ACR50 and (c) ACR70 response, according to initially randomized dose group (NRI). *P < 0.05 versus tofacitinib 5 mg b.i.d. ACR, American College of Rheumatology response criteria; FU, follow‐up; NRI, non‐responder imputation; SE, standard error.\n\nAt Week 16, 16 (37.2%) patients receiving tofacitinib 5 mg b.i.d., and 24 (54.5%) receiving tofacitinib 10 mg b.i.d., achieved a PASI90 response (Table 2), which followed a similar pattern to PASI75 through 52 weeks (Fig. 3). Improvements in nail psoriasis were observed with both tofacitinib doses by Week 16, which continued to improve through Week 52 (Table 3). Patients also reported reduced itching with tofacitinib at Week 16 irrespective of dose, which was maintained through Week 52. More than half of patients who had a baseline ISI score of more than 1 reported little or no itching (score up to 1) at Week 16 and through Week 52 (Table 3); as early as the first post‐dose visit at Week 2, 13.0% (SE 5.0) and 18.2% (SE 5.8) of patients reported little or no itching with tofacitinib 5 and 10 mg b.i.d., respectively. Similarly, mean DLQI scores decreased by Week 16, representing an improvement in HRQoL, which was maintained to Week 52. Most patients with a baseline DLQI score of more than 1 achieved a score of up to 1, representing no effect of the skin condition (e.g, psoriasis) on HRQoL through Week 52. Improvements in ISI and DLQI were not dose‐related.\n\nTable 3 Summary of secondary efficacy end‐points at Weeks 16, 20 and 52 according to initial randomized dose at baseline (FAS)\n\n\tInitial tofacitinib 5 mg b.i.d.\tInitial tofacitinib 10 mg b.i.d.\t\nMean change from baseline in NAPSI score† (observed cases) (SD)\t\nWeek 16\t−11.3 (14.9)\t−10.2 (13.2)\t\nWeek 20\t−15.1 (15.0)\t−14.6 (13.1)\t\nWeek 52\t−20.6 (15.2)\t−16.3 (15.3)\t\nPatients achieving NAPSI75 response, n/n (%) (NRI)\t\nWeek 16\t5/34 (14.7)\t6/31 (19.4)\t\nWeek 20\t8/34 (23.5)\t13/31 (41.9)\t\nWeek 52\t19/34 (55.9)\t17/31 (54.8)\t\nMean change from baseline in ISI score (observed cases) (SD)\t\nWeek 16\t−4.4 (3.3)\t−4.5 (3.1)\t\nWeek 20\t−5.1 (3.1)\t−4.1 (3.3)\t\nWeek 52\t−4.6 (3.5)\t−4.2 (3.1)\t\nProportion of patients with ISI score of ≤1‡, n/n (%) (NRI)\t\nWeek 16\t31/46 (67.4)\t31/44 (70.5)\t\nWeek 20\t35/46 (76.1)\t25/44 (56.8)\t\nWeek 52\t30/46 (65.2)\t24/44 (54.5)\t\nMean change from baseline in DLQI score (observed cases) (SD)\t\nWeek 16\t−8.5 (6.4)\t−6.7 (5.8)\t\nWeek 20\t−8.8 (6.7)\t−6.8 (5.6)\t\nWeek 52\t−9.7 (6.4)\t−6.1 (5.2)\t\nProportion of patients with DLQI score of ≤1‡, n/n (%) (NRI)\t\nWeek 16\t29/45 (64.4)\t26/44 (59.1)\t\nWeek 20\t30/45 (66.7)\t24/44 (54.5)\t\nWeek 52\t27/45 (60.0)\t25/44 (56.8)\t\n\n†In patients with nail psoriasis at baseline. ‡In patients with a baseline score of more than 1. DLQI, Dermatology Life Quality Index; FAS, full analysis set (both plaque psoriasis and psoriatic arthritis populations); ISI, Itch Severity Item; NAPSI, Nail Psoriasis Severity Index; NRI, non‐responder imputation; SD, standard deviation.\n\nJohn Wiley & Sons, LtdSafety\nIn the SAS, the median duration of tofacitinib exposure was 365 days (Table 4). During the double‐blind phase, AEs were similar between treatment groups; most common AEs are presented in Table 4. Throughout the study, four serious AEs were reported: one case of vertigo with tofacitinib 10 mg b.i.d. during the double‐blind period and three cases of herpes zoster in the open‐label variable‐dose period (one receiving 5 mg b.i.d. and two receiving 10 mg b.i.d. at onset of herpes zoster). Two additional serious AEs were reported during follow‐up after Week 52: one case of rapid progression of psoriasis on post‐dose Day 14, and impetigo and erythrodermic psoriasis in the same patient on post‐dose Day 7; this patient was receiving tofacitinib 10 mg b.i.d. at the earliest onset of impetigo. Patients with serious AEs were permanently withdrawn from the study; all serious AEs, including those occurring during follow‐up, resolved, except the erythrodermic psoriasis that was still resolving at the time of this report.\n\nTable 4 Summary of all‐causality AEs (SAS)\n\n\tTofacitinib 5 mg b.i.d., n (%)\tTofacitinib 10 mg b.i.d., n (%)\t\nMedian duration of exposure, days (range)\t365 (139–372)\t365 (7–370)\t\nWeek 0–16\t\nn = 47\t\nn = 47\t\nAEs\t27 (57.4)\t28 (59.6)\t\nSerious AEs\t0\t1 (2.1)\t\nDiscontinuations due to AEs\t0\t1 (2.1)\t\nMost common AEs (≥5% of patients in any group)\t\nNasopharyngitis\t9 (19.1)\t8 (17.0)\t\nHeadache\t1 (2.1)\t3 (6.4)\t\nInfluenza\t3 (6.4)\t0\t\nDecreased hemoglobin\t0\t3 (6.4)\t\nWeeks 0–52†\n\tTotal n = 94\t\t\nAEs\t78 (83.0)\t\t\nSerious AEs\t4 (4.3)\t\t\nDiscontinuations due to AEs\t8 (8.5)\t\t\nMost common AEs (≥5% of patients)\t\nNasopharyngitis\t28 (29.8)\t\t\nHerpes zoster (serious and non‐serious)\t16 (17.0)‡\n\t\t\nPsoriasis\t9 (9.6)\t\t\nTinea pedis\t9 (9.6)\t\t\nInfluenza\t6 (6.4)\t\t\nIncreased blood creatine phosphokinase\t5 (5.3)\t\t\nDecreased hemoglobin\t5 (5.3)\t\t\n\n†AEs occurring up to day 372 are included. ‡Three cases were serious. AEs, adverse events; SAS, safety analysis set.\n\nJohn Wiley & Sons, LtdOverall, herpes zoster occurred in 16 patients, all but two events (neither considered serious) occurred during the open‐label variable‐dosing period. Tofacitinib doses at onset of herpes zoster were 5 mg b.i.d. in two patients, 10 mg b.i.d. in 13 patients, and one case occurred during follow‐up after the patient had been receiving 10 mg b.i.d. One case was considered severe, and no cases of multidermatomal, disseminated, systemic or ophthalmic herpes zoster were reported (serious cases are described above). Commonly occurring infections included nasopharyngitis, influenza and tinea pedis (Table 4), none of which were serious.\n\nNo serious infections other than herpes zoster were reported during the double‐blind period. In the open‐label period, further to the three herpes zoster cases described above, one serious infection of impetigo was reported, as described above.\n\nDiscontinuations due to AEs included one patient with worsening psoriasis receiving tofacitinib 10 mg b.i.d. in the double‐blind period. In the open‐label period three patients with serious herpes zoster described above, two with worsening psoriasis and two with AEs relating to liver function test abnormalities discontinued the study.\n\nNo malignancies, cardiovascular events, or deaths were reported in this study.\n\nChanges in laboratory parameters throughout time are summarized in Figure 5. Neutrophil levels decreased with initiation of tofacitinib, but remained stable through the study and returned to baseline upon treatment cessation (Fig. 5a). Lymphocyte levels initially rose with tofacitinib treatment, then, gradually decreased to baseline levels at Week 52 (Fig. 5b). Decreased hemoglobin levels were reported with tofacitinib 10 mg b.i.d. (Table 4); however, levels remained stable for the duration of the study (Fig. 5c). There were no confirmed cases (two consecutive measurements or occurring at the final visit) of patients with neutrophil counts <0.5 × 103/mm3, lymphocyte counts <0.5 × 103/mm3, hemoglobin levels <10 g/dL, or aspartate aminotransferase levels ≥3× upper limit of normal (ULN). Two patients with normal baseline alanine aminotransferase levels had confirmed post‐dose levels ≥3× ULN (one in each initial dose group). Creatine phosphokinase levels initially increased in the first 16 weeks, and remained stable for the remainder of the study (Fig. 5d). No rhabdomyolysis events were reported, and no potential Hy's Law cases were found. Levels of low‐density lipoprotein cholesterol (LDL‐C) and high‐density lipoprotein cholesterol (HDL‐C) increased upon treatment initiation and returned to baseline levels upon treatment cessation (Fig. 5e, f); the LDL‐C/HDL‐C ratio remained stable throughout the study (Fig. 5g).\n\nFigure 5 Change from baseline in laboratory parameters through follow‐up, for (a) neutrophil counts, (b) lymphocyte counts, (c) hemoglobin levels, (d) creatine phosphokinase, (e) LDL cholesterol, (f) HDL cholesterol and (g) LDL/HDL ratio, by initially randomized dose group (safety analysis set). HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; SD, standard deviation.\n\nNo notable changes in blood pressure, ECG, or physical examination were observed at any time point, or between treatment groups.\n\nDiscussion\nThis phase 3 study demonstrated short‐term efficacy of tofacitinib at both 5 and 10 mg b.i.d. doses and maintenance of efficacy for 52 weeks with a manageable safety profile in Japanese patients with moderate to severe plaque psoriasis and/or active psoriatic arthritis.\n\nThis study population exhibited a considerable disease burden at baseline; all had previously used topical therapies and approximately half had previously had inadequate responses to, or were intolerant to, commonly used conventional systemic or phototherapy. In addition, 16% of patients had previously received biologics. Patient HRQoL was also affected by their disease, as evidenced by mean DLQI scores of 8.4–10.7 at baseline corresponding to a moderate to large effect on the patient's HRQoL.\n\nClinical responses in patients with plaque psoriasis at Week 16 were slightly higher than those reported in one phase 2 study and four global phase 3 studies of 12–24 weeks of tofacitinib treatment in patients with moderate to severe plaque psoriasis.26, 27, 28, 29 In this study, mean PASI75 responses with tofacitinib at Week 16 in patients with plaque psoriasis were numerically higher with tofacitinib 10 mg b.i.d. (72.7%) than with 5 mg b.i.d. (62.8%), and mean PGA responses were similar with 10 mg b.i.d. (68.2%) and 5 mg b.i.d. (67.4%). However, this apparent difference was narrower than in the global studies, which reported PASI75 rates of 59–68% with 10 mg b.i.d. and 40–46% with 5 mg b.i.d. after 12–24 weeks.26, 27, 28, 29 Week 16 mean PGA responses in our study were similar between doses (68% with 10 mg b.i.d. and 67% with 5 mg b.i.d.), again in contrast with the above global studies which showed a marked difference between doses: 59–68% with 10 mg b.i.d. and 41–47% with 5 mg b.i.d. after 12–24 weeks.\n\nPASI75 response rates previously reported in global studies of patients with psoriasis after 12–16 weeks of treatment with other oral systemic agents have ranged from 10 to 41% with methotrexate33 and apremilast.34, 35 PASI75 responses after 10–24 weeks of treatment with biologics have ranged from 53 to 82% with infliximab, adalimumab, ustekinumab, and secukinumab in global studies36, 37, 38, 39, 40 and were similar in Japanese patients.10, 11, 12, 13 PASI75 responses with tofacitinib in this study appeared to be higher than those reported with oral systemic therapies and were in the range for those with biologics, but direct comparisons cannot be made due to differences in study designs and patient populations between studies; head‐to‐head studies would be required. The slight increase in PASI75 response rates observed with tofacitinib in Japanese patients in the present study compared with the global tofacitinib studies was not readily apparent in the above studies of biologics in global and Japanese patient populations.\n\nIn the present study, all 12 patients with psoriatic arthritis achieved an ACR20 response by Week 16 with both tofacitinib dose groups; rates were maintained with tofacitinib treatment to Week 52, although interpretation of the response is limited by low patient numbers. This is the first study to show efficacy of tofacitinib in psoriatic arthritis. ACR20 rates in global studies of patients with psoriatic arthritis after 12–16 weeks of apremilast treatment were 31–44%.41, 42 In global studies with biologics, ACR20 rates have ranged from 44 to 59% after 12–24 weeks of treatment with golimumab,43 adalimumab,44 ustekinumab,45 etanercept (US only),46 and infliximab47 in patients with psoriatic arthritis. Tofacitinib showed promising efficacy in the context of the above studies, although direct comparisons cannot be drawn, as patient numbers were low in the present study and study populations and designs differed.\n\nTofacitinib has been evaluated in multiple phase 2 and 3 studies in RA, including one phase 2 study in a Japanese RA population.48 Week 12 ACR20 rates were 73% and 85% with tofacitinib 5 and 10 mg b.i.d., respectively, which were in line with the high response rates observed in the present study. However, caution must be used in comparing efficacy in patients with psoriatic arthritis and RA, due to differences in the background diseases and demographics for each patient population.\n\nPatients in the present study reported improvements in their nail psoriasis, itch and dermatology‐related QoL for the duration of the study; most patients (54.5–65.2%) reported little or no itching following 52 weeks of tofacitinib treatment with some reporting improvements as early as Week 2. The mean change from baseline in the DLQI total score (−9.7 in patients initially assigned tofacitinib 5 mg b.i.d., −6.1 in patients initially assigned 10 mg b.i.d.) was greater than the estimated minimally important difference of 4 points,49 demonstrating clinically meaningful improvements in HRQoL with tofacitinib by Week 16, which were maintained through Week 52. These results are consistent with those seen in Japanese patients with moderate to severe plaque psoriasis treated with ustekinumab11 or adalimumab.10 Nail psoriasis can be difficult to treat and can affect patients' QoL.50 In addition, itching has been identified as one of the most bothersome symptoms of psoriasis and psoriatic arthritis with skin involvement.25 Therefore, effective treatment of these conditions, as indicated here, is an important factor in disease management.\n\nThe safety profile of tofacitinib did not raise any new safety signals compared with the global phase 3 tofacitinib studies; rates of AEs, serious AEs and discontinuations were similar to those previously reported with tofacitinib in plaque psoriasis,27, 28, 29 except for herpes zoster and tinea pedis, discussed below. In addition, 52‐week rates for AEs were similar to those reported in Japanese patients with moderate to severe plaque psoriasis treated with ustekinumab11 or secukinumab,12 and in global studies of methotrexate33 and apremilast34 in moderate to severe plaque psoriasis. AEs with tofacitinib were fewer than those in a study of Japanese patients with moderate to severe plaque psoriasis treated with 24 weeks of adalimumab, which reported AEs in 91–97% of patients,10 although direct comparisons would require head‐to‐head studies. The most common AEs reported here were similar to those previously reported with biologics with the exception of tinea pedis, which occurred in 10% of patients in the present study. Tinea pedis was not reported as a common AE (<2–12% of patients) in the above studies of biologics,10, 11, 13, 36, 37, 38, 39, 40, 43, 44, 45, 46, 47 except for a subanalysis in Japanese patients of a phase 3 study of the interleukin (IL)‐17 inhibitor secukinumab in patients with psoriasis, which reported tinea pedis in 6% of patients.12 This was not reported as a common AE in the parent study.40 IL‐17 levels have been shown to decrease in patients treated with tofacitinib,51 but tinea pedis was not identified as a common AE in the tofacitinib global studies.26, 27, 28, 29 Further research would be necessary to identify any link between tofacitinib and tinea pedis in Japanese patients with psoriasis.\n\nPrevious global studies in psoriasis and RA with tofacitinib identified an increased incidence rate of herpes zoster in patients from Japan and South Korea compared with the rest of the study population.52, 53 In the current study, herpes zoster was reported in 17% of patients. Most patients who developed herpes zoster were receiving the 10 mg b.i.d. dose. A 56‐week phase 3 global study of tofacitinib in patients with moderate to severe plaque psoriasis reported eight patients (1.1%) with herpes zoster.28 In RA, higher incidence rates of herpes zoster with tofacitinib have been reported in Japanese patients versus global study populations (8.0 vs 4.4 events/100 patient‐years).52, 54 In addition, analysis of data from global phase 2, 3 and long‐term extension studies of tofacitinib in patients with psoriasis revealed that Asian race (mostly Japanese) was found to be independently associated with the development of herpes zoster versus non‐Asian race (hazard ratio, 5.87; 95% confidence interval, 3.06–11.26).53 Further analysis of incidence rates in Japanese and global study populations with tofacitinib is required to understand the potential difference in herpes zoster rates between these patient populations. The incidence rate of herpes zoster in Japanese patients with psoriasis has been estimated at 4.15/1000 patient‐years.55\n\n\nThis study had a number of limitations. Between Weeks 16 and 20, all patients received tofacitinib 10 mg b.i.d. and many patients remained on tofacitinib 10 mg b.i.d. thereafter, so comparisons between doses were not feasible after Week 16. Although there were a low number of patients with psoriatic arthritis, the study did show signs of tofacitinib efficacy in these patients, and phase 3 studies are ongoing to further evaluate tofacitinib in patients with psoriatic arthritis (clinicaltrials.gov NCT01882439 and NCT01877668). Furthermore, there was no placebo control.\n\nIn this study, oral tofacitinib demonstrated efficacy for the treatment of patients with moderate to severe plaque psoriasis and/or psoriatic arthritis during a 52‐week period, with a manageable safety profile that was generally consistent with the global population. Many patients had received prior systemic therapy, which reflects clinical practice where many patients have previously received systemic therapies. Furthermore, the open‐label period of the study reflected what may take place in clinical practice, where physicians could increase the dose from 5 to 10 mg b.i.d. in cases of inadequate response. Differences in clinical response between the 5 and 10 mg b.i.d. doses were small in this study compared with global studies; however, the proportion of patients with PASI75 response showed a small increase from 62.8% to 67.4% when patients switched from 5 to 10 mg b.i.d. from Week 16 to 20. These responses were maintained through Week 52 in the majority of patients, which may suggest a patient could be treated with tofacitinib 5 mg b.i.d. initially, and that tofacitinib 10 mg b.i.d. could be a feasible option for patients who do not achieve a sufficient response at the 5 mg b.i.d. dose. However, higher rates of herpes zoster seen with tofacitinib 10 mg b.i.d. must be taken into account, and further research with larger patient numbers is required to confirm this conclusion.\n\nThis study adds to a growing body of evidence of tofacitinib efficacy and safety in plaque psoriasis and supports the continued investigation of tofacitinib in the management of moderate to severe plaque psoriasis in Japan.\n\nConflict of interest\nThis study was sponsored by Pfizer Inc. A. A., A. I., S. I., H. S. and M. O. have received consultancy fees from Pfizer Inc. Y. S., Y. T., S. T. and M. N. are employees of Pfizer Japan Inc. T. E. has nothing to disclose.\n\nSupporting information\n\nAppendix S1. Principal study investigators at each center.\n\nClick here for additional data file.\n\n Acknowledgments\nThe authors would like to thank the investigators and patients of the A3921137 study. This study was sponsored by Pfizer Inc. Medical writing support under the guidance of the authors was provided by Kate Silverthorne, Ph.D., at Complete Medical Communications and was funded by Pfizer Inc.\n==== Refs\nReferences\n1 \n\nGudjonsson \nJE \n, \nElder \nJT \n. Psoriasis In: Goldsmith LA , Katz SI , Gilchrest BA , Paller A , Leffell DJ , Wolff K , eds. Fitzpatrick's Dermatology in General Medicine , 8th edn \nNew York : McGraw‐Hill Medical , 2012 ; 197 –232 .\n2 \n\nSchön \nMP \n, \nBoehncke \nWH \n. Psoriasis . N Engl J Med \n2005 ; 352 : 1899 –1912 .15872205 \n3 \n\nRapp \nSR \n, \nFeldman \nSR \n, \nExum \nML \n, \nFleischer \nAB \nJr\n, \nReboussin \nDM \n. Psoriasis causes as much disability as other major medical diseases . J Am Acad Dermatol \n1999 ; 41 : 401 –407 .10459113 \n4 \n\nKubota \nK \n, \nKamijima \nY \n, \nSato \nT \n\net al\nEpidemiology of psoriasis and palmoplantar pustulosis: a nationwide study using the Japanese national claims database . BMJ Open \n2015 ; 5 : e006450 .\n5 \n\nGelfand \nJM \n, \nStern \nRS \n, \nNijsten \nT \n\net al\nThe prevalence of psoriasis in African Americans: results from a population‐based study . J Am Acad Dermatol \n2005 ; 52 : 23 –26 .15627076 \n6 \n\nParisi \nR \n, \nSymmons \nDP \n, \nGriffiths \nCE \n, \nAshcroft \nDM \n. Global epidemiology of psoriasis: a systematic review of incidence and prevalence . J Invest Dermatol \n2013 ; 133 : 377 –385 .23014338 \n7 \n\nRachakonda \nTD \n, \nSchupp \nCW \n, \nArmstrong \nAW \n. Psoriasis prevalence among adults in the United States . J Am Acad Dermatol \n2014 ; 70 : 512 –516 .24388724 \n8 \n\nTakahashi \nH \n, \nNakamura \nK \n, \nKaneko \nF \n, \nNakagawa \nH \n, \nIizuka \nH \n. Analysis of psoriasis patients registered with the Japanese Society for Psoriasis Research from 2002‐2008 . J Dermatol \n2011 ; 38 : 1125 –1129 .21951304 \n9 \n\nOhara \nY \n, \nKishimoto \nM \n, \nTakizawa \nN \n\net al\nPrevalence and Clinical Characteristics of Psoriatic Arthritis in Japan . J Rheumatol \n2015 ; 42 : 1439 –1442 .26077408 \n10 \n\nAsahina \nA \n, \nNakagawa \nH \n, \nEtoh \nT \n, \nOhtsuki \nM \n. Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study . J Dermatol \n2010 ; 37 : 299 –310 .20507398 \n11 \n\nIgarashi \nA \n, \nKato \nT \n, \nKato \nM \n, \nSong \nM \n, \nNakagawa \nH \n. Efficacy and safety of ustekinumab in Japanese patients with moderate‐to‐severe plaque‐type psoriasis: long‐term results from a phase 2/3 clinical trial . J Dermatol \n2012 ; 39 : 242 –252 .21955098 \n12 \n\nOhtsuki \nM \n, \nMorita \nA \n, \nAbe \nM \n\net al\nSecukinumab efficacy and safety in Japanese patients with moderate‐to‐severe plaque psoriasis: subanalysis from ERASURE, a randomized, placebo‐controlled, phase 3 study . J Dermatol \n2014 ; 41 : 1039 –1046 .25354738 \n13 \n\nTorii \nH \n, \nNakagawa \nH \n. Infliximab monotherapy in Japanese patients with moderate‐to‐severe plaque psoriasis and psoriatic arthritis. A randomized, double‐blind, placebo‐controlled multicenter trial . J Dermatol Sci \n2010 ; 59 : 40 –49 .20547039 \n14 \n\nOhtsuki \nM \n, \nTerui \nT \n, \nOzawa \nA \n\net al\nJapanese guidance for use of biologics for psoriasis (the 2013 version) . J Dermatol \n2013 ; 40 : 683 –695 .24033880 \n15 \n\nHsu \nS \n, \nPapp \nKA \n, \nLebwohl \nMG \n\net al\nConsensus guidelines for the management of plaque psoriasis . Arch Dermatol \n2012 ; 148 : 95 –102 .22250239 \n16 \n\nWeger \nW \n. Current status and new developments in the treatment of psoriasis and psoriatic arthritis with biological agents . Br J Pharmacol \n2010 ; 160 : 810 –820 .20590580 \n17 \n\nHalioua \nB \n, \nSaurat \nJH \n. Risk: benefit ratio in the treatment of psoriasis with systemic retinoids . Br J Dermatol \n1990 ; 122 (Suppl 36 ): 135 –150 .2142437 \n18 \n\nStern \nRS \n, \nNichols \nKT \n, \nVakeva \nLH \n. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow‐Up Study . N Engl J Med \n1997 ; 336 : 1041 –1045 .9091799 \n19 \n\nStudniberg \nHM \n, \nWeller \nP \n. PUVA, UVB, psoriasis, and nonmelanoma skin cancer . J Am Acad Dermatol \n1993 ; 29 : 1013 –1022 .8245237 \n20 \n\nWeinberg \nJM \n. An overview of infliximab, etanercept, efalizumab, and alefacept as biologic therapy for psoriasis . Clin Ther \n2003 ; 25 : 2487 –2505 .14667953 \n21 \n\nZisapel \nM \n, \nZisman \nD \n, \nMadar‐Balakirski \nN \n\net al\nPrevalence of TNF‐alpha Blocker Immunogenicity in Psoriatic Arthritis . J Rheumatol \n2015 ; 42 : 73 –78 .25399390 \n22 \n\nNaldi \nL \n, \nGriffiths \nCE \n. Traditional therapies in the management of moderate to severe chronic plaque psoriasis: an assessment of the benefits and risks . Br J Dermatol \n2005 ; 152 : 597 –615 .15840088 \n23 \n\nUmar \nN \n, \nSchaarschmidt \nM \n, \nSchmieder \nA \n, \nPeitsch \nWK \n, \nSchollgen \nI \n, \nTerris \nDD \n. Matching physicians' treatment recommendations to patients' treatment preferences is associated with improvement in treatment satisfaction . J Eur Acad Dermatol Venereol \n2013 ; 27 : 763 –770 .22631875 \n24 \n\nTorii \nH \n, \nNakagawa \nH \n. Questionnaire survey of perceived satisfaction with treatment of patients with psoriasis . Jpn J Dermatol \n2013 ; 123 : 1935 –1944 .\n25 \n\nLebwohl \nMG \n, \nBachelez \nH \n, \nBarker \nJ \n\net al\nPatient perspectives in the management of psoriasis: results from the population‐based Multinational Assessment of Psoriasis and Psoriatic Arthritis Survey . J Am Acad Dermatol \n2014 ; 70 : 871 –881 .24576585 \n26 \n\nPapp \nKA \n, \nMenter \nA \n, \nStrober \nB \n\net al\nEfficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo‐controlled dose‐ranging study . Br J Dermatol \n2012 ; 167 : 668 –677 .22924949 \n27 \n\nBachelez \nH \n, \nvan de Kerkhof \nPCM \n, \nStrohal \nR \n\net al\nTofacitinib versus etanercept or placebo in moderate‐to‐severe chronic plaque psoriasis: a phase 3 randomised non‐inferiority trial . Lancet \n2015 ; 386 : 552 –561 .26051365 \n28 \n\nBissonnette \nR \n, \nIversen \nL \n, \nSofen \nH \n\net al\nTofacitinib withdrawal and retreatment in moderate‐to‐severe chronic plaque psoriasis: a randomized controlled trial . Br J Dermatol \n2015 ; 172 : 1395 –1406 .25418186 \n29 \n\nPapp \nKA \n, \nMenter \nA \n, \nAbe \nM \n\net al\nTofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo‐controlled, phase III trials . Br J Dermatol \n2015 ; 173 : 949 –961 .26149717 \n30 \n\nTaylor \nW \n, \nGladman \nD \n, \nHelliwell \nP \n, \nMarchesoni \nA \n, \nMease \nP \n, \nMielants \nH \n. Classification criteria for psoriatic arthritis: development of new criteria from a large international study . Arthritis Rheum \n2006 ; 54 : 2665 –2673 .16871531 \n31 \n\nRich \nP \n, \nScher \nRK \n. Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis . J Am Acad Dermatol \n2003 ; 49 : 206 –212 .12894066 \n32 \n\nFinlay \nAY \n, \nKhan \nGK \n. Dermatology Life Quality Index (DLQI)–a simple practical measure for routine clinical use . Clin Exp Dermatol \n1994 ; 19 : 210 –216 .8033378 \n33 \n\nSaurat \nJH \n, \nStingl \nG \n, \nDubertret \nL \n\net al\nEfficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION) . Br J Dermatol \n2008 ; 158 : 558 –566 .18047523 \n34 \n\nPapp \nK \n, \nCather \nJC \n, \nRosoph \nL \n\net al\nEfficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial . Lancet \n2012 ; 380 : 738 –746 .22748702 \n35 \n\nPapp \nKA \n, \nKaufmann \nR \n, \nThaci \nD \n, \nHu \nC \n, \nSutherland \nD \n, \nRohane \nP \n. Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: results from a phase II, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, dose‐comparison study . J Eur Acad Dermatol Venereol \n2013 ; 27 : e376 –e383 .23030767 \n36 \n\nReich \nK \n, \nNestle \nFO \n, \nPapp \nK \n\net al\nInfliximab induction and maintenance therapy for moderate‐to‐severe psoriasis: a phase III, multicentre, double‐blind trial . Lancet \n2005 ; 366 : 1367 –1374 .16226614 \n37 \n\nGordon \nKB \n, \nLangley \nRG \n, \nLeonardi \nC \n\net al\nClinical response to adalimumab treatment in patients with moderate to severe psoriasis: double‐blind, randomized controlled trial and open‐label extension study . J Am Acad Dermatol \n2006 ; 55 : 598 –606 .17010738 \n38 \n\nLeonardi \nCL \n, \nKimball \nAB \n, \nPapp \nKA \n\net al\nEfficacy and safety of ustekinumab, a human interleukin‐12/23 monoclonal antibody, in patients with psoriasis: 76‐week results from a randomised, double‐blind, placebo‐controlled trial (PHOENIX 1) . Lancet \n2008 ; 371 : 1665 –1674 .18486739 \n39 \n\nPapp \nKA \n, \nLangley \nRG \n, \nLebwohl \nM \n\net al\nEfficacy and safety of ustekinumab, a human interleukin‐12/23 monoclonal antibody, in patients with psoriasis: 52‐week results from a randomised, double‐blind, placebo‐controlled trial (PHOENIX 2) . Lancet \n2008 ; 371 : 1675 –1684 .18486740 \n40 \n\nLangley \nRG \n, \nElewski \nBE \n, \nLebwohl \nM \n\net al\nSecukinumab in plaque psoriasis–results of two phase 3 trials . N Engl J Med \n2014 ; 371 : 326 –338 .25007392 \n41 \n\nKavanaugh \nA \n, \nMease \nPJ \n, \nGomez‐Reino \nJJ \n\net al\nTreatment of psoriatic arthritis in a phase 3 randomised, placebo‐controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor . Ann Rheum Dis \n2014 ; 73 : 1020 –1026 .24595547 \n42 \n\nSchett \nG \n, \nWollenhaupt \nJ \n, \nPapp \nK \n\net al\nOral apremilast in the treatment of active psoriatic arthritis: results of a multicenter, randomized, double‐blind, placebo‐controlled study . Arthritis Rheum \n2012 ; 64 : 3156 –3167 .22806399 \n43 \n\nKavanaugh \nA \n, \nMcInnes \nI \n, \nMease \nP \n\net al\nGolimumab, a new human tumor necrosis factor alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: twenty‐four‐week efficacy and safety results of a randomized, placebo‐controlled study . Arthritis Rheum \n2009 ; 60 : 976 –986 .19333944 \n44 \n\nMease \nPJ \n, \nGladman \nDD \n, \nRitchlin \nCT \n\net al\nAdalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double‐blind, randomized, placebo‐controlled trial . Arthritis Rheum \n2005 ; 52 : 3279 –3289 .16200601 \n45 \n\nRitchlin \nC \n, \nRahman \nP \n, \nKavanaugh \nA \n\net al\nEfficacy and safety of the anti‐IL‐12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non‐biological and biological anti‐tumour necrosis factor therapy: 6‐month and 1‐year results of the phase 3, multicentre, double‐blind, placebo‐controlled, randomised PSUMMIT 2 trial . Ann Rheum Dis \n2014 ; 73 : 990 –999 .24482301 \n46 \n\nMease \nPJ \n, \nKivitz \nAJ \n, \nBurch \nFX \n\net al\nEtanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression . Arthritis Rheum \n2004 ; 50 : 2264 –2272 .15248226 \n47 \n\nKavanaugh \nA \n, \nKrueger \nGG \n, \nBeutler \nA \n\net al\nInfliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial . Ann Rheum Dis \n2007 ; 66 : 498 –505 .17114188 \n48 \n\nTanaka \nY \n, \nTakeuchi \nT \n, \nYamanaka \nH \n, \nNakamura \nH \n, \nToyoizumi \nS \n, \nZwillich \nS \n. Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12‐week, randomized, phase 2 study . Mod Rheumatol \n2015 ; 25 : 514 –521 .25496464 \n49 \n\nBasra \nMK \n, \nSalek \nMS \n, \nCamilleri \nL \n, \nSturkey \nR \n, \nFinlay \nAY \n. Determining the minimal clinically important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further data . Br J Dermatol \n2015 ; 230 : 27 –33 .\n50 \n\nGupta \nAK \n, \nCooper \nEA \n. Psoriatic nail disease: quality of life and treatment . J Cutan Med Surg \n2009 ; 13 (Suppl 2 ): S102 –S106 .19799826 \n51 \n\nKrueger \nJ \n, \nSuarez‐Farinas \nM \n, \nFuentes‐Duculan \nJ \n\net al\nPathologic immune pathways in psoriasis are rapidly attenuated by tofacitinib treatment . Br J Dermatol \n2014 ; 171 : e120 .\n52 \n\nWinthrop \nKL \n, \nYamanaka \nH \n, \nValdez \nH \n\net al\nHerpes zoster and tofacitinib therapy in patients with rheumatoid arthritis . Arthritis Rheumatol \n2014 ; 66 : 2675 –2684 .24943354 \n53 \n\nWinthrop \nK \n, \nLebwohl \nM \n, \nCohen \nAD \n\net al\nHerpes zoster and tofacitinib therapy in patients with psoriasis . J Invest Dermatol \n2015 ; 135 : S1 .\n54 \n\nYamaoka \nK \n, \nTanaka \nY \n, \nMorishima \nY \n\net al\nHerpes zoster and tofacitinib therapy in Japanese patients with rheumatoid arthritis . Japan College of Rheumatology – 59th Annual Scientific Meeting 2015 ; 25 : S96 .\n55 \n\nToyama \nN \n, \nShiraki \nK \n. Epidemiology of herpes zoster and its relationship to varicella in Japan: a 10‐year survey of 48 388 herpes zoster cases in Miyazaki prefecture . J Med Virol \n2009 ; 81 : 2053 –2058 .19856466\n\n",
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"title": "Oral tofacitinib efficacy, safety and tolerability in Japanese patients with moderate to severe plaque psoriasis and psoriatic arthritis: A randomized, double-blind, phase 3 study.",
"title_normalized": "oral tofacitinib efficacy safety and tolerability in japanese patients with moderate to severe plaque psoriasis and psoriatic arthritis a randomized double blind phase 3 study"
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"abstract": "An 86-year-old female nursing home resident was typically described by the nursing staff as alert, pleasant, and conversant, although disoriented to time and place at times. She was frequently seen in the hallways, often breaking into song with her melodious voice. Her past medical history was significant for dementia, epilepsy, and bipolar disorder, for which she took lithium carbonate. One day, she complained to her nurse that she had been stuttering, finding it difficult to complete a sentence, as well as sing. This persisted for 3 more months until a lithium level was checked, and came back elevated at 2.0 mmol/L (0.6 to 1.2 mmol/L). Lithium carbonate was promptly stopped and after about 2 weeks, her stuttering had completely resolved. We found considerable interest in this case, as lithium has rarely been associated with drug-induced stuttering. We reviewed drug-induced stuttering, enumerated the medications implicated in various case reports, and discussed its mechanisms and management.",
"affiliations": "Department of Geriatrics, Cleveland Clinic Florida, 2950 Cleveland Clinic Boulevard, Weston, FL 33331, USA. sabills@ccf.org",
"authors": "Sabillo|Sheryl|S|;Samala|Renato V|RV|;Ciocon|Jerry O|JO|",
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"title": "A stuttering discovery of lithium toxicity.",
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"abstract": "Treatment of gestational multidrug-resistant tuberculosis (MDR-TB) is controversial. We describe follow-up of 6 children exposed to second-line antituberculous agents in utero. Each child (average age, 3.7 years) underwent comprehensive clinical evaluation. One child had MDR-TB diagnosed. There was no evidence of significant late-presentation toxicity among the children. The results suggest that aggressive management of gestational MDR-TB may benefit both mother and child.",
"affiliations": "Department of Social Medicine and Health Inequalities, Brigham and Women's Hospital, Boston, MA 02120, USA. pdrobac@partners.org",
"authors": "Drobac|Peter C|PC|;del Castillo|Hernan|H|;Sweetland|Annika|A|;Anca|Genaro|G|;Joseph|J Keith|JK|;Furin|Jennifer|J|;Shin|Sonya|S|",
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"title": "Treatment of multidrug-resistant tuberculosis during pregnancy: long-term follow-up of 6 children with intrauterine exposure to second-line agents.",
"title_normalized": "treatment of multidrug resistant tuberculosis during pregnancy long term follow up of 6 children with intrauterine exposure to second line agents"
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"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-01667",
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"abstract": "BACKGROUND\nNeutrophilic eccrine hidradenitis (NEH) is a rare condition described mostly in adult patients receiving chemotherapy for acute myelogenous leukemia. When it affects the facial region, it can mimic cellulitis and delay the diagnostic, thus proper recognition is essential.\n\n\nOBJECTIVE\nThis article describes a classic case of NEH. We will review the diagnostic, the differential diagnostic (mostly cellulitis) and the management of this condition.\n\n\nMETHODS\nAfter a literature review, the patient's file was properly studied in order to portray a clear picture of this condition. Medical photographs and appropriate physical examination upon presentation are also included.\n\n\nRESULTS\nThe diagnostic for NEH was suggested by the clinical presentation and confirmed histopathologically (skin biopsy).\n\n\nCONCLUSIONS\nThe diagnostic of NEH is essential in order to prevent multiple unnecessary antibiotics.",
"affiliations": "Division of Dermatology, Department of Medicine, Université de Sherbrooke, Qué., Canada.;Division of Hematology and Oncology, Department of Medicine, Université de Sherbrooke, Qué., Canada.;Department of Pathology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Qué., Canada.;Division of Infectiology, Department of Microbiology and Infectiology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Qué., Canada.;Division of Dermatology, Department of Medicine, Université de Sherbrooke, Qué., Canada.",
"authors": "Copaescu|Ana-Maria|AM|;Castilloux|Jean-François|JF|;Chababi-Atallah|Myrna|M|;Sinave|Christian|C|;Bertrand|Janie|J|",
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"doi": "10.1159/000356229",
"fulltext": "\n==== Front\nCase Rep DermatolCase Rep DermatolCDECase Reports in Dermatology1662-6567S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000356229cde-0005-0340Published online: November, 2013A Classic Clinical Case: Neutrophilic Eccrine Hidradenitis Copaescu Ana-Maria a*Castilloux Jean-François bChababi-Atallah Myrna cSinave Christian dBertrand Janie aaDivision of Dermatology, Department of Medicine, Université de Sherbrooke, Qué., CanadabDivision of Hematology and Oncology, Department of Medicine, Université de Sherbrooke, Qué., CanadacDepartment of Pathology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Qué., CanadadDivision of Infectiology, Department of Microbiology and Infectiology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Qué., Canada*Ana-Maria Copaescu, 6525 Avenue Wilderton, PH #1, Montreal, QC H3S 2L4 (Canada), E-Mail ana-maria.copaescu@usherbrooke.caSep-Dec 2013 28 9 2013 28 9 2013 5 3 340 346 Copyright © 2013 by S. Karger AG, Basel2013This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Background\nNeutrophilic eccrine hidradenitis (NEH) is a rare condition described mostly in adult patients receiving chemotherapy for acute myelogenous leukemia. When it affects the facial region, it can mimic cellulitis and delay the diagnostic, thus proper recognition is essential.\n\nObjective\nThis article describes a classic case of NEH. We will review the diagnostic, the differential diagnostic (mostly cellulitis) and the management of this condition.\n\nMethods\nAfter a literature review, the patient's file was properly studied in order to portray a clear picture of this condition. Medical photographs and appropriate physical examination upon presentation are also included.\n\nResults\nThe diagnostic for NEH was suggested by the clinical presentation and confirmed histopathologically (skin biopsy).\n\nConclusion\nThe diagnostic of NEH is essential in order to prevent multiple unnecessary antibiotics.\n\nKey Words\nNeutrophilic dermatosisNeutrophilic eccrine hidradenitisFacial cellulitisChemotherapy\n==== Body\nBackground\nThe term was used for the first time in 1982 to describe the skin reaction in a patient undergoing chemotherapy for myeloblastic leukemia; neutrophilic eccrine hidradenitis (NEH) unfortunately remains a poorly understood concept. The diagnosis is made histologically and usually refers to a neutrophilic infiltration around the eccrine sweat glands and mostly around the proximal portion coils.\n\nNEH is usually described in relation to other neutrophilic dermatoses, a group of skin diseases characterized by an infiltration of the skin by normal polymorphonuclear neutrophils No infectious or other causes are identified [1]; thus, its clinical aspect makes NEH sometimes difficult to distinguish from the Sweet Syndrome, an entity that will not be addressed in detail in this article.\n\nNEH is a rare condition, though epidemiology was not precisely studied for this condition. Neutrophilic dermatoses in granulocytopenic patients receiving chemotherapy occur at an incidence rate of 2.6% (according to an article published in 1995) [2]. Furthermore, some case reports describe a facial NEH that can mimic cellulitis. For these patients, proper recognition of NEH can prevent unnecessary usage of antibiotics.\n\nIn this article, we describe a classic case of NEH with facial involvement in a patient receiving chemotherapy for acute myelogenous leukemia. A literature review will also be discussed.\n\nCase Report\nA 58-year-old patient was admitted to the Centre Hospitalier Universitaire de Sherbrooke for weight loss, fatigue, sleep alteration, mouth pain and difficulty in mastication due to gingival infiltration. Except for chronic back pain and a 40-pack-year smoking history, the patient did not report any medical problems. His mother was known to suffer from leukemia. After proper investigations, he was diagnosed with acute myelogenous leukemia (AML-5b monoblastic and monocytic) and prescribed the 7 + 3 induction chemotherapy protocol (table 1). This treatment combines cytarabine (days 1–7) with idarubicin (days 1–3) [3]. The patient also received amikacin (aminoglycoside) and meropenem for a febrile neutropenia and valacyclovir for orolabial herpes.\n\nTwelve days after the beginning of his treatment, the patient was referred to the dermatology division because of an acute, non-itchy, non-scaly skin eruption that progressed over 2–3 days and affected various regions of his body (the face and neck region, arms, upper back, and legs).\n\nThe examination revealed dark erythematous, violaceous and edematous plaques on the right and left periorbital areas, on the nose root (fig. 1), and on the neck. The right forearm had a unique, dry, non-scaly, round and well-delimited purple plaque. Similar lesions were also detected on the right upper back (fig. 2) and legs. Some plaques seemed indurated. Several petechiae were also found, mostly on the thighs and ankles.\n\nScalp, nails, mucosa and genitalia were not involved. The rest of the physical exam was negative.\n\nA 3-mm punch biopsy was done in the right upper lateral chest wall. Histological features consisted of an inflammatory neutrophilic infiltrate surrounding the deep part of the eccrine glands and edema of the dermis (fig. 3, fig. 4). These findings were consistent with a diagnosis of NEH. No leukocytoblastic vasculitis was observed. The periodic acid shiff coloration was negative for infection. Sweet syndrome was eliminated after this biopsy. Another skin specimen was sent for culture and was negative for bacteria, mycobacteria, mycoses and virus.\n\nFollowing the confirmed diagnosis, symptomatic treatment with potent corticosteroid cream was enforced. The neutrophil count normalized without filgrastim after 3 weeks. As for the NEH, it slowly resolved with topical corticosteroid treatment, leaving faint, post-inflammatory erythematous plaques in the areas described above. A preventive treatment with oral dapsone was recommended for a possible consolidation chemotherapy step involving cytarabine.\n\nDiscussion\nNEH is a benign, neutrophilic dermatosis of unknown etiology. It is associated with an adult population diagnosed with leukemia and receiving chemotherapy. A computerized literature review by Bachmeyer and Aractingi [4] analyzed 51 patients from 1982 to 1998. From 1998 until May 2013, 34 other cases were published (Medline EBSCO). Several articles are mentioned below.\n\nWhile considering this diagnosis, one must first rule out an infection. Tissue cultures for bacteria, mycobacteria, fungi and viruses must be considered and are generally negative.\n\nIn this case, the patient presented erythematous and edematous plaques in the periorbital region, mimicking orbital cellulitis. Other cases have been reported in the literature. Six patients receiving induction chemotherapy with cytarabine for acute myelogenous leukemia presented facial plaques with similar descriptions [5, 6, 7, 8]. However, observations regarding the evolution of the plaques are poor except for 3 of the cases in whom the lesions slowly extended across the face [5, 7] or neck-trunk region [7]. Finally, all of the 6 patients presented with febrile neutropenia.\n\nInterestingly, we found one article describing a patient with periorbital, violaceous patches to acetaminophen [9]. Ultimately, facial NEH was also described in 1 healthy patient with no medical history [10].\n\nIs it clinically possible to distinguish periorbital NEH from facial cellulitis? One characteristic is the color. In NEH, the lesions are dark, erythematous, violaceous, or purpuric compared to cellulitis, where erythema with poorly defined margins (or sharp borders in erysipelas) is described. Secondly, cellulitis involves pain and tenderness. Clinical cases have described NEH with tender and painful lesions [11]. Also, warmth of the affected area was not used to describe NEH, but may contribute to a cellulitis diagnosis. Finally, edema is found in both conditions. Cellulitis continues to be a far more common clinical problem and the final NEH diagnosis remains histopathological.\n\nNevertheless, case reports inform us that infectious causes for NEH do exist. Infectious agents such as HIV [12, 13, 14], Gram-positive cocci [15], Streptoccoccus spp. (endocarditis [16]), Serratia marescens [17], Nocardia spp. [18], Enterobacter cloacae [4] and Staphyloccocus aureus [4] were reported in patients who presented classical histological features of NEH.\n\nAs mentioned above, the diagnosis is histological and the biopsy demonstrates a neutrophilic infiltrate of the eccrine unit, edema of the dermis, and necrosis of the eccrine coils and glands. The mechanism by which the eccrine sweat unit is affected remains unknown. One hypothesis underlines the drug-induced direct cytotoxic effect. Toxic byproducts are secreted through sweat, and thus, by neutrophilic chemotaxis induced by cellular damage, infiltration with neutrophils of the eccrine coils and glands occurs [4]. Consequently, the toxic concentration of the drugs within the eccrine gland may lead to necrosis of the epithelial cells [8]. Even so, no studies that evaluated the drug concentration in sweat glands were found.\n\nAnother model describes NEH as a part of the neutrophilic dermatoses spectrum [1], as a paraneoplastic condition. As mentioned, NEH has been described in a healthy population as well [10]. Therefore, a theory regarding possible sweat gland abnormalities was formulated [4].\n\nGenerally, NEH is a self-limiting condition. Associations other than malignancy or chemotherapy have been made in the literature. The treatment is symptomatic and mainly involves topical or systemic corticosteroids [1, 7, 9]. Nonetheless, corticosteroids should be used with caution in neutropenic patients. Pain should be managed with usual analgesic medication if tender lesions are present. One study in a healthy patient reports colchicine use with improvement after 1 month [10]. As for the prevention of possible recurrences of NEH with the same drug use, one case report encourages dapsone use, which has specific effects on neutrophil migration, with a dosage of 100 mg daily for 48 h before the treatment [11].\n\nConclusion\nWe have reported a febrile neutropenic patient undergoing chemotherapy for acute myelogenous leukemia who presented classic NEH lesions. The differential diagnosis includes cellulitis, and thus we emphasize the necessity of a prompt diagnosis in order to prevent the use of multiple antibiotics. In our case, cytarabine was the drug likely responsible for NEH.\n\nDisclosure Statement\nThe authors declare no conflicts of interest.\n\nFig. 1 Violaceous and oedematous plaques on the right and left periorbital areas and on the nose root at day 12 of induction therapy with cytarabine and idarubicin.\n\nFig. 2 Dry, non-scaly, round and well-delimited violaceous plaques on the right upper back. The site of the biopsy is shown.\n\nFig. 3 Low and medium power view. Inflammation surrounding the eccrine secretory coils.\n\nFig. 4 Close-up view. Neutrophils surrounding and infiltrating the sweat gland epithelium.\n\nTable 1 Chemotherapy protocol\n\nChemotherapy\tDose\tDays\t\nCytarabine\t175 mg IV in 250 ml NS; 12 ml/h; continuous\t1–7\t\nIdarubicin\t21 mg IV in 50 ml NS; 15 min DIE\t1–3\t\nNS = Normal saline; DIE = once a day.\n==== Refs\nReferences\n1 Wallach D Les dermatoses neutrophiliques Rev Med Interne 2005 26 41 53 15639325 \n2 Aractingi S Neutrophilic dermatoses during granulocytopenia Arch Dermatol 1995 131 1141 1145 7574830 \n3 Solimando DA Waddell JA Guide to Combination Cancer Chemotherapy Regimens 2013 St. Louis Thomas Land Publishers 342 344 \n4 Bachmeyer C Aractingi S Neutrophilic eccrine hidradenitis Clin Dermatol 2000 18 319 330 10856664 \n5 Srivastava M Neutrophilic eccrine hidradenitis masquerading as facial cellulitis J Am Acad Dermatol 2007 65 693 696 17109994 \n6 Bardenstein D Neutrophilic eccrine hidradenitis simulating orbital cellulitis Arch Ophthalmol 1994 112 1460 1463 7980136 \n7 Keane F Neutrophilic eccrine hidradenitis in two neutropaenic patients Clin Exp Dermatol 2001 26 162 165 11298106 \n8 Thorisdottir KT Kenneth J Bergfeld WF Andresen SW Neutrophilic eccrine hidradenitis J Am Acad Dermatol 1993 28 775 776 8496425 \n9 Sayed FE Neutrophilic eccrine hidradenitis to acetaminophen J Eur Acad Dermatol Venereol 2006 20 1338 1340 17062062 \n10 Belot V Adult idiopathic neutrophilic eccrine hidradenitis treated with colchicine (in French) Presse Med 2006 35 1475 1478 17028536 \n11 Shear N Dapsone in the prevention of recurrent neutrophilic eccrine hidradenitis J Am Acad Dermatol 1996 35 819 822 8912594 \n12 Rouanet I Neutrophilic eccrine hidradenitis in an HIV-1-infected patient AIDS 2012 26 775 776 22436540 \n13 Bachmeyer C Reygagne P Aractingi S Recurrent neutrophilic eccrine hidradenitis in an HIV-1-infected patient Dermatology 2000 200 328 330 10894966 \n14 Krische J Neutrophil eccrine hidradenitis in a patient with AIDS J Dermatol 1998 25 199 200 9575685 \n15 Oono T A case of infectious eccrine hidradenitis J Dermatol 2006 33 142 145 16556286 \n16 Takai T Matsunaga A A case of neutrophilic eccrine hidradenitis associated with streptococcal infectious endocarditis Dermatology 2006 212 203 205 16484830 \n17 Combemale P Neutrophilic eccrine hidradenitis secondary to infection with Serratia marcescens Br J Dermatol 2000 142 784 788 10792233 \n18 Antonovich D Infectious eccrine hidradenitis caused by Nocardia J Am Acad Dermatol 2004 50 315 318 14726895\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6567",
"issue": "5(3)",
"journal": "Case reports in dermatology",
"keywords": "Chemotherapy; Facial cellulitis; Neutrophilic dermatosis; Neutrophilic eccrine hidradenitis",
"medline_ta": "Case Rep Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101517685",
"other_id": null,
"pages": "340-6",
"pmc": null,
"pmid": "24474918",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports",
"references": "14726895;10792233;7574830;16556286;16484830;8496425;7980136;10894966;17028536;17109994;15639325;11298106;8912594;10856664;22436540;9575685;17062062",
"title": "A classic clinical case: neutrophilic eccrine hidradenitis.",
"title_normalized": "a classic clinical case neutrophilic eccrine hidradenitis"
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"abstract": "We aimed to compare the therapeutic effect of recombinant tissue plasminogen activator (rt-PA) administered at different time windows within the first 6 hours after onset of acute ischemic stroke (AIS). A retrospective analysis was performed of data collected from 194 patients who received rt-PA thrombolysis within 4.5 hours after AIS onset and from 29 patients who received rt-PA thrombolysis between 4.5-6 hours after AIS onset. The National Institutes of Health Stroke Scale (NIHSS) scores were statistically decreased in both groups (P < 0.05) at 24 hours and 7 days after onset. There was no statistical difference in the modified Rankin score or mortality at day 90 after treatment between the two groups (P > 0.05). In conclusion, AIS patients who received rt-PA treatment between 4.5-6 hours after onset were similar in therapeutic efficacy to those who received rt-PA within 4.5 hours after onset. Our results suggest that intravenous thrombolytic therapy for AIS within 4.5-6 hours after onset is effective and safe.",
"affiliations": "Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.;Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.;Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.;Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.;Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.;Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.;Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.;Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.;Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.;Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.",
"authors": "Wang|Hai-rong|HR|;Chen|Miao|M|;Wang|Fei-long|FL|;Dai|Li-hua|LH|;Fei|Ai-hua|AH|;Liu|Jia-fu|JF|;Li|Hao-jun|HJ|;Shen|Sa|S|;Liu|Ming|M|;Pan|Shu-ming|SM|",
"chemical_list": "D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator",
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"doi": "10.1038/srep11743",
"fulltext": "\n==== Front\nSci RepSci RepScientific Reports2045-2322Nature Publishing Group srep1174310.1038/srep11743ArticleComparison of Therapeutic Effect of Recombinant Tissue Plasminogen Activator by Treatment Time after Onset of Acute Ischemic Stroke Wang Hai-rong 1*Chen Miao 1*Wang Fei-long 1*Dai Li-hua 1Fei Ai-hua 1Liu Jia-fu 1Li Hao-jun 1Shen Sa 1Liu Ming 1Pan Shu-ming a11 Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.a whr75@hotmail.com* These authors contributed equally to this work.\n\n24 07 2015 2015 5 1174327 10 2014 18 05 2015 Copyright © 2015, Macmillan Publishers Limited2015Macmillan Publishers LimitedThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/We aimed to compare the therapeutic effect of recombinant tissue plasminogen activator (rt-PA) administered at different time windows within the first 6 hours after onset of acute ischemic stroke (AIS). A retrospective analysis was performed of data collected from 194 patients who received rt-PA thrombolysis within 4.5 hours after AIS onset and from 29 patients who received rt-PA thrombolysis between 4.5–6 hours after AIS onset. The National Institutes of Health Stroke Scale (NIHSS) scores were statistically decreased in both groups (P < 0.05) at 24 hours and 7 days after onset. There was no statistical difference in the modified Rankin score or mortality at day 90 after treatment between the two groups (P > 0.05). In conclusion, AIS patients who received rt-PA treatment between 4.5–6 hours after onset were similar in therapeutic efficacy to those who received rt-PA within 4.5 hours after onset. Our results suggest that intravenous thrombolytic therapy for AIS within 4.5–6 hours after onset is effective and safe.\n==== Body\nCerebral stroke is the leading cause of disability and the second leading cause of death by disease in China1. About 6–7 million Chinese suffer from this disease with around 2 million new cases every year. Approximately 1.5 million patients will die each year from cerebral stroke. It dominates among diseases that cause disabilities; patients with acute ischemic stroke (AIS) account 60%–80% of all cerebral stroke patients.\n\nIntravenous (IV) recombinant tissue plasminogen activator (rt-PA) is one of the most effective methods available for treatment of AIS. The National Institute of Neurological Disorders and Stroke (NINDS) was the first to report its efficacy in 1995, noting that 0.9 mg/kg rt-PA could significantly improve the clinical symptoms and outcome of patients with AIS within 3 hours of onset, an exceptionally early stage2. In 1996, IV rt-PA was approved by the FDA to treat AIS patients within 6 hours of the onset of symptoms. Unfortunately, although significant efforts have been made to increase the number of patients who arrive at treatment centers within 3 hours of the onset of symptoms, less than 1% of AIS patients in the United States receive rt-PA3.\n\nIt became evident that, in order to offer an opportunity for AIS patients who could not be treated within the preferred 3 hour time window to undergo thrombolytic therapy, extending the rt-PA treatment window was critical. The second trial of the European Cooperative Acute Stroke Study (ECASS II) tested the risk and benefit of such an extension: ECASS II was similar to ECASS I, except that the IV rt-PA dose was lowered to 0.9 mg/kg45. The results, released in 1998, showed that outcomes for AIS patients were improved when compared with ECASS I. Patients were stratified into 2 windows: 0–3 hours and 3–6 hours from symptom onset, with the majority of patients recruited in the 3–6 hour window. The primary favorable endpoint was a modified Rankin Scale (mRS) score of 0–1 at 3 months. Differences between treatment and placebo were similar in both time windows. The overall 3.7% absolute increase in improved outcomes in the IV rt-PA arm compared to the placebo arm was not statistically different (P = 0.277), but post hoc analysis using a modified favorable outcome definition of mRS score 0–2 produced an 8.3% absolute difference in favor of IV rt-PA (P = 0.024). The results of the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study, designed to test the use of rt-PA 3–5 hours after stroke onset, were published in 1999. ATLANTIS originally included patients treated with tPA from 0 to 6 hours from symptom onset, but was later modified to patients treated at 3 to 5 hours post onset (ATLANTIS B)6. The primary effective outcome measure was a 3-month United States National Institutes of Health Stroke Scale (NIHSS) score of 0 or 1 in ATLANTIS B. No significant benefit of rt-PA was found on the 3-month efficacy endpoints in patients treated between 3 and 5 hours.\n\nThe third ECASS trial (ECASS III) initially enrolled patients treated within 3 to 4 hours from symptom onset and later included those treated up to 4.5 hours7. Based on lessons learned from ECASS I, ECASS II, and ATLANTIS, criteria were deliberately selected to maximize the chances of favorable response. Patients with high stroke severity (NIHSS score >25), of extreme age (>80 years), with a combination of prior stroke and diabetes, and on any anticoagulant therapy regardless of international normalized ratio (INR) were excluded. The primary outcome measure, a 3-month mRS score 0 to 1, occurred in 52.4% of the IV rt-PA arm compared to 45.2% of the placebo arm (P = 0.04), a difference that remained statistically significant after adjustments for initial stroke severity and time from symptom onset to treatment. ECASS III was the first positive randomized phase III fibrinolysis trial for a treatment window extended beyond 3 hours. In 2008, the same year ECASS III was published, an observational study called Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) compared outcomes in patients treated between 3–4.5 hours or within 3 hours. There were no significant differences between the two cohorts for any outcome measure: rate of symptomatic intracerebral haemorrhage, or mortality and independence, indicating that rt-PA remained safe when given at 3–4.5 h after AIS onset8. Published in 2010, the Canadian Alteplase for Stroke Effectiveness Study (CASES) reported similar results: there were no differences between the 3–4.5 hour and <3 hour windows; both attained a 3 month mRS ≤19. Liao XL et al. also reported that intravenous rt-PA treatment at 3 to 4.5 hours of symptom onset remains safe and effective in Chinese patients with AIS in 20131. Finally, the third International Stroke Trial (IST-3) studied the efficacy of a 0–6 hour fibrinolysis window, and confirmed the benefit of IV rt-PA. An Oxford Handicap Score (OHS) of 0 or 1 was considered to be a favorable outcome, and was achieved by 24% of the rt-PA group and 21% of the control group (P = 0.018)10. IST-3 did not report on outcomes of treatment between 4.5–6.0 hours from onset of AIS symptoms.\n\nSince 2008, about 300 AIS patients have received rt-PA treatment in our department. However, some patients were not sent to hospital immediately after symptoms occurred, for various reasons including lack of understanding of the disease. For those patients who presented within 4.5–6 hours after onset of AIS symptoms, a selective emergency thrombolysis treatment was administered after thorough evaluation of the patient’s condition, relevant risks, and requirements of patients and their families. In this article, we summarize the results of rt-PA thrombolysis treatment in our hospital of AIS patients within 4.5 hours and between 4.5–6 hours after onset of symptoms.\n\nMaterials and Methods\nInclusion Criteria\nThe study protocol was approved by the ethics committees of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine. The study was carried out in accordance with the Helsinki Declaration. AIS was diagnosed in accordance with the standards for diagnosis of cerebral infarction from the Fourth National Academic Meeting of Cerebrovascular Disease in 1995, and in accordance with the National Guideline for Diagnosis and Treatment of Acute Ischemic Stroke 2010 of China, except the time frame of treatment was extended from 4.5 to 6 hours after onset of AIS symptoms11. Inclusion criteria for subjects were: (1) age: 18–80 years; (2) physical signs of brain function damage persisted for 1 hour, paralysis < degree 3; (3) intracranial hemorrhage excluded by cerebral CT, and no massive cerebral infarction indicated by imaging changes.\n\nExclusion Criteria\nWe followed the National Guideline for Diagnosis and Treatment of Acute Ischemic Stroke 2010 of China12 to exclude: (1) patients with intracranial hemorrhage including suspicious hemorrhage in subarachnoid space, head trauma in the previous 3 months, gastrointestinal hemorrhage or urinary system hemorrhage in the previous 3 weeks, major surgery in the previous 2 weeks, arterial puncture sites where hemostasis by compression was not convenient to perform in the previous week; (2) patients with cerebral infarction or myocardial infarction in the previous 3 months, excluding old lacunula infarction without sequela of neurologic functional symptoms; (3) patients with severe functional insufficiency of cardiac, hepatic or renal systems or with diabetes mellitus; (4) signs of active hemorrhage or trauma (such as fracture) observed upon physical examination; (5) patients who took oral anti-coagulation drugs, and INR >15; patients who received heparin therapy within 48 hours (APrT exceeding normal range); (6) platelet count below 100 × 109/L, blood glucose <2.7 mmol/L; (7) systolic blood pressure >180 mmHg or diastolic pressure >100 mmHg; (8) pregnant or lactating female patients; (9) non-cooperative patients.\n\nGeneral Information\nTwo hundred twenty-three AIS patients received rt-PA thromoblysis therapy at our institution between June 2010 and October 2014. One hundred ninety-four patients received thromoblysis therapy within 4.5 hours of symptom onset, and 29 patients received the same treatment within 4.5 to 6 hours of the onset of AIS symptoms.\n\nTreatment Method\nRt-PA 0.9 mg/kg (maximum dose 50 mg) was administered. Initially, 10% (1 minute) was intravenously injected, followed by the remaining 90% continuously infused by an intravenous pump over 60 minutes. Thrombolysis treatment was discontinued if severe headache, acute elevation of blood pressure, nausea or vomiting ensued. Head CT scans were re-examined to detect any cerebral hemorrhage. No anti-coagulation drugs or aspirin were administered within 24 hours after thrombolysis treatment. Platelet and blood coagulation function were re-examined immediately if cerebral hemorrhage appeared, and fresh plasma or 1 U platelets were then transfused. Four parameters of blood coagulation and head CT were examined 24 hours after thrombolysis treatment. Low molecular weight heparin was injected subcutaneously for 7 days, and administered orally thereafter. Treatments to improve brain cell metabolism were also administered at the same time.\n\nEfficacy Evaluation\nThe NIHSS was used to quantify impairment before treatment and 24 hours and 7 days after thrombolysis treatment. The mRS was used to evaluate patients’ daily functional abilities at 90 days after thrombolysis treatment.\n\nStatistical Method\nData was expressed as mean ± standard deviation (SD), median, and interquartile range (IQR). Continuous variables were analyzed by Student’s t test. Discrete variables were compared by Chi Square tests, Signed rank sum test and Mann-Whitney U test. A P value <0.05 was considered as statistically significant. Statistical analysis of the data was done using the Statistical Package for the Social Sciences (SPSS) version 17 or SAS6.12.\n\nResults\nGeneral Information\nThe mean age of patients who accepted treatment <4.5 hours after onset was 64.4 ± 10.0 years, and the mean age of patients who accepted treatment between 4.5–6 hours after onset was 66.8 ± 9.2 years. There was no statistical difference between the two groups in age, gender, or AIS risk factors such as ratio of patients with hypertension, diabetes mellitus or atrial fibrillation (P > 0.05; Table 1). The patients in the two groups were therefore comparable.\n\nComparison of Therapeutic Effect in Treatment Windows\nThe patient mortality rate was 5.2% (10 of 194) in the 0–4.5 hour group, and 6.9% (2 of 29) in the 4.5–6 hour group, with no statistically significant difference (i2 = 0.1503, P = 0.6982). All deaths were caused by cerebral hemorrhage except one patient in the 0–4.5 hour group who died of upper gastrointestinal hemorrhage and another patient in the 0–4.5 hour group who died of cardiac arrest. Death data were therefore excluded from statistical analysis of the therapeutic effect. The median baseline NIHSS score in the 0–4.5 hour group was 7.0, IQR was [5.0–12.0], which decreased to 2.0 [1.0–6.0] at 24 hours after thrombolysis treatment, a statistically significant reduction (Z = −10.3306, P < 0.0001). The NIHSS score of this group decreased further to 1.0 [0–4.0] at 7 days after thrombolysis treatment, also a statistically significant reduction compared with the baseline score (Z = −12.4174, P <0.0001; Fig. 1). For patients in the 4.5–6 hour group, the baseline NIHSS score was 7.0 [6.0–10.0], which decreased to 3.0 [1.0–5.0] at 24 hours after thrombolysis treatment (Z = −4.8022, P < 0.0001), and decreased to 1.0 [0–3.0] at 7 days after treatment (Z = −6.0832, p <0.0001 compared to the baseline score; Fig. 1). These results indicated that patients in both groups benefited from rt-PA treatment.\n\nThere was no statistical difference in baseline NIHSS scores between patients in the 4.5–6 hour group and in the 0–4.5 hour group (Z = −0.3418, p = 0.7325). Moreover, there was no statistical difference in the improvement of NIHSS scores at 24 hours and 7 days after thrombolysis treatment, indicating that the effect of thrombolysis on patients in the two groups was very similar. The NIHSS score improved 4 [3.0–6.0] in the 0–4.5 hour group at 24 hours after thrombolysis, and 4.0 [2.0–6.0] (Z = −0.5770, P = 0.5639) in the 4.5–6 hour group. The NIHSS scores improved 5.0 [4.0–7.0] in the 0–4.5 hour group at 7 days after thrombolysis, while for the NIHSS scores in the 4.5–6 hour group improved 6.0 [4.0–7.0] (Z = 0.5165, P = 0.6055; Fig. 2).\n\nWe used the mRS to assess the daily functional abilities of patients at 3 months after thrombolysis treatment. The 3-month mRS for patients in the 0–4.5 hour group was 1.0 [0–3.0], and 1.0 [0–2.5] for patients in the 4.5–6 hour group (Z = 0.2770, P = 0.7818), an insignificant difference (Fig. 3). The overall improved outcomes (3-month mRS score 0 to 1) in the 0–4.5 hour group was 53.1% (103 of 194), compared to 51.7% (15 of 29) in the 4.5–6 hour group (χ2 = 0.0190, P = 0.8905), indicating that the comprehensive daily functional abilities and independence of patients in the two groups were similar.\n\nAdverse Reactions and Complications\nThe incidence of symptomatic intracerebral hemorrhage was 10.8% (21 of 194) and mortality was 5.2% (10 of 194) in the 0–4.5 hour group. In this group, 8 patients died because of symptomatic intracerebral hemorrhage, one suffered from fatal upper gastrointestinal hemorrhage and another patient died of cardiac arrest. In the 4.5–6 hour group, 5 patients developed symptomatic intracerebral hemorrhage (5 of 29, for an incidence rate of 17.2%), and 2 of whom were died (6.9% of total). There was no statistical difference in incidences of either cerebral hemorrhage or mortality (χ2 = 1.0085, p = 0.3153 and χ2 = 0.4529, p = 0.5010, respectively).\n\nDiscussion\nAIS results from the sudden interruption of arterial blood flow to a dependent area of the brain parenchyma. A central zone of ischemic tissue known as the core is completely deprived of critical oxygen and glucose delivery, and irreversible neuronal injury begins within minutes. Surrounding the core are areas of markedly decreased perfusion where “stunned” brain parenchyma receives a diminished blood supply from cerebral collateral vessels and potentially from residual arterial flow. This area, known as the ischemic penumbra, contains many viable nerve cells and is potentially salvageable if significant arterial flow can be quickly restored; thus, it is the therapeutic target of reperfusion stroke therapies1213.\n\nEmergency rt-PA thrombolysis treatment has become one of the most effective therapeutic options available since it was first reported in 1995. It can significantly improve the clinical outcomes of patients with AIS if applied within 3 hours2. Extending the therapeutic window for thrombolysis is an important strategy in maximizing the proportion of patients treated. The ECASS III study in 2008 showed that rt-PA administered within 3 to 4.5 h after symptom onset significantly improved clinical outcomes in patients with AIS7. It is widely acknowledged at present that rt-PA thrombolysis treatment administered within 4.5 hours after occurrence of symptoms is safe and effective1791415. In 2012, the IST-3 study provided evidence that the therapeutic window for thrombolysis may extend to 6 hours after AIS commences10. Research indicates that the penumbra area is detectable in about 70% of patients who accept examination within 6 hours after stroke, which means that it would be possible to expand the window of thrombolysis treatment up to 6 hours16. Based on the factors above, we performed rt-PA thrombolysis on patients who presented 4.5–6 hours after AIS onset.\n\nIn this study, the baseline NIHSS scores in the 4.5–6 hour group and 0–4.5 hour group were no statistical difference, and the NIHSS scores of patients in both groups improved significantly after thrombolysis treatments. After rt-PA treatment, there was no statistical difference between the two groups in the improvement of NIHSS score at 24 hours and 7 days. The 3-month mRS score of 0 to 1 in the 0–4.5 hour group was 53.1% compared to 51.7% in the 4.5–6 hour group, an insignificant difference, indicating that the patients’ comprehensive daily functionality is similar in the two groups.\n\nAlthough the symptomatic intracerebral hemorrhage rate was 17.2% in the 4.5–6-hour group compared to 10.8% in the 0–4.5-hour group, there was no statistically significant difference between them. The symptomatic intracerebral hemorrhage rate in the 0–4.5 hour group (10.8%) was similar to that of the thrombolysis group of NINDS (6.4%), ECASS III (7.9%) and IST-3 (7%), while the symptomatic intracerebral hemorrhage rate in the 4.5–6 hour group (17.2%) was higher than that of the thrombolysis group of these trials2710. The 90-day mortality rate was 5.2% in the 0–4.5 hour groups and 6.9% in the 4.5–6 hour group, which were similar to that of the thrombolysis group of ECASS III (6.7%), and lower than NINDS (7.7%) and IST-3 (27%)2710. Therefore, we consider that it is safe to perform rt-PA thrombolysis within 4.5–6.0 hours after AIS occurs.\n\nOur team had thrombolysis experience in more than 300 AIS cases since 2008, and we had been awarded the ‘Thrombolysis Pioneer Award’ by the Stroke Quality Control Center of the Ministry of Health of China in 2013. So our results should be interpreted with caution as it they might be applicable to other stroke centers; however, the mantra still holds true: the earlier thrombolysis treatment begins, the better the effect is likely to be and the less risk there is17. We recommend that in those hospitals with experience in rt-PA thrombolysis and after a patient’s condition has been thoroughly evaluated, the thrombolysis time window can be extended up to 6 hours after onset of symptoms for AIS patients who have low NIHSS scores.\n\nAdditional Information\nHow to cite this article: Wang, H. et al. Comparison of Therapeutic Effect of Recombinant Tissue Plasminogen Activator by Treatment Time after Onset of Acute Ischemic Stroke. Sci. Rep.\n5, 11743; doi: 10.1038/srep11743 (2015).\n\nAuthor Contributions H.W., M.C., F.W. and S.P. designed the experiments, H.W., M.C., F.W., L.D., A.F., J.L., H.L. and S.P. performed the experiments; H.W., M.C., F.W., S.P., L.D., A.F., J.L., H.L., S.S. and M.L. collected the data; All the authors wrote the main manuscript and reviewed the manuscript.\n\nFigure 1 Comparison between NIHSS scores of the two groups before and after thrombolysis:\n*indicates P < 0.05.\n\nFigure 2 Comparison of improvement of NIHSS scores of patients after thrombolysis in the two groups:\n△ P > 0.05.\n\nFigure 3 Modified Rankin Scale scores of patients in the two groups 90 days after thrombolysis:\n△ indicates P > 0.05.\n\nTable 1 Demographic and baseline characteristics of patients in the two treatment windows.\n \tAge (years)\tGender (male/female)\tHypertension(%)\tDiabetes (%)\tAtrial Fibrillation (%)\t\n<4.5 h\t64.4 ± 10.0\t118/76\t73.7(143/194)\t24.7(48/194)\t21.1(41/194)\t\n4.5−6 h\t66.8 ± 9.2\t22/7\t79.3(23/29)\t17.2(5/29)\t34.5(10/29)\t\nStatistical\tt = −1.24\tχ2 = 2.4414\tχ2 = 0.4157\tχ2 = 0.7834\tχ2 = 2.5485\t\nP value\t0.2156\t0.1182\t0.5190\t0.3761\t0.1104\n==== Refs\nGao X. \net al.\nAdmission clinical characteristics and early clinical outcomes among acute ischemic stroke patients . J Biomed Res \n26 , 152 –158 (2012 ).23554744 \nThe National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke . N Engl J Med \n333 , 1581 –1587 (1995 ).7477192 \nBarber P. A. , Zhang J. , Demchuk A. M. , Hill M. D. & Buchan A. M. \nWhy are stroke patients excluded from TPA therapy? An analysis of patient eligibility . Neurology. \n56 , 1015 –1020 (2001 ).11320171 \nHacke W. \net al.\nIntravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS) . JAMA. \n274 , 1017 –1025 (1995 ).7563451 \nHacke W. \net al.\nRandomised doubleblind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators . Lancet \n352 , 1245 –1251 (1998 ).9788453 \nClark W. M. \net al.\nRecombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase thrombolysis for acute noninterventional therapy in ischemic stroke . JAMA. \n282 , 2019 –2026 (1999 ).10591384 \nHacke W. \net al.\nThrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke . N Engl J Med \n359 , 1317 –1329 (2008 ).18815396 \nWahlgren N. \net al.\nThrombolysis with alteplase 3–4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study . Lancet \n372 , 1303 –1309 (2008 ).18790527 \nShobha N. , Buchan A. M. & Hill M. D. \nCanadian Alteplase for Stroke Effectiveness Study (CASES). Thrombolysis at 3–4.5 hours after acute ischemic stroke onset–evidence from the Canadian Alteplase for Stroke Effectiveness Study (CASES) registry . Cerebrovasc Dis. \n31 , 223 –228 (2011 ).21178345 \nThe IST-3 Collaborative Group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial . Lancet. \n23 , 23 (2012 ).\nWriting group of the National Guideline for diagnosis and treatment of acute ischemic stroke, Cerebrovascular Disease team, Neurology Sub-branch, Chinese Medical Association. National Guideline for diagnosis and treatment of acute ischemic stroke . Chin J Neurol. \n43 , 146 –153 (2010 ).\nHähnel S. \net al.\nLocal intra-arterial fibrinolysis of thromboemboli occurring during euroendovascular procedures with recombinant tissue plasminogen activator . Stroke. \n34 , 1723 –1728 (2003 ).12805492 \nThurman R. J. , Jauch E. C. , Panagos P. D. , Reynolds M. R. & Mocco J. \nFour evolving strategies in the emergent treatment of acute ischemic stroke . Emerg Med Pract \n14 , 1 –26 (2012 ).22872954 \nAcute ischemic stroke treatment guideline writing group, cerebrovascular science section, neurology branch of Chinese Medical Association. Chinese guidelines for treatment of acute ischemic stroke . Chin J Neurol \n43 , 146 –153 (2010 ).\nWhiteh Segal. \nTreatment of acute ischemic troke Current medical literature . Neurology. \n24 , 61 –81 (2008 ).\nLiu M. \nNeurologic Medicine. [Liu M. (ed).] [53 ] (People’s Health Publishing House, Beijing, 2008 ).18344803 \nDel Zoppo G. J. , Saver J. L. , Jauch E. C. , Adams H. P. Jr & American Heart Association Stroke Council. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association . Stroke. \n40 , 2945 –2948 (2009 ).19478221\n\n",
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"title": "Comparison of Therapeutic Effect of Recombinant Tissue Plasminogen Activator by Treatment Time after Onset of Acute Ischemic Stroke.",
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"abstract": "A 27-year-old man with a history of cocaine abuse ingested a large quantity of street cocaine in an apparent suicide attempt. Shortly thereafter, he developed tonic-clonic seizures and became cyanotic. An arterial blood gas sample, collected in the emergency department, appeared chocolate-brown and showed pO2 279 mmHg, pCO2 53 mmHg, and pH 7.15. Hemoglobin spectral analysis revealed significant methemoglobinemia (37%). Subsequent gas-chromatographic and mass-spectral analysis of urine confirmed the presence of cocaine (106 mg/L), benzoylecgonine (94 mg/L), and other metabolites. Further testing revealed the presence of benzocaine, a compound known to produce methemoglobinemia. A powder submitted as the \"cutting\" substance was shown to be benzocaine. When confronted with a possible cocaine overdose (particularly by ingestion), the physician should consider the possible clinical effects of adulterants, especially local anesthetics such as benzocaine.",
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"abstract": "Patients undergoing treatment with an anti-tumor necrosis factor-alpha (TNF-α) agent can, as an adverse event, develop anti-TNF-α-induced lupus (ATIL). Neuropsychiatric symptoms such as depression and suicidal ideations are not commonly seen in patients who develop ATIL. We describe a case of a 56-year-old female who developed ATIL and suicidal ideations while on Adalimumab.\nA 56-year-old female with rheumatoid arthritis (RA) and no known prior history of systemic lupus erythematosus or depression presented with suicidal ideations, joint pains and a malar rash after a recent change in her Adalimumab dose. She was treated for an acute ATIL episode based on her symptoms and serologies which were positive for anti-double-stranded deoxyribonucleic acid antibody. An inpatient psychiatric consultation determined that the patient's suicidal ideations may be an associated symptom of her current ATIL episode or possibly secondary to her chronic pain and debilitation from her RA. The patient's Adalimumab was discontinued and she was treated with a course of intravenous glucocorticoid. The patient's suicidal ideations resolved and her anti-double-stranded deoxyribonucleic acid antibody serologies became negative. She was subsequently started on Abatacept and has achieved remission of her RA with no further suicidal ideations.\nThe development of ATIL in patients undergoing treatment with an anti-TNF-α agent is a rare occurrence. The aim of reporting our case is to increase understanding of ATIL by highlighting the occurrence of neuropsychiatric symptoms in a patient who developed ATIL.",
"affiliations": "Department of Medicine, Division of Rheumatology, Harlem Hospital Center, Columbia University Medical Center, New York, NY, USA, jafrif@nychhc.org.;Department of Medicine, Division of Rheumatology, Harlem Hospital Center, Columbia University Medical Center, New York, NY, USA, jafrif@nychhc.org.",
"authors": "Jafri|Fatima|F|;Sammut|Amanda|A|",
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"fulltext": "\n==== Front\nOpen Access RheumatolOpen Access RheumatolOpen Access Rheumatology: Research and ReviewsOpen Access Rheumatology : Research and Reviews1179-156XDove Medical Press 10.2147/OARRR.S168559oarrr-10-113Case ReportA rare case of suicidal ideation related to Adalimumab use Jafri Fatima Sammut Amanda Department of Medicine, Division of Rheumatology, Harlem Hospital Center, Columbia University Medical Center, New York, NY, USA, jafrif@nychhc.orgCorrespondence: Fatima Jafri, Department of Medicine, Harlem Hospital Center, 506 Lenox Avenue, New York, NY 10037, USA, Tel +01 212 939 1506, Fax +01 212 939 2263, Email jafrif@nychhc.org2018 17 8 2018 10 113 115 © 2018 Jafri and Sammut. This work is published and licensed by Dove Medical Press Limited2018The 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.Introduction\nPatients undergoing treatment with an anti-tumor necrosis factor-alpha (TNF-α) agent can, as an adverse event, develop anti-TNF-α–induced lupus (ATIL). Neuropsychiatric symptoms such as depression and suicidal ideations are not commonly seen in patients who develop ATIL. We describe a case of a 56-year-old female who developed ATIL and suicidal ideations while on Adalimumab.\n\nCase presentation\nA 56-year-old female with rheumatoid arthritis (RA) and no known prior history of systemic lupus erythematosus or depression presented with suicidal ideations, joint pains and a malar rash after a recent change in her Adalimumab dose. She was treated for an acute ATIL episode based on her symptoms and serologies which were positive for anti-double-stranded deoxyribonucleic acid antibody. An inpatient psychiatric consultation determined that the patient’s suicidal ideations may be an associated symptom of her current ATIL episode or possibly secondary to her chronic pain and debilitation from her RA. The patient’s Adalimumab was discontinued and she was treated with a course of intravenous glucocorticoid. The patient’s suicidal ideations resolved and her anti-double-stranded deoxyribonucleic acid antibody serologies became negative. She was subsequently started on Abatacept and has achieved remission of her RA with no further suicidal ideations.\n\nDiscussion\nThe development of ATIL in patients undergoing treatment with an anti-TNF-α agent is a rare occurrence. The aim of reporting our case is to increase understanding of ATIL by highlighting the occurrence of neuropsychiatric symptoms in a patient who developed ATIL.\n\nKeywords\nAdalimumablupusrheumatoid arthritissuicidal ideation\n==== Body\nIntroduction\nAdalimumab is currently approved for the treatment of rheumatoid arthritis (RA).1 A rare adverse event associated with the use of Adalimumab is the development of antitumor necrosis factor-alpha (anti-TNF-α)–induced lupus (ATIL).2 ATIL has been described as the development of the syndrome of drug-induced lupus secondary to an anti-TNF-α agent.3 While the occurrence of autoantibodies is not uncommonly noted in patients treated with anti-TNF-α agents, what is uncommon is the development of lupus-like symptoms.4 Furthermore, the relationship between the presence of neuropsychiatric symptoms in patients who have developed ATIL is not well understood, given the paucity of reported ATIL cases in the literature and the probable overall challenging nature in identifying neuropsychiatric symptoms. As of now, depression and suicide are not significantly known to be direct adverse events associated with Adalimumab use.5 The aim of reporting our case is to increase our understanding of ATIL by highlighting the occurrence of neuropsychiatric symptoms in a patient who developed ATIL. Informed written and verbal consent was obtained from the patient to permit us to publish her case for further scientific learning.\n\nCase report\nA 56-year-old female with a past medical history of hypertension and hyperlipidemia was diagnosed ~15 years ago with RA in Honduras. She first established care in our rheumatology clinic ~4 years ago. She endorsed ongoing symptoms of joint pains, joint tenderness and morning stiffness. Her outpatient physical exam was consistent with swelling, tenderness and limited mobility of multiple joints. Her labs were significant for an elevated level of anti-citrullinated peptide antibody, an elevated level of C-reactive protein and an elevated erythrocyte sedimentation rate. Her rheumatoid factor was negative. She also had radiographic evidence of bony erosions on X-ray. In addition, she was evaluated as not having a diagnosis of systemic lupus erythematosus (SLE). Her RA diagnosis met the 2010 American College of Rheumatology diagnostic criteria for the diagnosis of RA.6\n\nThe patient was initially treated with methotrexate, but after failure to achieve remission, methotrexate was stopped and she was started on Adalimumab at a dose of 40 mg subcutaneously every 2 weeks. She continued to have recurrent symptoms of joint pain and her dose of Adalimumab was subsequently increased to Adalimumab 40 mg subcutaneously every week. Approximately 2 weeks after increasing her dose of Adalimumab, she presented to the rheumatology clinic with a facial rash, oral ulcers, bilateral shoulder pain, bilateral knee pain and suicidal ideations. She was sent to the emergency room for further evaluation. She described no previous suicidal ideations or suicidal attempts and stated that she started to develop suicidal ideations over the last few days. On presentation, she was tachycardic with a heart rate of 108 beats per minute and afebrile. Her examination was notable for a facial rash, oral ulcers, mild bilateral shoulder and bilateral knee pain on palpation. Her laboratory results were significant for an elevated anti-nuclear antibody titer of 1:1,280 (normal is <1:80), a strongly positive anti-histone antibody level of 2.6 (normal is <1 Unit) and a borderline positive anti-double-stranded DNA antibody (anti-dsDNA ab) level of 33 IU/mL (normal is <30 IU/mL). She was admitted for an ATIL episode and a psychiatric consultation. The assessment made by the psychiatric consultation team was that while the patient had suicidal ideations, there was no history of a current plan for suicide and her suicidal ideations might be an associated symptom of her current ATIL episode or possibly secondary to her chronic pain and debilitation from her RA. The recommendation from the psychiatry team was close follow-up with better control of the patient’s RA symptoms and to continue to treat the active ATIL episode.\n\nThe patient’s Adalimumab was stopped at the start of her hospitalization and she was treated with a course of intravenous glucocorticoid. Her joint pains resolved, rashes improved and she was no longer having suicidal ideations. She was subsequently started on Abatacept and closely followed up in the outpatient setting. After a few weeks, her anti-dsDNA abs were repeated and were negative. Remission of her RA was also gradually achieved with no further episodes of suicidal ideations.\n\nDiscussion\nMost cases of ATIL are diagnosed when there is a temporal relationship between the development of lupus-like symptoms and current use of an anti-TNF- α agent.7,8 In addition, there should also be the presence of serologic American College of Rheumatology criteria of SLE and no known previous history of SLE. The most common symptoms of ATIL are occurrence of a rash, joint pain and fever.9 The estimated incidence of ATIL is 0.19%–0.22% for infliximab, 0.18% for etanercept and 0.10% for Adalimumab.9 Neuropsychiatric features are not a common occurrence in ATIL.10 This is one case in which the patient had associated suicidal ideations with ATIL. It is, however, not possible based on this case to prove a causal relationship of Adalimumab use and suicidal ideation. It is possible that this patient was at risk for ATIL and that she had suicidal ideations as a rare manifestation of ATIL. A limitation in this case is that neither there was any objective measure used to assess for depression or suicidal ideations, such as use of the Beck Depression Inventory or Beck Suicidal Ideation Scale, when the patient presented with suicidal ideations, nor did we use any objective measures to reassess symptoms on follow-up. We suggest that it may be beneficial for future consideration to screen patients with ATIL for neuropsychiatric manifestations using objective measures to better understand their rate of occurrence.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1 Navarro-Sarabia F Ariza-Ariza R Hernández-Cruz B Villanueva I Adalimumab for treating rheumatoid arthritis J Rheumatol 2006 33 6 1075 1081 16652437 \n2 Ramos-Casals M Brito-Zerón P Muñoz S Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases Medicine 2007 86 4 242 251 17632266 \n3 Debandt M Vittecoq O Descamps V Le Loët X Meyer O Anti-TNF alpha-induced systemic lupus syndrome Clin Rheumatol 2003 22 56 61 12605321 \n4 Kang MJ Lee YH Lee J Etanercept-induced systemic lupus erythematosus in a patient with rheumatoid arthritis J Korean Med Sci 2006 21 5 946 949 17043436 \n5 Scheinfeld N Adalimumab: a review of side effects Expert Opin Drug Saf 2005 4 4 637 641 16011443 \n6 Aletaha D Neogi T Silman AJ 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative Arthritis Rheum 2010 62 9 2569 2581 20872595 \n7 De Bandt M Sibilia J Le Loët X Systemic lupus erythematosus induced by anti-tumour necrosis factor alpha therapy: a French national survey Arthritis Res Ther 2005 7 3 R545 R551 15899041 \n8 Ramos-Casals M Brito-Zerón P Soto MJ Cuadrado MJ Khamashta MA Autoimmune diseases induced by TNF-targeted therapies Best Pract Res Clin Rheumatol 2008 22 5 847 861 19028367 \n9 Almoallim H Al-Ghamdi Y Almaghrabi H Alyasi O Anti-tumor necrosis factor-α induced systemic lupus erythematosus Open Rheumatol J 2012 6 315 319 23198006 \n10 Williams EL Gadola S Edwards CJ Anti-TNF-induced lupus Rheumatology 2009 48 7 716 720 19416947\n\n",
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"title": "A rare case of suicidal ideation related to Adalimumab use.",
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"abstract": "Folliculotropic mycosis fungoides (FMF) is an aggressive variant of mycosis fungoides (MF) characterized by infiltration of the hair follicle epithelium by neoplastic T cells. FMF demonstrates poor response rates to standard skin-directed therapies such as phototherapy and topical corticosteroids. Imiquimod, an immunomodulatory agent that stimulates the antitumor immune response, has been used successfully in treatment of early-stage MF. We report a 21-year-old patient with unilesional FMF who achieved clinical remission with imiquimod application. This case highlights a potential for use of imiquimod as a treatment option for patients with FMF and limited skin involvement.",
"affiliations": "Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.;Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.;Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA. neda.nikbakht@jefferson.edu.",
"authors": "Shalabi|Doaa|D|;Vadalia|Nish|N|;Nikbakht|Neda|N|",
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"fulltext": "\n==== Front\nDermatol Ther (Heidelb)\nDermatol Ther (Heidelb)\nDermatology and Therapy\n2193-8210\n2190-9172\nSpringer Healthcare Cheshire\n\n31407190\n317\n10.1007/s13555-019-00317-2\nCase Report\nRevisiting Imiquimod for Treatment of Folliculotropic Mycosis Fungoides: A Case Report and Review of the Literature\nShalabi Doaa\nVadalia Nish\nNikbakht Neda neda.nikbakht@jefferson.edu\n\ngrid.265008.9 0000 0001 2166 5843 Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA USA\n12 8 2019\n12 8 2019\n12 2019\n9 4 807814\n19 6 2019\n© The Author(s) 2019\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\nFolliculotropic mycosis fungoides (FMF) is an aggressive variant of mycosis fungoides (MF) characterized by infiltration of the hair follicle epithelium by neoplastic T cells. FMF demonstrates poor response rates to standard skin-directed therapies such as phototherapy and topical corticosteroids. Imiquimod, an immunomodulatory agent that stimulates the antitumor immune response, has been used successfully in treatment of early-stage MF. We report a 21-year-old patient with unilesional FMF who achieved clinical remission with imiquimod application. This case highlights a potential for use of imiquimod as a treatment option for patients with FMF and limited skin involvement.\n\nKeywords\n\nFolliculotropic mycosis fungoides\nImiquimod\nToll-like receptor 7 agonist\nissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\n\nMycosis fungoides (MF) is the most common variant of cutaneous T cell lymphoma (CTCL) and is primarily characterized by the proliferation of neoplastic CD4+ T cells in the skin [1]. Early-stage MF presents as patches and plaques that may progress to a more advanced stage with tumors, blood, lymph node or visceral involvement [2]. Several skin-directed therapies (SDTs), including topical corticosteroids, phototherapy, mechlorethamine gel, and topical retinoids, are commonly used in the treatment of early-stage MF [3–5].\n\nFolliculotropic MF (FMF) is an aggressive subtype of MF with distinct histopathological features demonstrating the infiltration of the pilosebaceous unit with atypical CD4+ T cells. Clinically, it has variable presentations and can frequently involve the scalp and face, areas spared in classic MF [6, 7]. Folliculotropic mycosis fungoides is associated with worse prognosis than conventional MF and has a poor 5-year overall survival rate [6, 8, 9]. More importantly, it has often been difficult to treat FMF patients with the standard SDTs used in classic MF, with many patients being refractory to initial treatments and requiring systemic medications earlier [6, 8]. It is proposed that the deep extension of lymphocytes into the follicular units may limit the response to superficial therapies such as phototherapy and topical corticosteroids [8, 10].\n\nImiquimod, a topical immune modulator that activates toll-like receptor 7 (TLR7), has demonstrated therapeutic benefit in small case series of MF patients [11–19]. When applied on MF lesional skin, it often creates erosions or ulcerations, presumably by triggering an exuberant immune response with significant depth [12, 14, 17]. Thus, the inflammatory response triggered by imiquimod may be of sufficient depth to target the deeper folliculotropic lymphocytes in FMF. Herein, we present the case of a young female with a single FMF lesion whom we successfully treated with topical imiquimod application. Informed consent for publication was obtained from all patients for whom identifying information is included in this article.\n\nCase\n\nA 21-year-old female patient initially presented to our cutaneous lymphoma clinic after histopathology findings of a single persistent lesion on the breast were concerning for MF. The lesion had been present for approximately one year despite three months of treatment with topical corticosteroids; it was pruritic but not painful. Physical examination revealed a pink 1.5-cm indurated plaque with mild surrounding erythema on the left anteromedial breast. The patient had no other lesions and no lymphadenopathy. Histopathology review revealed atypical CD4+ lymphocytes infiltrating the follicular epithelium, consistent with FMF (Fig. 1a, b). Immunohistochemistry analysis showed predominantly CD3+ CD4+ T cells (Fig. 1c) with an increase in CD4/CD8 ratio. Peripheral blood flow cytometric analysis revealed no abnormal cell populations.Fig. 1 a, b Atypical CD4+ lymphocytes infiltrating the dermis (a; H&E, 40 ×) and follicular epithelium (b H&E, 100×). c Immunohistochemistry analysis showing predominantly CD4+ T cells in the infiltrate (CD4 stain, 40×)\n\nTopical steroid was discontinued, and treatment with daily topical 5% imiquimod was started. One month after therapy, the patient presented with an indurated plaque with shallow erosions and reported some application-site irritation and pruritus. After another month of treatment, shallow ulcerations developed at the site (Fig. 2a). At this visit, imiquimod therapy was discontinued. One month after imiquimod discontinuation, the plaque had completely resolved, leaving an atrophic pink patch without scale (Fig. 2b). There was no reappearance of the lesion on follow-up five months after imiquimod discontinuation.Fig. 2 a Shallow ulceration with surrounding erythema on left breast after two months of imiquimod therapy. b Atrophic pink patch seen one month after imiquimod therapy discontinuation\n\nDiscussion\n\nUnlike conventional MF, patients with FMF demonstrate poor response rates to SDTs. In Gerami et al.’s study, 13 of 43 patients with FMF received SDTs as initial therapy, including topical corticosteroids, psoralen plus ultraviolet A (PUVA), narrow-band ultraviolet B, localized irradiation, nitrogen mustard, and topical bexarotene [6]. Only three patients demonstrated a partial response (PR) or complete response (CR), with two of these patients requiring localized irradiation to achieve this effect. More importantly, patients who showed PR or CR had limited disease with less than 3% body surface area involvement. Therefore, in cases of FMF with limited skin involvement, potent SDTs may be effective. Similarly, imiquimod therapy in our patient with limited skin involvement led to an exuberant reaction and demonstrated efficacy in FMF.\n\nSeveral studies indicate that the innate and cytotoxic antitumor responses in MF are dysfunctional. This is supported by reduced T-helper type 1(Th1) activity levels and proinflammatory cytokines including interferon (IFN)-α, IFN-γ, and interleukin (IL)-12 [20, 21] and a dominant T-helper type 2 (Th2) phenotype [22, 23]. FMF is a distinct entity with a similar pathogenesis, consisting of a CD4+ lymphocytic infiltrate with a shift towards a Th2 environment [6]. Therefore, therapies that can promote immune activation and enhance the Th1 response can be beneficial in both MF and FMF. One example of such therapies that can be used topically is imiquimod.\n\nImiquimod is an immunomodulatory agent that induces TLR7 activity on plasmacytoid dendritic cells. Once activated, TLR7 signaling leads to release of proinflammatory cytokines including IFN-α, IFN-γ, and IL-12 that promote the innate immune response and shift the microenvironment to a Th1-dominant milieu [24, 25]. Subsequently, imiquimod enhances antigen presentation and cellular cytotoxicity, inducing an effective antitumor response [26]. It is likely that the exuberant skin reaction that occurred in our patient resulted from the release of imiquimod-induced proinflammatory cytokines. A subsequent increase in the antitumor immune response might have led to the resolution of her lymphoma lesion.\n\nSeveral small-scale studies describe imiquimod’s efficacy in early-stage MF (Table 1) [11–19, 27]. In our review of these studies, we found a total of 24 MF patients, stage IA–IIB, treated with topical imiquimod therapy. Only one patient was identified with FMF [18]. In patients who had documented clearance of treated lesions (N = 13, 54%), CR was achieved after an average of 4.3 months of imiquimod treatment. Patients who developed more severe inflammatory skin reactions were more likely to achieve clearance of their lymphoma lesions. We did not notice an association between time to CR with imiquimod and number of prior treatments or presence of simultaneous treatments. Interestingly, in one case, imiquimod treatment potentiated the patient’s response to PUVA [12]. As expected, the most commonly reported adverse events were skin reactions including erythema, erosions, and ulcerations at the site of application.Table 1 Cases of imiquimod therapy in mycosis fungoides\n\nAuthor (year)\tPatient(s) and MF presentation\tPrior treatment(s)\tDuration of imiquimod treatment\tAdverse events (AEs)\tResults\t\nSuchin et al. (2002) [11]\t52-year-old female\n\nStage IA, one lesion on abdomen\n\n\tTS, NM, and carmustine\tNightly × 4 months\tErythema, vesiculation, erosions, xerosis, pruritus during month 1 of treatment\n\n • Therapy discontinued for 2 days\n\n\tBiopsy-proven CR of lesion\n\nNo recurrence 10 months after therapy completion\n\n\t\nDummer et al. (2003) [12]\t65-year-old male*\n\nMultiple lesions on face, trunk, extremities\n\n\tPUVA, acitretin\tDaily × 8 weeks only to facial plaques\n\n • PUVA continued on trunk and extremities\n\n\tUlceration during day 10 of treatment\tCR of all facial and trunk/extremity lesions\n\nNo recurrence 12 months after therapy completion\n\n\t\nChong et al. (2004) [13]\t4 male patients, ages 39–61 years\n\nAll stage IB\n\n\tNot specified\tDaily × 16 weeks\n\nOne patient received placebo\n\n\tMild lesional irritation**\tMean decrease in surface area of 8.9% of treated lesions\n\nMean increase in surface area of 39.9% of distant control lesions\n\nMild improvements in erythema and lesion thickness\n\nPatient on placebo had increase in lesion thickness, surface area, and scaling\n\n\t\nDeeths et al. (2005) [14]\t2 male and 4 female patients, ages 41–79 years\n\nStage IA (N = 3), IB (N = 2), IIB (N = 1)\n\n\tNone in 2 patients\n\nPUVA, NM, EB, SR, TS, IMQ, IFN, and MTX in 4 patients\n\n\t3× weekly × 12 weeks on selected lesions\n\nConcurrent PUVA in 2 patients (stage IB and IIB)\n\nConcurrent IFN in 1 patient (stage IB)\n\n\tApplication-site irritation in 4 patients\n\nErosion during week 3 of treatment in 1 patient\n\nUlcer and erythema during week 3 of treatment in another patient\n\nTherapy frequency decreased in some patients\n\n\tNo change in 1 patient\n\nSlight improvement in 2 patients\n\nModerate improvement in 1 patient\n\nMarked improvement in 1 patient\n\nAlmost clear in 1 patient\n\n\t\nCoors et al. (2006) [15]\t4 male patients, ages 43–78 years\n\nStage IA (N = 3), IB (N = 1)\n\n\tPUVA in all patients, IFN in 2 patients, and SR in 1 patient\t3–7× weekly × 8–24 weeks depending on initial response\n\nConcurrent PUVA in 1 patient\n\nConcurrent chlorambucil and prednisolone in 1 patient\n\n\tErythema, papules, and pruritus**\tCR of treated lesions in 2 patients after 8 and 16 weeks of treatment\n\nPD in 1 patient\n\nNo change in 1 patient\n\n\t\nChiam et al. (2007) [16]\t32-year old male\n\nStage 1A, penile plaque\n\n\tTS\tEvery other day × 4–5 months\tLocal pain during week 1 of treatment\n\nSkin erosion during month 3 of treatment\n\n\tCR of lesion\n\nNo recurrence 6 months after treatment completion\n\n\t\nMartínez-González et al. (2008) [17]\t1: 70-year-old male\n\n • Stage IIB (tumor)\n\n2: 62-year-old male\n\n • Stage IA\n\n3: 79-year-old male\n\n • Stage IA\n\n4: 60-year-old female*\n\n\t1: TS, XRT, PUVA, IFN, NM\n\n2: TS, PUVA\n\n3: TS, PUVA\n\n4: TS, nbUVB, PUVA\n\n\t1: 3× weekly × 3 months\n\n2: 3× weekly × 14 months\n\n3: 3× weekly × 7 months\n\n4: 3× weekly × 4 months\n\n\t1: Erythema and ulcerations at month 1\n\n2: Not specified\n\n3: Minimal erythema\n\n4: Intense inflammatory response during initial days\n\n\t1: CR of treated lesions, CR of some nearby untreated lesions\n\n2: CR of treated lesion; new lesion elsewhere\n\n3: CR of treated lesions; CR 3 months after treatment completion\n\n4: CR of treated lesion\n\n\t\nGordon et al. (2015) [18]\t1:80-year-old female\n\n • Stage IB (folliculotropic)\n\n2:60-year-old male\n\n • Stage IIB (tumor)\n\n\t1: TS, carmustine, TR, PUVA, MTX\n\n2: TS, nbUVB\n\n\t1: 2× weekly titrated to 3× weekly × 6 months; concomitant INF therapy\n\n2: 5 × weekly × 3 months\n\n\t1: Mild erythema during initial few weeks\n\n2: Inflammatory response during 2 months of treatment\n\n\t1: CR of treated lesion; no recurrence of lesions 10 months after treatment, but new lesions elsewhere\n\n2: CR of treated lesions; no recurrence of lesions 9 months after treatment, but new lesions elsewhere\n\n\t\nLewis et al. (2017) [19]\t1: 68-year-old male\n\n • Stage IIB\n\n2: 65-year-old female\n\n • Stage IIB with LCT\n\n\t1: XRT, SR, NM, TS\n\n2: SR, nbUVB\n\n\t1: Nightly × 4 weeks\n\n2: 5× weekly × 4 weeks\n\n\t1: None\n\n2: Irritation and flu-like symptoms**\n\n\t1: CR of treated lesion; no recurrence of lesion 8 years after treatment; new lesions elsewhere\n\n2: CR of treated lesion; no recurrence 2 years after treatment\n\n\t\nPUVA psoralen plus ultraviolet A light, NM nitrogen mustard, EB electron beam, SR systemic retinoids, TS topical steroids, IMQ imiquimod, IFN interferon, MTX methotrexate, TR topical retinoids, nbUVB narrow-band ultraviolet B phototherapy, XRT radiation, LCT large cell transformation, PD progressive disease\n\n*Staging not specified\n\n**Timing of AE not specified\n\nConclusions\n\nOur patient with FMF who failed to respond to topical steroid treatment achieved CR after 2 months of imiquimod therapy. Given the tendency of FMF to resist SDTs, the rapid response to imiquimod observed in this case supports the unique role of topical imiquimod as an early treatment agent for FMF subtype with limited skin involvement. Overall, these findings highlight the need for large-scale studies to evaluate efficacy of imiquimod in treatment of MF and FMF.\n\nAcknowledgements\n\nWe would like to thank the patient for participation.\n\nFunding\n\nNo funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nDisclosures\n\nDoaa Shalabi, Nish Vadalia and Neda Nikbakht have nothing to disclose.\n\nCompliance with Ethics Guidelines\n\nWhile the institutional review board approval was not required for this single case study, the patient provided consent for publication of this report. Additional informed consent was obtained from all patients for whom identifying information is included in this article.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\n\nEnhanced Digital Features\n\nTo view enhanced digital features for this article go to 10.6084/m9.figshare.9104903.\n==== Refs\nReferences\n\n1. Willemze R Jaffe ES Burg G WHO-EORTC classification for cutaneous lymphomas Blood 2005 105 10 3768 3785 15692063\n2. Scarisbrick JJ Staging and management of cutaneous T-cell lymphoma Clin Exp Dermatol 2006 31 2 181 186 16487086\n3. Lindahl LM Fenger-Gron M Iversen L Topical nitrogen mustard therapy in patients with mycosis fungoides or parapsoriasis J Eur Acad Dermatol Venereol 2013 27 2 163 168 22229501\n4. Hoppe RT Abel EA Deneau DG Mycosis fungoides: management with topical nitrogen mustard J Clin Oncol 1987 5 11 1796 1803 3681368\n5. Breneman D Duvic M Kuzel T Phase 1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cutaneous T-cell lymphoma Arch Dermatol 2002 138 3 325 332 11902983\n6. Gerami P Rosen S Kuzel T Folliculotropic mycosis fungoides: an aggressive variant of cutaneous T-cell lymphoma Arch Dermatol 2008 144 6 738 746 18559762\n7. Lehman JS Cook-Norris RH Weed BR Folliculotropic mycosis fungoides: single-center study and systematic review Arch Dermatol 2010 146 6 607 613 20566923\n8. van Doorn R Scheffer E Willemze R Follicular mycosis fungoides, a distinct disease entity with or without associated follicular mucinosis: a clinicopathologic and follow-up study of 51 patients Arch Dermatol 2002 138 2 191 198 11843638\n9. van Santen S Roach RE van Doorn R Clinical staging and prognostic factors in folliculotropic mycosis fungoides JAMA Dermatol 2016 152 9 992 1000 27276223\n10. Klemke CD Dippel E Assaf C Follicular mycosis fungoides Br J Dermatol 1999 141 1 137 140 10417530\n11. Suchin KR Junkins-Hopkins JM Rook AH Treatment of stage IA cutaneous T-cell lymphoma with topical application of the immune response modifier imiquimod Arch Dermatol 2002 138 9 1137 1139 12224972\n12. Dummer R Urosevic M Kempf W Imiquimod induces complete clearance of a PUVA-resistant plaque in mycosis fungoides Dermatology 2003 207 1 116 118 12835571\n13. Chong A Loo WJ Banney L Imiquimod 5% cream in the treatment of mycosis fungoides—a pilot study J Dermatolog Treat 2004 15 2 118 119 15204164\n14. Deeths MJ Chapman JT Dellavalle RP Treatment of patch and plaque stage mycosis fungoides with imiquimod 5% cream J Am Acad Dermatol 2005 52 2 275 280 15692473\n15. Coors EA Schuler G Von Den Driesch P Topical imiquimod as treatment for different kinds of cutaneous lymphoma Eur J Dermatol 2006 16 4 391 393 16935796\n16. Chiam LY Chan YC Solitary plaque mycosis fungoides on the penis responding to topical imiquimod therapy Br J Dermatol 2007 156 3 560 562 17300249\n17. Martinez-Gonzalez MC Verea-Hernando MM Yebra-Pimentel MT Imiquimod in mycosis fungoides Eur J Dermatol 2008 18 2 148 152 18424373\n18. Gordon MC Sluzevich JC Jambusaria-Pahlajani A Clearance of folliculotropic and tumor mycosis fungoides with topical 5% imiquimod JAAD Case Rep 2015 1 6 348 350 27051776\n19. Lewis DJ Byekova YA Emge DA Complete resolution of mycosis fungoides tumors with imiquimod 5% cream: a case series J Dermatolog Treat 2017 28 6 567 569 28635518\n20. Rook AH Vowels BR Jaworsky C The immunopathogenesis of cutaneous T-cell lymphoma. Abnormal cytokine production by Sezary T cells Arch Dermatol 1993 129 4 486 489 8466223\n21. Rook AH Kubin M Cassin M IL-12 reverses cytokine and immune abnormalities in Sezary syndrome J Immunol 1995 154 3 1491 1498 7822812\n22. Vowels BR Rook AH Cassin M Expression of interleukin-4 and interleukin-5 mRNA in developing cutaneous late-phase reactions J Allergy Clin Immunol 1995 96 1 92 96 7622768\n23. Vowels BR Lessin SR Cassin M Th2 cytokine mRNA expression in skin in cutaneous T-cell lymphoma J Invest Dermatol 1994 103 5 669 673 7963654\n24. Sauder DN Immunomodulatory and pharmacologic properties of imiquimod J Am Acad Dermatol 2000 43 1 Pt 2 S6 S11 10861101\n25. Urosevic M Dummer R Conrad C Disease-independent skin recruitment and activation of plasmacytoid predendritic cells following imiquimod treatment J Natl Cancer Inst 2005 97 15 1143 1153 16077073\n26. Suzuki H Wang B Shivji GM Imiquimod, a topical immune response modifier, induces migration of Langerhans cells J Invest Dermatol 2000 114 1 135 141 10620129\n27. Shalabi D Bistline A Alpdogan O Immune evasion and current immunotherapy strategies in mycosis fungoides (MF) and Sezary syndrome (SS) Chin Clin Oncol 2019 8 1 11 30691274\n\n",
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"keywords": "Folliculotropic mycosis fungoides; Imiquimod; Toll-like receptor 7 agonist",
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"references": "7622768;10417530;7822812;11902983;18559762;15692473;16935796;10861101;12835571;8466223;22229501;20566923;16077073;30691274;15692063;17300249;27276223;10620129;3681368;11843638;16487086;27051776;18424373;7963654;15204164;28635518;12224972",
"title": "Revisiting Imiquimod for Treatment of Folliculotropic Mycosis Fungoides: A Case Report and Review of the Literature.",
"title_normalized": "revisiting imiquimod for treatment of folliculotropic mycosis fungoides a case report and review of the literature"
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"abstract": "There are several case reports on risperidone-related bleeding; however, to our knowledge, there is no report about gingival bleeding associated with risperidone in the literature. We presented a case who experienced gingival bleeding when risperidone dose was increased to 0.5 mg/day, and subsided after decreasing the dose to 0.25 mg/day, suggesting a dose-dependent side-effect. The bleeding side effect of risperidone might be caused by several mechanisms, including 5-hydroxytryptamine 2A receptor antagonism. Although bleeding associated with risperidone is rarely reported, clinicians should be aware of this side effect.",
"affiliations": "Department of Child and Adolescent Psychiatry, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey.;Department of Psychiatry, Konya Training and Research Hospital, Konya, Turkey.;Department of Orthodontis, Faculty of Dentistry, Selcuk University, Konya, Turkey.",
"authors": "Hergüner|Sabri|S|;Özayhan|Hatice Yardım|HY|;Erdur|Emire Aybuke|EA|",
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"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 2712143310.9758/cpn.2016.14.2.210cpn-14-210Case ReportRisperidone-induced Gingival Bleeding in a Pediatric Case: A Dose-dependent Side Effect Hergüner Sabri 1Özayhan Hatice Yardım 2Erdur Emire Aybuke 31 Department of Child and Adolescent Psychiatry, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, \nTurkey2 Department of Psychiatry, Konya Training and Research Hospital, Konya, \nTurkey3 Department of Orthodontis, Faculty of Dentistry, Selcuk University, Konya, \nTurkeyAddress for correspondence: Sabri Hergüner, MD, Meram Tıp Fakultesi, Cocuk ve Ergen Psikiyatrisi AD, Meram, Konya, Turkey, Tel: +90-533-742-81-50, Fax: +90-332-233-41-40, E-mail: herguners@yahoo.com5 2016 31 5 2016 14 2 210 211 17 7 2015 24 8 2015 25 8 2015 Copyright © 2016, Korean College of Neuropsychopharmacology2016This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.There are several case reports on risperidone-related bleeding; however, to our knowledge, there is no report about gingival bleeding associated with risperidone in the literature. We presented a case who experienced gingival bleeding when risperidone dose was increased to 0.5 mg/day, and subsided after decreasing the dose to 0.25 mg/day, suggesting a dose-dependent side-effect. The bleeding side effect of risperidone might be caused by several mechanisms, including 5-hydroxytryptamine 2A receptor antagonism. Although bleeding associated with risperidone is rarely reported, clinicians should be aware of this side effect.\n\nBleedingRisperidoneChildAdverse effects\n==== Body\nINTRODUCTION\nRisperidone has been reported to be effective in management of disruptive behaviors, including hyperactivity, irritability, aggression, and temper tantrums. Increased appetite, weight gain, headache, and sedation are among the most reported adverse effects. Bleeding is a rarely reported side effect of risperidone. Literature search revealed only four published reports of risperidone-related bleeding, including hemorrhagic cystitis,1) nasal bleeding,2,3) and gastrointestinal bleeding.4)\n\nWe hereby describe the first pediatric case of gingival bleeding during risperidone treatment.\n\nCASE\nAn 11-year-old-girl was referred to our out-patient clinic for her hyperactivity, temper tantrums, sleep problems, and self-injurious behaviors. According to her psychiatric assessment and psychometric evaluation, she was diagnosed with mild intellectual disability. She was started on risperidone 0.25 mg/day treatment for her disruptive behaviors and two weeks later the dose was increased to 0.5 mg/day. One-week after the dose increase, she experienced gingival bleeding when she brushed her teeth. Her mother reported that bloodstains were evident on her pillow in the morning. Risperidone was considered to be the reason for bleeding, therefore we decided to reduce the dose to 0.25 mg/day. Gingival bleeding ceased within a week. Because worsening of her behavioral problems, her mother increased the dose to 0.33 mg/day. She experienced gingival bleeding rarely (twice a month) and mildly during this dose regime, therefore we stopped the medication. She received risperidone 0.33 mg/day treatment for 4 weeks with partial response. We decided to change risperidone to methylphenidate; however, her parents refused to continue to the treatment because of their worries about the potential side effects.\n\nHer physical examination and laboratory investigation, including platelet count, were normal. Dental referral did not reveal any cause for her bleeding. She had no history of any bleeding disorder or any other medical condition including current allergies. Her mother reported no family history of bleeding disorders. She was not taking any other medication other than risperidone at the time of the development of bleeding.\n\nDISCUSSION\nThere are several case reports about risperidone-related bleeding; however, to our knowledge, there is no report of gingival bleeding associated with risperidone in the literature. We presented a case who experienced gingival bleeding when risperidone dose was increased to 0.5 mg/day, and subsided after decreasing the dose to 0.25 mg/day, suggesting a dose-dependent side-effect.\n\nIt may be argued that bleeding occurred spontaneously without any obvious cause. However, the chronological relationship between the time of risperidone 0.5 mg/day administration and emergence of bleeding in the absence of an identifiable medical condition suggests risperidone to be the causative agent. There was no other agent likely to be the cause of bleeding, except risperidone, and bleeding ceased when the dose was decreased. Although an etiological relationship between risperidone use and gingival bleeding cannot be drawn from a single case, the Naranjo probability scale score (8) reveals a probable relationship.5)\n\nThe bleeding side effect of risperidone might be caused by several mechanisms, including thrombocytopenia and 5-hydroxytryptamine 2A (5-HT2A) receptor antagonism.3) Thrombocytopenia is a known adverse effect of atypical antipsychotics and has also been reported during risperidone.6) In our reported case platelet count was normal, therefore, gingival bleeding could not be a consequence of thrombocytopenia. Antagonism of 5-HT2A receptor was suggested to cause bleeding by inhibiting the release of vasoconstrictors from platelets and reducing the platelet aggregation.4) Therefore, we may speculate that risperidone’s high affinity to 5-HT2A receptors might have probably resulted gingival bleeding. This case suggests that bleeding associated with risperidone may be a dose-dependent side effect. However, these potential explanations may not describe the entire mechanism of this adverse reaction. It is also possible that she might have some undetermined predisposing factors for bleeding that is triggered by risperidone.\n\nThere are several reports on gingival bleeding during anti-depressants;7) however, this is the first case on gingival bleeding associated with risperidone. Although bleeding is a rare side effect, clinicians should be aware that risperidone may cause bleeding. Risperidone may also increase the risk of bleeding in susceptible patients with a history of coagulation disorders, and with concomitant use of other drugs, including non-steroidal anti-inflammatory drugs, aspirin, or other medications that affect coagulation.\n==== Refs\nREFERENCES\n1 Hudson RG Cain MP Risperidone associated hemorrhagic cystitis J Urol 1998 160 159 10.1016/S0022-5347(01)63077-5 9628639 \n2 Mowla A Dastgheib SA Ebrahimi AA Pani A Nasal bleeding associated with fluoxetine and risperidone interaction: a case report Pharmacopsychiatry 2009 42 204 205 10.1055/s-0029-1220889 19724985 \n3 Harrison-Woolrych M Clark DW Nose bleeds associated with use of risperidone BMJ 2004 328 1416 10.1136/bmj.328.7453.1416 15191978 \n4 Coskun M Mukaddes NM Possible risperidone-related gastrointestinal bleeding or epistaxis in two pediatric cases J Child Adolesc Psychopharmacol 2008 18 299 300 10.1089/cap.2007.0107 18582187 \n5 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 10.1038/clpt.1981.154 7249508 \n6 Semba J Okui S Risperidone-induced thrombocytopenia: a case report Gen Hosp Psychiatry 2009 31 97 98 10.1016/j.genhosppsych.2008.06.005 19134517 \n7 Yavasoglu I Kadikoylu G Bolaman Z Gingival bleeding due to venlafaxine Ann Pharmacother 2008 42 144 145 10.1345/aph.1K180 18029426\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1088",
"issue": "14(2)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Adverse effects; Bleeding; Child; Risperidone",
"medline_ta": "Clin Psychopharmacol Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101207332",
"other_id": null,
"pages": "210-1",
"pmc": null,
"pmid": "27121433",
"pubdate": "2016-05-31",
"publication_types": "D002363:Case Reports",
"references": "18029426;15191978;19724985;9628639;7249508;18582187;19134517",
"title": "Risperidone-induced Gingival Bleeding in a Pediatric Case: A Dose-dependent Side Effect.",
"title_normalized": "risperidone induced gingival bleeding in a pediatric case a dose dependent side effect"
} | [
{
"companynumb": "TR-CIPLA LTD.-2016TR06641",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Single nucleotide polymorphisms in the cytochrome P450 (CYP) 2B6 gene have been associated with high interindividual variation in efavirenz pharmacokinetics. However, clinical data on the relationship of CYP2B6 polymorphisms with the occurrence of efavirenz-induced central nervous system (CNS) symptoms are limited.\n\n\n\nWe analysed four polymorphisms in the CYP2B6 (516 G>T), CYP3A5 (6986 A>G) and ATP-binding cassette, sub-family B, member 1 (ABCB1) (2677 G>T/A and 3435 C>T) genes in HIV-infected adults virologically suppressed on a protease inhibitor-based regimen who switched to a regimen containing emtricitabine, didanosine and efavirenz in the setting of the ANRS ALIZE trial. Kaplan-Meier methods and Cox regression analysis were used to investigate their association with efavirenz plasma levels and CNS events up to 48 months after switching.\n\n\n\nIn total, 191 patients with a median age of 41 years, who were 87% male and 85% Caucasian, were enrolled in the study. Variant allelic frequencies were 0.49, 0.93, 0.59 and 0.63 for CYP2B6 516, CYP3A5 392, ABCB1 2677 and ABCB1 3435, respectively. The median efavirenz plasma concentration (MEPC) was 2.2 mg/L [interquartile range (IQR) 1.7-2.8 mg/L] and was significantly higher in patients with the deficient CYP2B6 516T. Overall, 242 CNS events were reported in 104 individuals (54%). No correlation was found between MEPC and CNS events. The occurrence of a first CNS event was lower in patients with the CYP2B6 516 G/G genotype vs. CYP2B6 516 T genotypes [50% (IQR: 40-60%) vs. 66% (IQR: 56-75%), respectively; P = 0.02]. In an adjusted Cox regression model, there was a tendency towards a higher risk of a first CNS event among carriers of the variant CYP2B6 516 T allele (relative risk 1.4 [95% CI, 0.99-2.1]; P?=?.06), compared with noncarriers.\n\n\n\nThe deficient CYP2B6 516 T allele is associated with higher efavirenz plasma drug levels and more frequent CNS-related symptoms.",
"affiliations": "Sorbonne Paris Cité, Université Paris Diderot Paris 7, Paris, France.;INSERM U1219, Bordeaux, France.;Université Paris Descartes, Sorbonne Paris Cité, Paris, France.;Assistance Publique-Hôpitaux de Paris (AP-HP), Pharmacie, Hôpital Saint-Louis, Paris, France.;Service de médecine interne, Hôpital Saint-André, Bordeaux, France.;Département des Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire Montpellier, Montpellier, France.;Service de Maladies Infectieuses, CHU Nantes, Nantes, France.;INSERM U1219, Bordeaux, France.;Sorbonne Paris Cité, Université Paris Diderot Paris 7, Paris, France.",
"authors": "Gallien|S|S|0000-0002-8033-0936;Journot|V|V|;Loriot|M-A|MA|;Sauvageon|H|H|;Morlat|P|P|;Reynes|J|J|;Reliquet|V|V|;Chêne|G|G|;Molina|J-M|JM|;|||",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz",
"country": "England",
"delete": false,
"doi": "10.1111/hiv.12488",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1464-2662",
"issue": "18(8)",
"journal": "HIV medicine",
"keywords": "central nervous system; cytochrome P450 2B6 (CYP2B6); efavirenz; pharmacogenetics; toxicity",
"medline_ta": "HIV Med",
"mesh_terms": "D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines; D002493:Central Nervous System Diseases; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D015658:HIV Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma; D020641:Polymorphism, Single Nucleotide",
"nlm_unique_id": "100897392",
"other_id": null,
"pages": "537-545",
"pmc": null,
"pmid": "28145050",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Cytochrome 2B6 polymorphism and efavirenz-induced central nervous system symptoms : a substudy of the ANRS ALIZE trial.",
"title_normalized": "cytochrome 2b6 polymorphism and efavirenz induced central nervous system symptoms a substudy of the anrs alize trial"
} | [
{
"companynumb": "FR-CIPLA LTD.-2017FR01983",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EFAVIRENZ"
},
"drugadditional": null,
... |
{
"abstract": "ELANE neutropenia is associated with myelodysplasia and acute leukemia (MDS-AL), and severe infections. Because the MDS-AL risk has also been shown to be associated with exposure to GCSF, since 2005, in France, patients receiving high daily GCSF doses (>15 μg/kg/day) are eligible for HSCT, in addition to classic indications (MDS-AL or GCSF refractoriness). We analyzed the effect of this policy. Among 144 prospectively followed ELANE-neutropenia patients enrolled in the French Severe Congenital Neutropenia Registry, we defined two groups according to period: \"before 2005\" for those born before 2005 and followed until 31/12/2004 (1588 person-years); and \"after 2005\" comprised of those born after 2005 or born before 2005 but followed after 2005 until 31/03/2019 (1327 person-years). Sixteen of our cohort patients underwent HSCT (14 long-term survivors) and six developed MDS-ALs. Six leukemic transformations occurred in the before-2005 group and none after 2005 (respective frequencies 3.8 × 10-3 vs. 0; P < 0.01), while four HSCTs were done before 2005 and 12 since 2005 (respective HSCT rates increased 2.5 × 10-3 vs. 9 × 10-3; P < 0.01). Our results support early HSCT for patients with ELANE mutations who received high GCSF doses, as it might lower the risk of leukemic transformation.",
"affiliations": "Registre des Neutropénies Chroniques, Centre de Référence des Neutropénies Chroniques, Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, Hôpital Trousseau, APHP, Paris, F-75012, France.;Registre des Neutropénies Chroniques, Centre de Référence des Neutropénies Chroniques, Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, Hôpital Trousseau, APHP, Paris, F-75012, France.;CHU de Nantes, Nantes, France.;University of Strasbourg, Strasbourg, France.;Registre des Neutropénies Chroniques, Centre de Référence des Neutropénies Chroniques, Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, Hôpital Trousseau, APHP, Paris, F-75012, France.;CHU La Timone, Marseille, France.;Department of Pediatric Hematology/Oncology, University Hospital of Rennes, Rennes, France.;Institut d'Hémato-Oncologie Pédiatrie IHOPE, Lyon, France.;Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.;CHU Clermont-Ferrand, Centre Régional de Cancérologie et Thérapie Cellulaire Pédiatrique, Clermont-Ferrand, France.;Unité d'Immunologie Hématologie Pédiatrique, Necker Children's Hospital, Paris, France.;Départment de Pédiatrie, Hémato-Oncologie, CHU de Bordeaux, Bordeaux, France.;Départment de Pédiatrie, Hémato-Oncologie, CHU de Rouen, Rouen, France.;Department d'Hématologie, Service de Transplantation Médullaire, Hôpital Saint-Louis, Paris, France.;Department d'Hématologie, Service de Transplantation Médullaire, Hôpital Saint-Louis, Paris, France.;Institut d'Hémato-Oncologie Pédiatrie IHOPE, Lyon, France.;Département de Génétique, APHP, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France.;Pediatric Hematology Department, Robert-Debré Hospital, Paris, France.;Registre des Neutropénies Chroniques, Centre de Référence des Neutropénies Chroniques, Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, Hôpital Trousseau, APHP, Paris, F-75012, France. jean.donadieu@trs.aphp.fr.",
"authors": "Rotulo|Gioacchino Andrea|GA|;Beaupain|Blandine|B|;Rialland|Fanny|F|;Paillard|Catherine|C|;Nachit|Ouahiba|O|;Galambrun|Claire|C|;Gandemer|Virginie|V|;Bertrand|Yves|Y|;Neven|Benedicte|B|;Dore|Eric|E|;Moshous|Despina|D|;Filhon|Bruno|B|;Aladjdi|Nathalie|N|;Sicre de Fontbrune|Flore|F|;de la Tour|Regis Peffault|RP|;Ouachee|Marie|M|;Bellanne-Chantelot|Christine|C|;Dalle|Jean-Hugues|JH|;Donadieu|Jean|J|http://orcid.org/0000-0002-4485-146X",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/s41409-020-0800-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "55(8)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000080984:Congenital Bone Marrow Failure Syndromes; D065187:Controlled Before-After Studies; D005602:France; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D009503:Neutropenia; D012042:Registries",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "1614-1622",
"pmc": null,
"pmid": "31992846",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10666190;15642668;25501410;27384854;28197346;18028488",
"title": "HSCT may lower leukemia risk in ELANE neutropenia: a before-after study from the French Severe Congenital Neutropenia Registry.",
"title_normalized": "hsct may lower leukemia risk in elane neutropenia a before after study from the french severe congenital neutropenia registry"
} | [
{
"companynumb": "FR-NEOVII_BIOTECH-2021000019",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "4",
... |
{
"abstract": "OBJECTIVE\nWe conducted the first pilot Italian study to assess the preventability of adverse drug reactions involving psychotropic drugs reported through spontaneous reporting system from 01/07/2012 to 31/12/2014 in Campania Region.\n\n\nMETHODS\nPreventability was assessed, case-by-case, using an adapted version of the P-method. The evaluation was performed only for those reports that had, as suspected drug, antipsychotics, mood stabilizers, antidepressants, anxiolytic and/or sedative-hypnotic.\n\n\nRESULTS\nEighty-one cases (19.2%) out of 421 reported during the study period were preventable. In seventy-seven (95.1%) out of 81 preventable cases, the underlying mechanism of the adverse drug reactions was dose-related, in four (4.9%) preventable cases the underlying mechanism of the adverse drug reactions was respectively susceptibility- (1; 1.2%), unknown- (1; 1.2%) and time-related (2; 2.5%). In the 81 preventable cases, 97 critical criteria were detected of which 29/97 (29.9%) related to healthcare professionals' practices, 0/97 (0.0%) to drug quality and 68/97 (70.1%) to patient behaviour.\n\n\nCONCLUSIONS\nWe proved that it was possible to apply and adapt the P-Method to assess the preventability of the adverse drug reactions involving psychotropic drugs, analysing individual case safety report sent through Campania Region spontaneous reporting system. Information acquired will be used to organize educational activities for both physicians and patients to promote a more appropriate drug use.",
"affiliations": "a Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology , Second University of Naples , Naples , Italy.;a Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology , Second University of Naples , Naples , Italy.;a Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology , Second University of Naples , Naples , Italy.;a Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology , Second University of Naples , Naples , Italy.;a Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology , Second University of Naples , Naples , Italy.;a Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology , Second University of Naples , Naples , Italy.;b Department of Psychiatry , Second University of Naples , Naples , Italy.;b Department of Psychiatry , Second University of Naples , Naples , Italy.;a Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology , Second University of Naples , Naples , Italy.;a Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology , Second University of Naples , Naples , Italy.;a Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology , Second University of Naples , Naples , Italy.",
"authors": "Sessa|Maurizio|M|;Rafaniello|Concetta|C|;Sportiello|Liberata|L|;Mascolo|Annamaria|A|;Scavone|Cristina|C|;Maccariello|Alessandra|A|;Iannaccone|Teresa|T|;Fabrazzo|Michele|M|;Berrino|Liberato|L|;Rossi|Francesco|F|;Capuano|Annalisa|A|",
"chemical_list": "D011619:Psychotropic Drugs",
"country": "England",
"delete": false,
"doi": "10.1080/14740338.2016.1221397",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-0338",
"issue": "15(sup2)",
"journal": "Expert opinion on drug safety",
"keywords": "Adverse events; drug safety; drug-drug interactions; pharmacovigilance; preventability; psychotropic drugs",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011619:Psychotropic Drugs; D055815:Young Adult",
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "9-15",
"pmc": null,
"pmid": "27875917",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Campania Region (Italy) spontaneous reporting system and preventability assessment through a case-by-case approach: a pilot study on psychotropic drugs.",
"title_normalized": "campania region italy spontaneous reporting system and preventability assessment through a case by case approach a pilot study on psychotropic drugs"
} | [
{
"companynumb": "IT-PFIZER INC-2016597254",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAZOLAM"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report a rare case with central-variant posterior reversible encephalopathy syndrome due to sulfasalazine.\n\n\nMETHODS\nA 55-year-old female patient presented with seizure and acute-onset hemiparesia. Thirty days earlier, treatment with sulfasalazine was commenced in response to a diagnosis of psoriatic arthritis. Laboratory examinations were normal. Brain magnetic resonance imaging showed symmetric edema within basal ganglia and thalami with sparing of the cerebral cortices. After stopping the treatment of sulfasalazine, clinical and radiological findings regressed dramatically.\n\n\nCONCLUSIONS\nThis was a case of central-variant posterior reversible encephalopathy syndrome due to sulfasalazine, and atypical imaging findings should be kept in mind for early diagnosis.",
"affiliations": "Clinic of Neurology, Tepecik Education and Research Hospital, Izmir, Turkey.",
"authors": "Ocek|Levent|L|;Sener|Ufuk|U|;Demirtas|Burcu S|BS|;Ozcelik|Metin M|MM|;Oztekin|Ozgur|O|;Zorlu|Yasar|Y|",
"chemical_list": "D018501:Antirheumatic Agents; D012460:Sulfasalazine",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000437386",
"fulltext": "\n==== Front\nMed Princ PractMed Princ PractMPPMedical Principles and Practice1011-75711423-0151S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 2630473010.1159/000437386mpp-0024-0578Case ReportCentral-Variant Posterior Reversible Encephalopathy due to Sulfasalazine: A Case Report Ocek Levent a*Sener Ufuk aDemirtas Burcu S. aOzcelik Metin M. aOztekin Ozgur bZorlu Yasar aaClinic of Neurology, Izmir, TurkeybClinics of Radiology, Tepecik Education and Research Hospital, Izmir, Turkey*Levent Ocek, Clinic of Neurology, Tepecik Education and Research Hospital, Gaziler Caddesi, 469, Yenisehir, TR-35170 Izmir (Turkey), E-Mail leventocek66@yahoo.com10 2015 21 8 2015 21 8 2015 24 6 578 580 14 1 2015 6 7 2015 Copyright © 2015 by S. Karger AG, Basel2015This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.Objective\nTo report a rare case with central-variant posterior reversible encephalopathy syndrome due to sulfasalazine.\n\nClinical Presentation and Intervention\nA 55-year-old female patient presented with seizure and acute-onset hemiparesia. Thirty days earlier, treatment with sulfasalazine was commenced in response to a diagnosis of psoriatic arthritis. Laboratory examinations were normal. Brain magnetic resonance imaging showed symmetric edema within basal ganglia and thalami with sparing of the cerebral cortices. After stopping the treatment of sulfasalazine, clinical and radiological findings regressed dramatically.\n\nConclusion\nThis was a case of central-variant posterior reversible encephalopathy syndrome due to sulfasalazine, and atypical imaging findings should be kept in mind for early diagnosis.\n\nKey Words\nSulfasalazineCentral-variant posterior reversible encephalopathy syndromeMagnetic resonance imaging\n==== Body\nIntroduction\nPosterior reversible encephalopathy syndrome (PRES) is typically characterized as bilateral symmetrical vasogenic edema in the parietal and occipital lobes [1,2]. In recent years, patients with PRES who had involvement of brainstem or basal ganglia lacking cortical or subcortical cerebral edema were reported [1,3]. This rare radiological entity had been diagnosed as central-variant PRES [1]. This paper describes a patient with central-variant PRES due to sulfasalazine (SSZ) treatment.\n\nCase Report\nA 55-year-old female patient was admitted to our hospital with seizure, mild headache and acute onset hemiparesia. There was nothing remarkable other than psoriatic arthritis in the medical history. Thirty days earlier, treatment with SSZ (2 g/day) was commenced in response to the diagnosis of psoriatic arthritis. At the time of admission, her blood pressure was 120/80 mm Hg and her temperature was 37°C. Her blood pressure was normal during patient monitoring. Neurological examination revealed retrograde amnesia and mild right hemiparesis. The fundoscopic examination was normal. Serum biochemical and hematologic tests were within normal limits. Cerebrospinal fluid (CSF) analysis was also normal and CSF cultures were negative. An electroencephalogram showed mild slowing of background activity particularly at anterior frontotemporal areas bilaterally. Cranial computed tomography was normal. Brain magnetic resonance imaging (MRI) revealed hyperintensity in basal ganglia, thalami, pons and white matter, with sparing of the cerebral cortices and subcortical white matter. The affected region had isointensity on diffusion-weighted imaging (fig. 1). The antiepileptic drug was given for recurrent generalized seizures. SSZ was stopped. All neurological symptoms and signs resolved 5 days after SSZ was discontinued. On the 30th day after presentation, a new MRI showed resolution of the edema (fig. 2).\n\nDiscussion\nThis case showed that central-variant PRES had occurred due to SSZ. In our patient, involvement of the basal ganglia, thalami, pons and temporal pole bilaterally, with sparing of the cerebral cortices and subcortical white matter, was consistent with central variant [1,3]. In 2 previously reported cases of reversible encephalopathy caused by SSZ, it was suggested that the potential mechanism of encephalopathy induced by SSZ was delayed hypersensitivity reaction to SSZ or metabolites [4,5].\n\nIt may be a difficult differential diagnosis due to nonspecific clinical features and a diversity of radiological findings. Ictal or postictal state, progressive multifocal leukoencephalopathy, severe leukoaraiosis, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), infectious encephalitis, acute disseminated encephalomyelitis, mitochondrial myopathy, encephalopathy, lactacidosis, and stroke-like episodes (MELAS) syndrome, vasculitis, and ischemic stroke (watershed or posterior cerebral artery territory) may cause a similar clinical picture [1,2]. In our patient, CSF analysis, tests for viral and all vasculitic markers were normal, and regression of the lesion on MRI could support our diagnosis.\n\nThe mechanism of PRES is thought to be from abnormalities in the cerebral autoregulatory and endothelial dysfunction. The most reported etiologic factors are hypertension and neurotoxic drugs. In PRES, 70–80% of the patients had moderate-or-severe hypertension. If the upper limit of autoregulation is exceeded, cerebral blood flow increases and there is a breakdown of the blood-brain barrier. Thus, fluid and blood products exude into the brain parenchyma [6]. In central variant PRES, endothelial cell dysfunction occurring within smaller, perforating vessels supplying the brainstem and basal ganglia is thought to be the pathophysiological process.\n\nImmune system activation leads to endothelial cell activation with release of various mediators in PRES with normal blood pressure. Moreover, endothelial surface antigens and leukocytes increase, then a blood-brain barrier dysfunction occurs leading to vasogenic cerebral edema [7]. In our case there was no history of hypertension and her blood pressure at presentation was at a normal level.\n\nConclusion\nThis was a case of central-variant PRES due to SSZ, and atypical imaging findings should be kept in mind for early diagnosis.\n\nDisclosure Statement\nThe authors have no conflicts of interest to disclose.\n\nFig. 1 \na On the T1-weighted image, there is subtle hypointensity in affected areas. b On the T2-weighted image, the basal ganglia and thalamus show bilateral and symmetric hyperintense regions. c On the FLAIR image, there is hyperintensity in the same affected areas. d On diffusion-weighted imaging, there is no diffusion restriction on the affected areas.\n\nFig. 2 On control MRI taken 4 weeks after the treatment, abnormalities on basal ganglia and thalamus have completely resolved.\n==== Refs\nReferences\n1 McKinney AM Jagadeesan BD Truwit CL Central-variant posterior reversible encephalopathy syndrome: brainstem or basal ganglia involvement lacking cortical or subcortical cerebral edema Am J Roentgenol 2013 201 631 638 23971457 \n2 Bartynski WS Boardman JF Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome Am J Neuroradiol 2007 28 1320 1327 17698535 \n3 Bartynski WS Posterior reversible encephalopathy syndrome. Part 1: fundamental imaging and clinical features Am J Neuroradiol 2008 29 1036 1042 18356474 \n4 Takahashi H Ito S Nagumo K Salazosulfapyridine-induced encephalopathy with symmetrical lesions in the basal ganglia and thalami Intern Med 2006 45 927 929 16946577 \n5 Mut SE Kutlu G Ucler S Reversible encephalopathy due to sulfasalazine Clin Neuropharmacol 2008 31 368 371 19050416 \n6 Pedraza R Marik PE Varon J Posterior reversible encephalopathy syndrome: a review Crit Care Shock 2009 12 135 143 \n7 Bartynski WS Posterior reversible encephalopathy syndrome. Part 2: controversies surrounding pathophysiology of vasogenic edema Am J Neuroradiol 2008 29 1043 1049 18403560\n\n",
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"abstract": "We describe the successful management of Anncaliia algerae microsporidial myositis in a man with graft versus host disease after hemopoietic stem cell transplantation. We also summarize clinical presentation and management approaches and discuss the importance of research into the acquisition of this infection and strategies for prevention.",
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"fulltext": "\n==== Front\nEmerg Infect Dis\nEmerging Infect. Dis\nEID\nEmerging Infectious Diseases\n1080-6040\n1080-6059\nCenters for Disease Control and Prevention\n\n30014835\n17-2002\n10.3201/eid2408.172002\nDispatch\nDispatch\nAnncaliia algerae Microsporidial Myositis, New South Wales, Australia\nAnncaliia algerae Microsporidial Myositis, New South Wales, Australia\nAnncaliia algerae Microsporidial Myositis\nSutrave Gaurav\nMaundrell Adam\nKeighley Caitlin\nJennings Zoe\nBrammah Susan\nWang Min-Xia\nPamphlett Roger\nWebb Cameron E.\nStark Damien\nEnglert Helen\nGottlieb David\nBilmon Ian\nWatts Matthew R.\nWestmead Hospital, Westmead, New South Wales, Australia (G. Sutrave, A. Maundrell, C. Keighley, C.E. Webb, H. Englert, D. Gottlieb, I. Bilmon, M.R. Watts);\nUniversity of Sydney, Sydney, New South Wales, Australia (G. Sutrave, M.-X. Wang, R. Pamphlett, C.E. Webb, D. Gottlieb, I. Bilmon, M.R. Watts);\nNew South Wales Health Pathology Institute of Clinical Pathology and Medical Research, Westmead (Z. Jennings, C.E. Webb, M.R. Watts);\nConcord Repatriation General Hospital, Concord West, New South Wales, Australia (S. Brammah);\nSt. Vincent’s Hospital, Darlinghurst, New South Wales, Australia (D. Stark)\nAddress for correspondence: Matthew R. Watts, Centre for Infectious Disease and Microbiology, Level 3 ICPMR-NSW Health Pathology, Westmead Hospital, University of Sydney, Darcy Rd, Westmead, NSW 2145, Australia; email: matthew.watts@health.nsw.gov.au\n8 2018\n24 8 15281531\nWe describe the successful management of Anncaliia algerae microsporidial myositis in a man with graft versus host disease after hemopoietic stem cell transplantation. We also summarize clinical presentation and management approaches and discuss the importance of research into the acquisition of this infection and strategies for prevention.\n\nKeywords:\n\nAnncaliia algerae\nmicrosporidial myositis\nNew South Wales\nAustralia\nmyositis\nmicrosporidia\nAnncaliia\ninfection\nimmunosuppressed\nstem cell transplant\ngraft versus host disease\nparasites\nfungi\n==== Body\nAnncaliia algerae is a microsporidian parasite that infects insects, including mosquitoes, and was first reported as a cause of fatal myositis in 2004 (1,2). Transmission occurs through contact with spores that are found in water, although the exact mechanism of transmission to humans is unknown (2). Myositis has been described in case-patients who were immunosuppressed because of rheumatoid arthritis, solid organ transplantation, and hematologic malignancy (1–5). It is currently unclear why 4 of the 6 previously published cases have originated in New South Wales, Australia, and the 2 other cases originated in North America (1–5). We document successful treatment of A. algerae infection after hemopoietic stem cell transplantation, provide an update on clinical features and management, and discuss possible routes of transmission and risk-mitigation strategies.\n\nCase Report\n\nA 66-year-old man sought care at a hospital, reporting a 5-week history of progressive myalgias, fatigue, and weakness. He also had a 3-week episode of nonbloody diarrhea that had resolved a week earlier. He reported no fevers, weight loss, dysphagia, or additional neurologic symptoms. He had chronic graft versus host disease (GVHD) with skin and pulmonary involvement treated with prednisone (25 mg/d orally), methotrexate (15 mg/wk orally), tacrolimus (1 mg 2×/d orally), and fluticasone/salmeterol (250 µg/50 µg 2×/d inhaled). GVHD occurred after a matched unrelated donor, allogeneic bone marrow transplant for acute myeloid leukemia. Before having acute myeloid leukemia, the patient received 6 cycles of combination chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) to treat high-grade diffuse large B cell lymphoma.\n\nThe patient lived in a semirural area surrounded by woodland in the Blue Mountains, New South Wales, Australia. His residence had an aboveground molded-plastic rainwater tank that was fed from roof guttering through polyvinyl chloride piping, with an outlet over a mesh-covered opening in the tank cover. Water entering the tank passed through a 5–7-cm layer of decaying plant material and other debris. The tank was periodically used as a source of showering and drinking water.\n\nOn examination the patient was afebrile and had exquisite muscle tenderness and edema of the upper and lower limbs. Power was reduced in the upper and lower limb muscles (Medical Research Council grade 3–4 out of 5). Other neurologic findings were unremarkable.\n\nSerum creatine kinase peaked at 858 U/L (reference range 55–150 U/L). On full blood count, hemoglobin was 126 g/L (reference range 130–180 g/L), and lymphocyte count was 0.9 × 109 cells/L (reference range 1.0–4.0 × 109 cells/L). C-reactive protein was 75 mg/L (reference range <3 mg/L), and erythrocyte sedimentation rate was 53 mm/hr (reference range 1–20 mm/hr). Alanine transaminase was 163 U/L and aspartate aminotransferase 235 U/L (reference range <40 U/L for both). Serum albumin nadir was 23 g/L (reference range 35–50 g/L). Serum creatinine, urinary albumin, and urinary protein levels were not elevated. Results of stool microscopy performed using Ryan’s modified trichrome stain were negative for microsporidia.\n\nResults of nerve conduction studies and electromyography were consistent with myopathy and axonal neuropathy. Magnetic resonance imaging of the lower limbs demonstrated myofascial edema. Light microscopy of a vastus lateralis biopsy demonstrated ovoid organisms either free in the endomysium, within the myofiber sarcoplasm, or within macrophages in myofibers (Figure 1). Electron microscopy revealed microsporidia of the Anncaliia genus (Figure 2). We confirmed A. algerae by using PCR DNA amplification and sequence analysis.\n\nFigure 1 Light micrographs of Gomori trichrome–stained frozen sections of vastus lateralis muscle from a 66-year-old man with Anncaliia algerae microsporidial myositis, New South Wales, Australia. A) Necrotising myositis with red-stained, ovoid spores in green-staining viable myocytes (solid arrows) and within macrophages invading necrotic myocytes (open arrows). B) A cluster of red stained, 2–3 µm spores within a viable myocyte. Scale bars indicate 25 µm.\n\nFigure 2 Transmission electron micrographs of vastus lateralis muscle from a 66 year-old man with Anncaliia algerae microsporidial myositis, New South Wales, Australia. A) Mature spore with 11 polar tubule coils (arrow) in a single row. Dense exospore and pale endospore. B) Binucleate, proliferative phase meront with characteristic vesicotubular appendages (arrow). Scale bars indicate 500 nm.\n\nThe patient was started on albendazole (400 mg 2×/d orally) and cyclosporine (100 mg 2x/d orally); tacrolimus and methrotrexate were ceased, and the prednisone dosage was reduced. Within 3 weeks, serum creatine kinase had normalized; muscle tenderness and peripheral edema had been reduced, and power increased. The patient had onset of limb contractures. Because of the ongoing immunosuppression required to manage GVHD, albendazole was continued for ≈9 months. Seven months after the patient’s initial examination, a repeat muscle biopsy indicated no evidence of infection.\n\nDiscussion\n\nOur review of published case reports and patient records indicated that systemic A. algerae infection has manifested as a skeletal muscle myositis (Table 1), with central nervous system and cardiac involvement documented in some cases (1–5). Dysphagia caused by bulbar muscle weakness is a particular concern because it has led to aspiration pneumonia (2). Limb contractures have not previously been described and, in the case of our patient, might have been related to GVHD.\n\nTable 1 Clinical features of 7 case-patients with Anncaliia algerae microsporidial myositis from North America and New South Wales, Australia*\n\nClinical feature\tNo. cases\t\nWeakness\t7\t\nMuscle pain\t7\t\nFever\t6\t\nFatigue\t6\t\nPeripheral edema\t6\t\nWeight loss\t5\t\nDysphagia\t4\t\nGlossitis\t4\t\nDiarrhea\t4\t\nDelirium\t3\t\nCongestive cardiac failure\t1\t\n*In 2 cases the clinical features were only sourced from published reports (1,5) rather than patient records (2–4).\n\nInvestigation findings in published case reports and patient records are summarized in Table 2 (1–5; Table 2). Muscle biopsies led to the diagnoses (1–5). Although Warthin-Starry and Gomori trichrome stains have been optimal for light microscopy, the spores can be confused with yeast cells because of their appearance (2,3; Figure 1). The features on transmission electron microscopy that allowed identification to the genus level include diplokaryotic nuclei, the absence of a parasitophorous vacuole, vesicotubular appendages, and 8–11 polar tubule coils (1–6; Figure 2). Species identification has been made with PCR amplification of the small subunit ribosomal RNA gene and sequence analysis by using DNA extracted from muscle and cerebrospinal fluid (1–5).\n\nTable 2 Serologic and laboratory test results for 7 case-patients with Anncaliia algerae microsporidial myositis from North America and New South Wales, Australia, 2004*\n\nTest\tAbnormal result\tNo. cases\t\nSerum creatine kinase\tElevated\t7\t\nCardiac troponin\tElevated\t2\t\nErythrocyte sedimentation rate and C-reactive protein\tElevated\t5\t\nFull blood count\tLymphocytopenia\t6\t\nSerum albumin\tDecreased\t5\t\nAlanine aminotransferase and aspartate aminotransferase\tElevated\t5\t\nSerum creatinine\tElevated\t2\t\nUrinary protein\tElevated\t3\t\nNerve conduction studies, electromyography\tMyopathy, axonal neuropathy\t6\t\nBrain radiologic imaging\tCerebral lesions\t2\t\nCardiac magnetic resonance imaging\tBiventricular dysfunction\t1\t\nSmall subunit rRNA gene PCR, muscle\tA. algerae DNA\t7\t\nSmall subunit rRNA gene PCR, cerebrospinal fluid\tA. algerae DNA\t1\t\n*In 2 cases test results were only sourced from published reports (1,5) rather than patient records (2–4).\n\nSuccessful management of A. algerae infection requires minimizing immunosuppression, avoiding complications such as aspiration pneumonia, and starting treatment based on albendazole (2). A β-tubulin sequence analysis and in vitro assays were consistent with A. algerae sensitivity to albendazole, although some viable spores remained in cell cultures after treatment (7). In a case of severe illness where substantial immunosuppression and treatment failure of albendazole monotherapy were factors, the addition of fumagillin was effective (5). The fumagillin, for which supplies were restricted, was obtained from the manufacturer in France through the Health Canada Special Access Program (5). Supply is also restricted in other jurisdictions, including the United States, where an Emergency Investigational New Drug application is required. In the case of the patient we describe, a management strategy was to change the calcineurin inhibitor from tacrolimus to cyclosporine, in light of in vitro evidence that cyclosporine chemosensitized Encephalitozoon spp. to the effect of albendazole (8).\n\nA. algerae infects the aquatic stages of mosquitoes when larvae ingest the sports or hatch from contaminated eggs (9). Attempts to infect athymic mice by intravenous, oral, and intranasal routes were unsuccessful; however, direct injection of spores into the tail and feet led to infection of myocytes, neural tissue, connective tissue, and bone marrow (10). Ingestion, inhalation, and direct inoculation are also possible routes of human infection. A diarrheal illness before hospitalization might indicate a gastrointestinal source, but stool microscopy and gut biopsies have been negative (2–4). The 2 infected lung transplant recipients described in the literature might have been susceptible to inhaled infection (3,4). Infection through a mosquito bite is regarded as less likely because the organism has not been found in the saliva of feeding mosquitoes, and exposure to water substantially increased the rate of germination in spores from mosquito tissue (10,11). Previous patients have resided near sources of environmental water, such as golf courses and woodlands (2). The case-patient we describe lived adjacent to a eucalypt forest environment and drank and showered with water from a rainwater tank system that might have contained mosquito larvae or had inflow from water-filled roof gutters containing mosquito larvae. Immunocompromised persons are advised to seek medical guidance before the consumption of rainwater tank water, and until further information regarding transmission is available, other sources of untreated water should be also avoided (12).\n\nClinical case reports lead to a greater understanding about the epidemiology, pathogenesis, and management of A. algerae myositis. Considering the widespread use of immunosuppressive therapies and the need to minimize the risk for infection, other priorities for research include the environmental biology of this pathogen and clarification of the transmission route to humans.\n\nDr. Sutrave is a hematologist with an interest in bone marrow transplantation. He is currently undertaking a PhD in evaluating adoptive cellular therapies for infections in immunocompromised patients and is working with the Cellular Therapies Group at the Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia.\n\nSuggested citation for this article: Sutrave G, Maundrell A, Keighley C, Jennings Z, Brammah S, Wang M-X, et al. Anncaliia algerae microsporidial myositis, New South Wales, Australia. Emerg Infect Dis. 2018 Aug [date cited]. https://doi.org/10.3201/eid2408.172002\n==== Refs\nReferences\n\n1. Coyle CM, Weiss LM, Rhodes LV III, Cali A, Takvorian PM, Brown DF, et al. Fatal myositis due to the microsporidian Brachiola algerae, a mosquito pathogen. N Engl J Med. 2004;351 :42–7. 10.1056/NEJMoa032655 15229306\n2. Watts MR, Chan RC, Cheong EY, Brammah S, Clezy KR, Tong C, et al. Anncaliia algerae microsporidial myositis. Emerg Infect Dis. 2014;20 :185–91. 10.3201/eid2002.131126 24447398\n3. Field AS, Paik JY, Stark D, Qiu MR, Morey A, Plit ML, et al. Myositis due to the microsporidian Anncaliia (Brachiola) algerae in a lung transplant recipient. Transpl Infect Dis. 2012;14 :169–76. 10.1111/j.1399-3062.2012.00724.x 22385431\n4. Chacko B, Trevillian P. Microsporidial myositis in a kidney transplant recipient [abstract 82]. Program and abstracts of Annual Scientific Meeting Transplantation Society of Australia and New Zealand. Canberra (ACT, Australia): Transplantation Society of Australia and New Zealand; 2013. p. 96.\n5. Boileau M, Ferreira J, Ahmad I, Lavallée C, Qvarnstrom Y, Dufresne SF. Successful treatment of disseminated Anncaliia algerae microsporidial infection with combination fumagillin and albendazole. Open Forum Infect Dis. 2016;3 :ofw158. 10.1093/ofid/ofw158 27704013\n6. Franzen C, Nassonova ES, Schölmerich J, Issi IV. Transfer of the members of the genus Brachiola (microsporidia) to the genus Anncaliia based on ultrastructural and molecular data. J Eukaryot Microbiol. 2006;53 :26–35. 10.1111/j.1550-7408.2005.00066.x 16441582\n7. Santiana M, Pau C, Takvorian PM, Cali A. Analysis of the beta-tubulin gene and morphological changes of the microsporidium Anncaliia algerae both suggest albendazole sensitivity. J Eukaryot Microbiol. 2015;62 :60–8. 10.1111/jeu.12160 25105446\n8. Leitch GJ, Scanlon M, Shaw A, Visvesvara GS. Role of P glycoprotein in the course and treatment of Encephalitozoon microsporidiosis. Antimicrob Agents Chemother. 2001;45 :73–8. 10.1128/AAC.45.1.73-78.2001 11120947\n9. Vavra J, Undeen AH. Nosema algerae n. sp. (Cnidospora, Microsporida) a pathogen in a laboratory colony of Anopheles stephensi Liston (Diptera, Culicidae). J Protozool. 1970;17 :240–9. 10.1111/j.1550-7408.1970.tb02365.x 4915459\n10. Trammer T, Dombrowski F, Doehring M, Maier WA, Seitz HM. Opportunistic properties of Nosema algerae (Microspora), a mosquito parasite, in immunocompromised mice. J Eukaryot Microbiol. 1997;44 :258–62. 10.1111/j.1550-7408.1997.tb05709.x 9183715\n11. Undeen AH, Alger NE. Nosema algerae: infection of the white mouse by a mosquito parasite. Exp Parasitol. 1976;40 :86–8. 10.1016/0014-4894(76)90068-0 950003\n12. US Centers for Disease Control and Prevention. Rainwater collection [cited 2017 Nov 21]. https://www.cdc.gov/healthywater/drinking/private/rainwater-collection.html\n\n",
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"keywords": "Anncaliia; Anncaliia algerae; Australia; New South Wales; fungi; graft versus host disease; immunosuppressed; infection; microsporidia; microsporidial myositis; myositis; parasites; stem cell transplant",
"medline_ta": "Emerg Infect Dis",
"mesh_terms": "D000368:Aged; D015766:Albendazole; D000981:Antiprotozoal Agents; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D016814:Microsporidia; D009220:Myositis; D009517:New South Wales; D013172:Spores, Fungal; D014184:Transplantation, Homologous",
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"title": "Anncaliia algerae Microsporidial Myositis, New South Wales, Australia.",
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"abstract": "BACKGROUND\nCisplatin monotherapy-induced cardiotoxicity is rare, and the prevalence remains unknown. It's extremely important to stop cisplatin when cardiotoxicity is considered.\nA 53-year-old woman developed cervical cancer. She was administered cisplatin (37 mg/m/wk) for 3 weeks, but the left ventricular ejection fraction (LVEF) declined from 70% to 48%.\n\n\nMETHODS\nElectrocardiogram showed first-degree atrioventricular block and ST-segment depression by 0.05 mv on leads II, III, and V3-5. Neither cardiac markers nor N-terminal pro-B-type natriuretic peptide (NT-pro BNP) was elevated. After a careful physical examination and laboratory investigation, we confirmed that cervical cancer did not progress and no other cause was evident. So we figured cardiotoxicity might be induced by cisplatin.\n\n\nMETHODS\nCisplatin was stopped and cardioprotective therapies were given to the patient.\n\n\nRESULTS\nAfter discontinuing cisplatin and adding cardioprotective therapies, the LVEF increased to 50% and 53%, respectively (M-mode echocardiography) after 17 and 90 days, which further confirmed our diagnosis.\n\n\nCONCLUSIONS\nAccording to this case and literature review, cisplatin-induced cardiotoxicity should be considered for the patient. When necessary, we should discontinue the suspected drug to confirm diagnosis. Cardioprotective therapies would minimize the drug-induced cardiovascular adverse events and improve patients' outcome.",
"affiliations": "Department of Pharmacy, Peking Union Medical College Hospital.;Department of Pharmacy, Hulunbeier People's Hospital, Mogolia.;Department of Pharmacy, Peking Union Medical College Hospital.;Department of Pharmacy, Peking Union Medical College Hospital.;Department of Cardiology, Peking Union Medical College Hospital, Beijing, China.;Department of Cardiology, Peking Union Medical College Hospital, Beijing, China.",
"authors": "Hu|Yang|Y|;Sun|Bin|B|;Zhao|Bin|B|;Mei|Dan|D|;Gu|Qing|Q|;Tian|Zhuang|Z|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30593170MD-D-18-0572310.1097/MD.0000000000013807138073400Research ArticleClinical Case ReportCisplatin-induced cardiotoxicity with midrange ejection fraction A case report and review of the literatureHu Yang MSaSun Bin MSbZhao Bin MSaMei Dan MSaGu Qing BScTian Zhuang MDc∗NA. a Department of Pharmacy, Peking Union Medical College Hospitalb Department of Pharmacy, Hulunbeier People's Hospital, Mogoliac Department of Cardiology, Peking Union Medical College Hospital, Beijing, China.∗ Correspondence: Zhuang Tian, Department of Cardiology, Peking Union Medical College Hospital, No.1 Shuai Fu Yuan, Wang Fu Jing, Dongcheng District, Beijing, 100730, China (e-mail: pumchxinzang@163.com).12 2018 28 12 2018 97 52 e1380720 8 2018 30 11 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nCisplatin monotherapy-induced cardiotoxicity is rare, and the prevalence remains unknown. It's extremely important to stop cisplatin when cardiotoxicity is considered.\n\nPatient concerns:\nA 53-year-old woman developed cervical cancer. She was administered cisplatin (37 mg/m2/wk) for 3 weeks, but the left ventricular ejection fraction (LVEF) declined from 70% to 48%.\n\nDiagnosis:\nElectrocardiogram showed first-degree atrioventricular block and ST-segment depression by 0.05 mv on leads II, III, and V3–5. Neither cardiac markers nor N-terminal pro-B-type natriuretic peptide (NT-pro BNP) was elevated. After a careful physical examination and laboratory investigation, we confirmed that cervical cancer did not progress and no other cause was evident. So we figured cardiotoxicity might be induced by cisplatin.\n\nInterventions:\nCisplatin was stopped and cardioprotective therapies were given to the patient.\n\nOutcomes:\nAfter discontinuing cisplatin and adding cardioprotective therapies, the LVEF increased to 50% and 53%, respectively (M-mode echocardiography) after 17 and 90 days, which further confirmed our diagnosis.\n\nLessons:\nAccording to this case and literature review, cisplatin-induced cardiotoxicity should be considered for the patient. When necessary, we should discontinue the suspected drug to confirm diagnosis. Cardioprotective therapies would minimize the drug-induced cardiovascular adverse events and improve patients’ outcome.\n\nKeywords\ncardiotoxicitycisplatinejection fractionOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nCisplatin is one of the first-generation platinum-based cell-cycle nonspecific antineoplastic agents with a wide range of anticancer activities. The major adverse events of cisplatin include nephrotoxicity, neurotoxicity, ototoxicity, and gastrointestinal toxicities (>50 mg/m2). Cisplatin-induced cardiotoxicity is rare, and the prevalence remains unknown. Jakubowski and Kemeny[1] showed that cardiotoxicity occurs in 6% of the patients receiving cisplatin and 5-fluorouracil (5-FU) and in 1.6% of the patients receiving 5-FU alone. In conventional multidrug regimens, investigating the effects of cisplatin on cardiotoxicity is rather challenging.[2] Here, we report a case that developed cardiotoxicity during the use of cisplatin alone. We also reviewed the literature with respect to clinical characteristics, pathophysiological mechanisms, and treatments of cisplatin-induced cardiotoxicity.\n\n2 Case report\nA 53-year-old woman was diagnosed with cervical squamous cell carcinoma stage IIB 1 month ago. After radiotherapy, the patient received cisplatin 37 mg/m2 per week. Five days after the third course of treatment, the patient complained of retrosternal burning. Hypotension and abnormal electrocardiogram (ECG) were also observed. Left ventricular ejection fraction (LVEF) declined from 70% to 48% (see Figs. 1 and 2). Electrocardiogram showed first-degree atrioventricular block and ST-segment depression by 0.05 mv on leads II, III, and V3–5. Neither cardiac markers nor N-terminal pro-B-type natriuretic peptide (NT-proBNP) was elevated. We inferred a causative relationship between cisplatin and cardiotoxicity. The clinical characteristics were complied with the diagnostic criteria of cardiotoxicity with midrange ejection fraction listed in the 2016 European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic cardiotoxicity.[3] The comparisons of echocardiographic findings before and after cisplatin were listed in Fig. 1.\n\nFigure 1 Comparisons of echocardiographic findings before and after DDP use. LVEDD stands for left ventricular end-diastolic ejection fraction; LVFS stands for left ventricular fractional shortening; LVEF stands for left ventricular ejection fraction (M-mode); MPA stands for main pulmonary artery; IVC stands for inferior vena cava.\n\nFigure 2 Parasternal short axis view at the mid-left ventricle (papillary muscle) of echocardiogram.\n\nTherefore, the cisplatin was stopped and LVEF reduced by 22%. Coenzyme Q10 (Ubidecarenone, 10 mg tid) and trimetazidine (Vasorel, 20 mg tid) were administered to protect cardiomyocytes. After 3 weeks, M-mode echocardiography showed that the left ventricular end-diastolic ejection fraction (LVEDD) was 46 mm, LVEF 50%, and E/A [eathy atrial (mitral diastolic filling)] ratio 1.0. Due to cisplatin-induced cardiotoxicity, the fourth course of cisplatin was not started. And the gynecologist suggested continued radiotherapy without cisplatin. The antigen level of squamous cell carcinoma was 1.0 ng/mL. She was in stable condition and was advised a repeat check by echocardiography after 3 months; the LVEF was found to be increased to 53% (M-mode echocardiography).\n\n3 Discussion\nThe patient in this study did not have a history of hypertension, coronary heart diseases, chest distress, and chest pain. Other risk factors such as smoking or drinking were also absent. In addition, we found no direct relationships between cardiotoxicity and comorbidities and the use of other drugs. We confirmed that the patient's cardiotoxicity was caused by cisplatin.\n\nAccording to the criteria of adverse drug reactions recommended by the World Health Organization (WHO),[4] we identified the “likely/probable” relationship between cisplatin and cardiotoxicity with HF with midrange HF (HFmrEF). The occurrence of HFmrEF is attributable to the accumulation of cisplatin. Based on the criteria of cardiac adverse events (NCI CTC4.0), the patient was graded 2 due to the left ventricular systolic dysfunction with 40% to 50% LVEF.\n\nAlthough current guidelines of European Society of Cardiology appropriate diagnostic tool to diagnose cardiotoxicity is calculation of ejection fraction using 2D Simpson method, 3-D based or Global longitudinal strain (GLS). In our department of cardiology, physicians always calculate ejection fraction using M-mode echocardiography in our hospital depend on local conditions. Based on M-mode echocardiography before and after the use of cisplatin, we can identify the “likely/probable” relationship.\n\nElevated NT-proBNP was not been found in this case, because sometimes it doesn’t occur in early stage of cardiotoxicity.[3]\n\nDue to the less number of the prevalent studies, the mechanisms of cisplatin-induced cardiotoxicity remain unclear. Jakubowski and Kemeny[1] reported that cardiotoxicity occurs in 6% of the patients receiving cisplatin and 5-FU. In this case, the following manifestations might contribute to the occurrence of cardiotoxicity after the use of cisplatin. Firstly, the patient with malignant tumor (cervical cancer stage IIB) receiving multiple courses of chemotherapy putatively developed emboli and thrombi and exhibited an imbalanced stress response. Fukuhara et al[5] demonstrated dose-dependent risks of adverse events with respect to the tumor stage; however, they did not indicate the specific risks for different stages. Secondly, the patient displayed abnormal ECG findings with ST-T segment depression and a PR interval of 0.231 seconds on multiple leads. Subsequently, we observed the newly occurred first-degree atrioventricular block, ST-segment depression by 0.05 mv on leads II, III, and V3–5, and a PR interval of 0.21 seconds. Although ECG abnormalities were not related to cisplatin, the usage might impair the proximal tubules, reduce the reabsorptions of potassium and magnesium, shorten the duration of the action potential, decrease calcium inflow, and finally result in early systolic dysfunction.[5] Thirdly, the patient received 3 courses cisplatin. Cisplatin activates the transmembrane protein kinase RNA (PKR)-like ER kinase (PERK) signaling pathway, phosphorylates IF2a, activates caspase 3, promotes the formation of apoptosome, and induces apoptosis of the cardiomyocytes.[6] Furthermore, cisplatin combines with histone-lacking mitochondrial DNA (mtDNA) to form various complexes,[7,8] disabling the nucleotide excision repair pathways that can remove such complexes. As a result, myocardial mtDNA is impaired, and mitochondria are unable to produce adenosine triphosphate. Cardiomyocytes suffer from dysfunction and subsequently hypoxic necrosis,[6] resulting in cardiotoxicity.\n\nFew strategies have been proposed to prevent and treat the cisplatin-induced cardiotoxicity effectively. Firstly, we dynamically monitored the echocardiography and ECG of the patient before and during the therapy. Secondly, we stopped the usage of cisplatin at a relatively early stage. Thirdly, we used coenzyme Q10 and trimetazidine to prevent the cardiac function from deterioration, based on potential pathophysiological mechanisms of cisplatin-induced cardiotoxicity.[9,10] Our experience might provide an example for time management for the use of medications for cardioprotection following cisplatin-induced cardiotoxicity.\n\nCardiotoxicity has rarely been reported in patients receiving cisplatin. Only 4 cases reported (from January 1, 1980, through April 1, 2017) cisplatin-induced cardiotoxicity or reduced ejection fraction. Table 1 summarizes the clinical characteristics of 5 cases. We reported the first case of cisplatin-induced cardiotoxicity exhibiting a distinct causative relationship between cisplatin use and cardiotoxicity. All the 4 previous cases received a combination therapy containing cisplatin. Two cases finally succumbed to mortality: 1 case was autopsied, and 1 case underwent heart transplantation. The lethal consequences of cisplatin should not be neglected in clinical practice. Cardiotoxicity with midrange ejection fraction and arrhythmias (first-degree atrioventricular block) might be induced by cisplatin in patients without any risk factors for coronary heart disease. The patients receiving cisplatin should be monitored closely for LVEF, cardiac markers, and ECG to identify cardiac dysfunction at an early stage. Once cardiotoxicity occurs, cisplatin should be reduced or discontinued. Consecutively, cardioprotective therapies should be administered to the patient, in particular for those with risk factors for cardiovascular diseases. Currently, neither a dose-dependent nor a temporal relationship between cisplatin and cardiotoxicity is observed. In addition, the 2016 ESC position study on cancer treatments and cardiovascular toxicity does not discuss the cisplatin-induced cardiovascular diseases.[3] The clinical staff is encouraged to accumulate and exchange relevant experience in order to minimize the drug-induced impairments, prevent disease progression, reduce drug-associated cardiovascular complications, and improve the patient's outcomes.\n\nTable 1 Summary of case reports of cisplatin-induced cardiotoxicity.\n\nAcknowledgments\nThis work was supported by Peking Union Medical College Hospital.\n\nAuthor contributions\nConceptualization: Yang Hu, Bin Sun, Bin Zhao.\n\nFormal analysis: Yang Hu.\n\nInvestigation: Bin Zhao, Dan Mei.\n\nMethodology: Yang Hu, Bin Sun, Qing Gu.\n\nSupervision: Bin Sun, Dan Mei, Zhuang Tian.\n\nVisualization: Bin Zhao.\n\nWriting – original draft: Yang Hu.\n\nWriting – review & editing: Yang Hu, Bin Sun, Bin Zhao, Dan Mei, Qing Gu, Zhuang Tian.\n\nAbbreviations: ECG = electrocardiogram/electrocardiographic, ESC = European Society of Cardiology, GLS = global longitudinal strain, HF = heart failure, HFmrEF = HF with midrange HF, LVEF = left ventricular ejection fraction, MtDNA = mitochondrial DNA, NT-proBNP = N-terminal Pro-B-type natriuretic peptide, PERK = Protein Kinase RNA (PKR)-like ER Kinase, WHO = World Health Organization.\n\nInformed consent: The informed consent has been obtained from the patient.\n\nThe authors have no conflicts of interest to declare.\n==== Refs\nReferences\n[1] Jakubowski AA Kemeny N \nHypotension as a manifestation of cardiotoxicity in three patients receiving cisplatin and 5-fluorouracil . Cancer \n1988 ;62 :266–9 .3383127 \n[2] Labianca R Beretta G Clerici M \nCardiac toxicity of 5-fluorouracil: a study on 1083 patients . Tumori \n1982 ;68 :505–10 .7168016 \n[3] Ponikowski P Voors AA Anker SD \n2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure . Rev Esp Cardiol (Engl Ed) \n2016 ;69 :1167.27894487 \n[4] Edwards IR Aronson JK \nAdverse drug reactions: definitions, diagnosis, and management . Lancet \n2000 ;356 :1255–9 .11072960 \n[5] Fukuhara H Yagi M Ando K \nLong-term administration of single-agent carboplatin (AUC 4) for advanced testicular seminoma safely achieved complete response in an 80-year-old man with chronic heart failure: a case report . Can Urol Assoc J \n2014 ;8 :E931–3 .25553172 \n[6] Ma H Jones KR Guo R \nCisplatin compromises myocardial contractile function and mitochondrial ultrastructure: role of endoplasmic reticulum stress . Clin Exp Pharmacol Physiol \n2010 ;37 :460–5 .19878217 \n[7] Jamieson ER Lippard SJ \nStructure, recognition, and processing of cisplatin-DNA adducts . Chem Rev \n1999 ;99 :2467–98 .11749487 \n[8] Perez RP \nCellular and molecular determinants of cisplatin resistance . Eur J Cancer \n1998 ;34 :1535–42 .9893624 \n[9] Fotino AD Thompson-Paul AM Bazzano LA \nEffect of coenzyme Q(1)(0) supplementation on heart failure: a meta-analysis . Am J Clin Nutr \n2013 ;97 :268–75 .23221577 \n[10] Zhang L Lu Y Jiang H \nAdditional use of trimetazidine in patients with chronic heart failure: a meta-analysis . J Am Coll Cardiol \n2012 ;59 :913–22 .22381427 \n[11] Guendouz S Buicuic O Kirsch M \nRestrictive cardiomyopathy associated with left ventricle and left atria endocardial calcifications following chemotherapy . J Am Coll Cardiol \n2011 ;57 :1633.21474043 \n[12] Martin M Diaz-Rubio E Furio V \nLethal cardiac toxicity after cisplatin and 5-fluorouracil chemotherapy. Report of a case with necropsy study . Am J Clin Oncol \n1989 ;12 :229–34 .2729179 \n[13] Pratt CB Crom DB Wallenberg J \nFatal congestive heart failure following mitoxantrone treatment in two children previously treated with doxorubicin and cisplatin . Cancer Treat Rep \n1983 ;67 :85–8 .6684503 \n[14] Cheriparambil KM Vasireddy H Kuruvilla A \nAcute reversible cardiomyopathy and thromboembolism after cisplatin and 5-fluorouracil chemotherapy–a case report . Angiology \n2000 ;51 :873–8 .11108333\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "97(52)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000970:Antineoplastic Agents; D066126:Cardiotoxicity; D002945:Cisplatin; D005260:Female; D006801:Humans; D008875:Middle Aged; D013318:Stroke Volume; D002583:Uterine Cervical Neoplasms; D018487:Ventricular Dysfunction, Left",
"nlm_unique_id": "2985248R",
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"pages": "e13807",
"pmc": null,
"pmid": "30593170",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Cisplatin-induced cardiotoxicity with midrange ejection fraction: A case report and review of the literature.",
"title_normalized": "cisplatin induced cardiotoxicity with midrange ejection fraction a case report and review of the literature"
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"companynumb": "CN-MYLANLABS-2019M1008126",
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"abstract": "The use of HLA-identical hematopoietic stem cell transplantation (HSCT) demonstrates overall survival rates greater than 75 % for T-B-NK+ severe combined immunodeficiency secondary to pathogenic mutation of recombinase activating genes 1 and 2 (RAG1/2). Limited data exist regarding the use of HSCT in patients with hypomorphic RAG variants marked by greater preservation of RAG activity and associated phenotypes such as granulomatous disease in combination with autoimmunity. We describe a 17-year-old with combined immunodeficiency and immune dysregulation characterized by granulomatous lung disease and autoimmunity secondary to compound heterozygous RAG mutations. A myeloablative reduced toxicity HSCT was completed using an unrelated bone marrow donor. With the increasing cases of immune dysregulation being discovered with hypomorphic RAG variants, the use of HSCT may advance to the forefront of treatment. This case serves to discuss indications of HSCT, approaches to preparative therapy, and the potential complications in this growing cohort of patients with immune dysregulation and RAG deficiency.",
"affiliations": "Division of Hematology/Oncology, CHOC Children's Hospital, 1201 W. La Veta Avenue, Orange, CA, 92868, USA. tamidjohn@gmail.com.;Division of Immunology, MassGeneral Hospital for Children, 55 Fruit Street, Boston, MA, 02114, USA.;Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.;Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Utah School of Medicine, 81 Mario Capecchi Drive, Salt Lake City, UT, USA.;Allergy and Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Bone Marrow Transplantation Unit, Federal University of Paraná, Rua XV de Novembro, 1299 - Centro, Curitiba, PR, 80060-000, Brazil.;Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.;Allergy and Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;NIAID, National Institutes of Health, Building 10CRC, Room 5-3940, 10 Center Drive, MSC 1456, Bethesda, MD, 20892-9806, USA.;Disciplina de Alergia, Imunologia Clínica e Reumatologia - UNIFESP, Sao Paulo, Brazil.;Division of Hematology, CHOC Children's Hospital, 1201 W. La Veta Avenue, Orange, CA, 92868, USA.;Division of Hematology, CHOC Children's Hospital, 1201 W. La Veta Avenue, Orange, CA, 92868, USA.;Division of Hematology, CHOC Children's Hospital, 1201 W. La Veta Avenue, Orange, CA, 92868, USA.;Division of Hematology, CHOC Children's Hospital, 1201 W. La Veta Avenue, Orange, CA, 92868, USA.;NIAID, National Institutes of Health, Building 10CRC, Room 5-3940, 10 Center Drive, MSC 1456, Bethesda, MD, 20892-9806, USA.;Department of Pediatrics, University of California, San Francisco, Box 1278, UCSF, San Francisco, CA, 94143, USA.;Division of Immunology, Children's Hospital Boston, Karp Building, Room 10217, 1 Blackfan Circle, Boston, MA, 02115, USA.;Division of Hematology, CHOC Children's Hospital, 1201 W. La Veta Avenue, Orange, CA, 92868, USA.",
"authors": "John|Tami|T|;Walter|Jolan E|JE|;Schuetz|Catherina|C|;Chen|Karin|K|;Abraham|Roshini S|RS|;Bonfim|Carmem|C|;Boyce|Thomas G|TG|;Joshi|Avni Y|AY|;Kang|Elizabeth|E|;Carvalho|Beatriz Tavares Costa|BT|;Mahajerin|Arash|A|;Nugent|Diane|D|;Puthenveetil|Geetha|G|;Soni|Amit|A|;Su|Helen|H|;Cowan|Morton J|MJ|;Notarangelo|Luigi|L|;Buchbinder|David|D|",
"chemical_list": "D015415:Biomarkers; D018398:Homeodomain Proteins; D016756:Immunoglobulins, Intravenous; C064658:RAG-1 protein",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10875-016-0326-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-9142",
"issue": "36(7)",
"journal": "Journal of clinical immunology",
"keywords": "RAG deficiency; autoimmunity; bone marrow transplantation; immune dysregulation; primary immunodeficiency",
"medline_ta": "J Clin Immunol",
"mesh_terms": "D000293:Adolescent; D000483:Alleles; D001327:Autoimmune Diseases; D015415:Biomarkers; D006105:Granulomatous Disease, Chronic; D018380:Hematopoietic Stem Cell Transplantation; D018398:Homeodomain Proteins; D006801:Humans; D016756:Immunoglobulins, Intravenous; D016130:Immunophenotyping; D007239:Infections; D018655:Lymphocyte Count; D009154:Mutation; D016511:Severe Combined Immunodeficiency; D013601:T-Lymphocytes; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "8102137",
"other_id": null,
"pages": "725-32",
"pmc": null,
"pmid": "27539235",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "23891352;25259923;27216217;11979301;26272482;25516070;24122031;25138334;24144642;26186701;18463379;26996199;20489056;23001410;20956421;22295088;25109802;21325599;25076946;16818281;26259076;11167808;26457731;15032591;24331380;24472623",
"title": "Unrelated Hematopoietic Cell Transplantation in a Patient with Combined Immunodeficiency with Granulomatous Disease and Autoimmunity Secondary to RAG Deficiency.",
"title_normalized": "unrelated hematopoietic cell transplantation in a patient with combined immunodeficiency with granulomatous disease and autoimmunity secondary to rag deficiency"
} | [
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"companynumb": "US-ASTELLAS-2018US000062",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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"abstract": "Huntington's disease (HD) is a progressive neurodegenerative disease characterized by involuntary movements and neuropsychiatric decline. With suicide rates five times higher in patients with HD compared to the general population, there is a need for further research into the management of affective symptoms in these patients. Electroconvulsive therapy (ECT) has been long used as a treatment for severe or medication-refractory mood disorders and catatonia. There are some case studies demonstrating ECT's positive effect on depression and agitation in HD, but the data is limited.\n\n\n\nIn this single site case series, we review ECT use for four HD patients with medication-refractory depression and/or psychosis to better assess the utility of ECT in this population. We also compile and review the existing literature on the topic.\n\n\n\nA single-center retrospective case series was conducted reviewing the indications, outcomes, and regimen of ECT treatments. Literature review was conducted via PubMed.\n\n\n\nFour patients received ECT treatment during an inpatient hospitalization with three continuing maintenance therapy as an outpatient. All four had improvements in depression, agitation, and suicidal ideation leading to successful hospital discharge. One of the four patients also demonstrated subjective improvement in cognitive and motor symptoms after ECT initiation. Nineteen reported cases were identified through the literature review and are summarized.\n\n\n\nThis case series adds to the existing literature demonstrating the successful use of ECT for psychiatric symptoms in HD. Larger scale studies are warranted to further investigate the specific role and protocol for the use of ECT in the management of refractory depression and psychosis in this population.",
"affiliations": "Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.;Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.;Department of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.;Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.",
"authors": "Adrissi|Jennifer|J|;Nadkarni|Neil A|NA|;Gausche|Eric|E|;Bega|Danny|D|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.3233/JHD-190361",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1879-6397",
"issue": "8(3)",
"journal": "Journal of Huntington's disease",
"keywords": "Electroconvulsive therapy; Huntington’s disease; depression; mood disorders; psychotic disorders",
"medline_ta": "J Huntingtons Dis",
"mesh_terms": "D000328:Adult; D004565:Electroconvulsive Therapy; D005260:Female; D006801:Humans; D006816:Huntington Disease; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101589965",
"other_id": null,
"pages": "291-300",
"pmc": null,
"pmid": "31322579",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Electroconvulsive Therapy (ECT) for Refractory Psychiatric Symptoms in Huntington's Disease: A Case Series and Review of the Literature.",
"title_normalized": "electroconvulsive therapy ect for refractory psychiatric symptoms in huntington s disease a case series and review of the literature"
} | [
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"companynumb": "US-DRREDDYS-USA/USA/19/0115186",
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"activesubstancename": "OLANZAPINE"
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"abstract": "Conditions, where the patient's immune system is compromised are the main risk factor for mucormycosis. Approximately 23% of the world's population is estimated to have a latent Mycobacterium tuberculosis infection and more than 10 million new cases were estimated in 2017. Pulmonary mucormycosis and tuberculosis co-infections are very rare. We present the case of a 56-year-old insulin-dependent diabetic patient with a pulmonary mucormycosis and tuberculosis co-infection. While the patient did not suffer from ketoacidosis, she had poor glycemic control. A chest X-ray and a computed tomography showed nodular and cavitary lesions in both lungs. The patient was diagnosed through a biopsy of the bronchial mucosa and an RT-PCR for M. tuberculosis from bronchoalveolar lavage. The patient was treated with the recommended 4-drug regimen for TB (i.e. isoniazid, rifampin, pyrazinamide, and ethambutol); concurrently, amphotericin B deoxycholate was administered to treat the mucormycosis infection. Thirty days after initial hospital admission the patient underwent a lobectomy on the right lung. The case described here is only the sixth case reported in the literature of concomitant pulmonary tuberculosis and mucormycosis and the third case associated with a TB and mucormycosis co-infection involving an uncontrolled DM patient to survive.",
"affiliations": "Hospital General León, Department of Internal Medicine, Mexico.;Hospital General León, Department of Radiology, Mexico.;Universidad de Guanajuato, Department of Medicine and Nutrition, Mexico.;Hospital Fundación Clínica Médica Sur, Department of Internal Medicine, Mexico.;Hospital General León, Department of Internal Medicine, Mexico.;Hospital General León, Department of Radiology, Mexico.;University of Groningen, University Medical Center Groningen, Department of Neurology, the Netherlands.",
"authors": "O|Jiménez-Zarazúa|JZ|;Ln|Vélez-Ramírez|VR|;M|Alcocer-León|AL|;Jd|Utrilla-Álvarez|UÁ|;Ma|Martínez-Rivera|MR|;Ga|Flores-Saldaña|FS|;Jd|Mondragón|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jctube.2019.100105",
"fulltext": "\n==== Front\nJ Clin Tuberc Other Mycobact DisJ Clin Tuberc Other Mycobact DisJournal of Clinical Tuberculosis and Other Mycobacterial Diseases2405-5794Elsevier S2405-5794(19)30031-210.1016/j.jctube.2019.100105100105ArticleA case of concomitant pulmonary tuberculosis and mucormycosis in an insulin-dependent diabetic patient O Jiménez-Zarazúa abLN Vélez-Ramírez cM Alcocer-León bdJD Utrilla-Álvarez eMA Martínez-Rivera abGA Flores-Saldaña cJD Mondragón j.d.mondragon.uribe@umcg.nlfg⁎a Hospital General León, Department of Internal Medicine, Mexicob Universidad de Guanajuato, Department of Medicine and Nutrition, Mexicoc Hospital General León, Department of Radiology, Mexicod Hospital General Regional ISSSTE León, Department of Internal Medicine, Mexicoe Hospital Fundación Clínica Médica Sur, Department of Internal Medicine, Mexicof University of Groningen, University Medical Center Groningen, Department of Neurology, the Netherlandsg University of Groningen, University Medical Center Groningen, Alzheimer Research Center, the Netherlands⁎ Corresponding author at: University Medical Center Groningen, Department of Neurology, PO Box 30001, Groningen 9700 RB, the Netherlands. j.d.mondragon.uribe@umcg.nl30 4 2019 8 2019 30 4 2019 16 100105© 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Conditions, where the patient's immune system is compromised are the main risk factor for mucormycosis. Approximately 23% of the world's population is estimated to have a latent Mycobacterium tuberculosis infection and more than 10 million new cases were estimated in 2017. Pulmonary mucormycosis and tuberculosis co-infections are very rare. We present the case of a 56-year-old insulin-dependent diabetic patient with a pulmonary mucormycosis and tuberculosis co-infection. While the patient did not suffer from ketoacidosis, she had poor glycemic control. A chest X-ray and a computed tomography showed nodular and cavitary lesions in both lungs. The patient was diagnosed through a biopsy of the bronchial mucosa and an RT-PCR for M. tuberculosis from bronchoalveolar lavage. The patient was treated with the recommended 4-drug regimen for TB (i.e. isoniazid, rifampin, pyrazinamide, and ethambutol); concurrently, amphotericin B deoxycholate was administered to treat the mucormycosis infection. Thirty days after initial hospital admission the patient underwent a lobectomy on the right lung. The case described here is only the sixth case reported in the literature of concomitant pulmonary tuberculosis and mucormycosis and the third case associated with a TB and mucormycosis co-infection involving an uncontrolled DM patient to survive.\n\nKeywords\nDiabetesImmunosuppressionPulmonary mucormycosisTuberculosis\n==== Body\n1 Introduction\nImmunosuppressed patients are at high risk of opportunistic infections. Mucormycosis is a group of diseases caused by infection of angiotrophic fungi in the order Mucorales [1]. Most mucormycoses are life-threatening, representing a medical emergency and usually involve immunocompromised patients [1], [2]. The estimated prevalence of mucormycoses among hospital discharges is 0.12 per 10,000 [3]. Mucormycosis can be classified based on anatomical localization: (1) rhinocerebral (i.e. rhino-orbito-cerebral); (2) pulmonary; (3) cutaneous; (4) gastrointestinal; (5) disseminated; and (6) uncommon presentations (e.g. endocarditis, mediastinitis, peritonitis, osteomyelitis, and renal abscesses) [1]. Conditions, where the patient's immune system is compromised are the main risk factor for mucormycosis. Among these risk factors are: (1) hematologic neoplasms; (2) neutropenia; (3) uncontrolled diabetes mellitus (DM), especially with ketoacidosis; (4) body trauma and wound contamination; (5) glucocorticoid use; (6) intravenous (IV) drugs; (7) iron overload; and (8) extreme malnutrition [2], [4]. Immunocompromised patients are also at risk of developing tuberculosis (TB). About 1.7 billion people (i.e. 23% of the world's population) are estimated to have a latent Mycobacterium tuberculosis infection and more than 10 million new cases were estimated in 2017 [5]. The clinical picture associated with pulmonary (i.e. endobronchial) TB includes thoracic pain, cough, fever, weight loss, hemoptysis, and dyspnea [6]. The diagnosis of pulmonary TB is based on the combination of clinical suspicion, clinical findings, imaging studies, and analysis of tissue and secretions [7].\n\nThe case of a patient with pulmonary TB and mucormycosis is reported here. The immunocompromised patient (i.e. long evolution and uncontrolled DM) was screened for autoimmune diseases and human immunodeficiency viruses (HIV) with negative results. After a bronchoscopy with bronchoalveolar lavage the histopathological diagnosis of mucormycosis and a reverse transcription polymerase chain reaction (RT-PCR) for M. tuberculosis from the bronchial secretions, the patient was diagnosed with pulmonary tuberculosis and mucormycosis. After medical treatment and lobectomy, the patient was discharged due to clinical improvement and consecutive negative bacilloscopies with directly observed therapy (DOT). Concomitant pulmonary mucormycosis and TB is very rare and has a poor prognosis. An opportune diagnosis and treatment are necessary in order to reduce the mortality of concomitant pulmonary mucormycosis and TB in immunocompromised patients.\n\n2 Case presentation\nA 56-year-old female arrived at the Emergency Department after complaining of localized pleuritic chest pain with an intensity of 7/10 on the visual analog scale for pain (VAS), that did not improve with the use of nonsteroidal anti-inflammatory drugs during the past 30 days. The patient reported profuse diaphoresis, dry cough, and dyspnea with mild to minimal activity for the previous three months to her hospital admission. During this time the patient experienced a 10 kg weight-loss and the patient noticed hemoptysis on several occasions, as well as fever reaching 39 °C and diaphoresis with predominance during the evening, improving with antipyretics. The patient previously attended another hospital, where she was managed with intramuscular (IM) ceftriaxone 1 g every (quaque, q) 12 h for four days without improvement. The patient's family history included a mother with type 2 diabetes (DM2) and arterial hypertension; other relevant aspects of family history were questioned and denied. The patient reported being diagnosed with DM2 for 15 years, currently treated with metformin 850 mg orally (per os, PO) q12 h, as well as 15 units of insulin glargine subcutaneously every night. The patient did not have optimal glycemic control, having two elevated hemoglobin A1c tests (i.e. 7.8 and 8.0%) within the previous 6 months. Among the patient's personal history, she denied tobacco or controlled substance use, allergies, past blood transfusions, traveling to regions with endemic diseases within the last three months, tattoos and body piercings. The patient had no history of lung disease or asthma during childhood.\n\nUpon initial physical examination, we found a patient recumbent with freely chosen body position, Glasgow coma score of 15, without focal neurologic deficits nor meningeal sings, aware of his environment, with reference to place, time, and people. The patient's integumentary system was diaphoretic with skin and mucosal membranes dehydrated +/+++, while the head and neck exploration had no alterations. Upon inspection, the respiratory apparatus with oral ventilation, tachypnea with thoracic and abdominal dissociation. The thorax had decreased expansion without vibrations or fremitus during palpation. No asymmetries or abnormal findings in tone intensity, pitch, duration, and quality through direct percussion. Upon auscultation, disseminated bilateral crepitant crackles and decreased inspiratory breath sounds at the right hemithorax base were found. Precordial auscultation revealed heart sounds of good intensity without extra heart sounds. Abdominal exploration without visceromegaly nor abnormalities upon light and deep palpation. The extremities had filiform pulse augmented in frequency and decreased in amplitude without trophic changes. Upon admission, the patient had the following vital signs: blood pressure 130/80 mmHg; heart rate 90 bpm; respiratory rate 17 rpm; SO2 with noninvasive ventilation at a rate of 3 L/min of 94%; temperature 37 °C; weight 70 kg; height 165 cm; body mass index 25.7 kg/m2; arterial blood gas test: pH = 7.4, PaO2 = 58 mmHg, PaCO2 = 24 mmHg, [HCO3−] = 16.9 mEq/L, O2 content= 88%, base excess= −7.0 mmol/L, lactate= 0.9 mmol/L.\n\nLaboratory results at admission are presented in Table 1 and the supplementary laboratory results in Table 2. Upon admission, a chest X-ray, posterior-anterior projection, shows right alveolar infiltrate at the base and presence of ipsilateral nodules (Fig. 1a). A computed tomography (CT) of the thorax, was performed showing three nodular images with a heterogeneous appearance (i.e. post-contrast enhancement, relating to a probable necrotic lesion) in the right superior lung (Fig. 1b); as well as a cavitary lesion in the left inferior lung (Fig. 1c). Due to the clinical and imaging presentation, as well as the initial laboratory results a lung and urinary tract (i.e. leukocyturia, hematuria and proteinuria) infections were integrated. Initial antibiotic management consisted of ceftriaxone 1 g intravenously (IV) q12 h and clarithromycin 500 mg PO q12 h for seven days.Table 1 Laboratory test results upon admission the emergency department.\n\nTable 1Full blood count\t\nHemoglobin at admission\t11.6 g/dL\t\nHematocrit\t37.1%\t\nErythrocyte count\t4500 µL\t\nPlatelet count\t268,000 µL\t\nMean corpuscular volume\t81.9 fL\t\nMean corpuscular hemoglobin concentration\t25.60 pg\t\nLeukocyte count\t10,500 µL\t\nLymphocytes\t8.0%\t\nNeutrophils\t89.1%\t\nMonocytes\t2.9%\t\nEosinophils\t0.0%\t\nBasophils\t0.0%\t\nBlood chemistry\t\t\nGlucose\t95 mg/dL\t\nCreatinine\t0.9 mg/dL\t\nUrea nitrogen\t43 mg/dL\t\nBlood urea nitrogen\t17 mg/dL\t\nUric acid\t6.5 mg/dL\t\nCholesterol\t120 mg/dL\t\nTriglycerides\t150 mg/dL\t\nLiver function enzymes\t\t\nAspartate transaminase\t25 U/L\t\nAlanine transaminase\t27 U/L\t\nLactate dehydrogenase\t285 U/L\t\nAlbumin\t3.4 g/dL\t\nAlkaline phosphatase\t85 U/L\t\nGamma-glutamyl transpeptidase\t40 U/L\t\nBlood coagulation\t\t\nProthrombine time\t13.4 s\t\nPartial thromboplastin time\t32.3 s\t\nInternational normalized ratio\t1.08\t\nElectrolytes\t\t\nSodium\t144 mEq/L\t\nPotassium\t4 mEq/L\t\nChlorine\t107 mEq/L\t\nCalcium\t8.6 mg/dL\t\nPhosphorus\t3.6 mg/dL\t\nMagnesium\t2 mg/dL\t\nTable 2 Supplementary laboratory test results.\n\nTable 2Antibodies\t\nCytoplasmic antineutrophil cytoplasmatic antibodies (cANCA)\t0.9\t\nPerinuclear antineutrophil cytoplasmatic antibodies (pANCA)\t0.1\t\nAnti-nuclear antibodies\t1.0\t\nAnti-double-stranded deoxyribonucleic acid\t2.61 U/mL\t\nAnti-cardiolipin IgM antibody\t7.7 U/mL\t\nAnti-cardiolipin IgG\t2 U/mL\t\nCyclic citrullinated peptide antibody\t1 < U/mL\t\nAnti. SSB (LA)\tNegative\t\nAnti –SSA(RO)\tNegative\t\nAnti-SM\tNegative\t\nComplement C3\t1 g/L\t\nComplement C4\t0.5 g/L\t\nViral panel\t\t\nHepatitis B virus\tNegative\t\nHepatitis C virus\tNegative\t\nHuman immunodeficiency virus 1 and 2\tNegative\t\nUrinalysis\t\t\nAppearance\tCrystalline\t\npH\t5.0\t\nSpecific gravity\t1.005\t\nProteins\t250\t\nKetones, glucose, and nitrite\tNegative\t\nLeukocytes\t500 per high power field\t\nErythrocytes\t111 per high power field\t\nBacteria\tLimited\t\nTuberculosis specific tests\t\t\nPCR for M. tuberculosis from expectoration\tNegative\t\nXpert MTB/RIF for M. tuberculosis from bronchial secretion\tPositive\t\nResistance to rifampicin\tNegative\t\nXpert MTB/RIF for M. tuberculosis from urine\tNegative\t\nFollow-up blood chemistry\t\n\tDay 10\tDay 15\tDay 20\tDay 30\tDay 120\t\nGlucose (mg/dL)\t95\t98\t100\t88\t104\t\nCreatinine (mg/dL)\t0.6\t1.33\t2.36\t3.04\t1.1\t\nUrea nitrogen (mg/dL)\t15.4\t27.58\t30\t35\t27\t\nBlood urea nitrogen (mg/dL)\t33\t59\t53\t17\t58\t\nUric acid (mg/dL)\t6.6\t7\t7.2\t7\t7.5\t\nElectrolytes\t\t\t\t\t\t\nSodium (mEq/L)\t141\t138.7\t140\t144\t138.7\t\nPotassium (mEq/L)\t4\t4.4\t3.4\t3\t4.5\t\nChlorine (mEq/L)\t105\t105\t108\t108\t105\t\nCalcium (mg/dL)\t8.7\t9.1\t8.9\t8.7\t9.1\t\nPhosphorus (mg/dL)\t4\t3.9\t3.1\t3\t3.9\t\nMagnesium (mg/dL)\t2\t1.76\t1.5\t1.5\t1.76\t\nFig. 1 Posterior-anterior X-ray and computerized tomography of thorax\n\n(A) Chest X-ray, posterior-anterior projection. Right alveolar infiltrate at the base and presence of ipsilateral masses with irregular borders in superior and middle segments (arrows). (B) Computed tomography (CT) of the thorax with contrast, coronal reconstruction with viewing window in the arterial phase. Three nodular images (arrows) with a heterogeneous appearance, post-contrast enhancement with air density within the lesion corresponding to a probable necrotic lesion, in the right superior lung. (C) CT of thorax with contrast, axial reconstruction with viewing window in the contrast phase. Subpleural mass with circumscribed edges and post-contrast enhancement in the left inferior lung (arrow), corresponding to a cavitary lesion.\n\nFig 1\n\n2.1 Clinical evolution\nUpon admission to the Department of Internal Medicine, consecutive blood cultures of each extremity, three bacilloscopies, IgG antibodies against Mycoplasma pneumonie, and a galactomannan assay to exclude aspergillosis were performed; all being reported negative. Serum procalcitonin levels of 0.02 ng/mL were reported. In search of an autoimmune etiology, immunoassays were requested and reported as negative (Table 2). An enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV-1 and HIV-2 were performed and reported negative (Table 2). Due to the high likelihood of pulmonary tuberculosis even after the three negative bacilloscopies, the patient was isolated and remained in isolation throughout her hospitalization. An initial RT-PCR for M. tuberculosis from sputum and urine were performed, both reported as negative. During the second week of hospitalization and without complete symptom improvement a bronchoscopy with bronchoalveolar lavage was performed, as well as a biopsy of the bronchial mucosa. An RT-PCR for M. tuberculosis from the bronchial secretions was performed with a positive result. An epidemiological survey was carried out among the patient's contacts, without the discovery of new cases. The histopathological report reported minimal inflammatory infiltrate, with the presence of abundant thick and pale hyphae without septa (Fig. 2a), compatible with a pulmonary mucormycosis diagnosis.Fig. 2 Bronchial secretion and lung biopsy histopathology\n\nHistopathology. Lung. (A) Bronchial secretion, 4x, hematoxylin and eosin staining. Minimal inflammatory infiltrate, with presence of abundant thick and pale hyphae without septa. (B) Lung mucosa biopsy, 4x, hematoxylin and eosin staining. Large caseous necrotic regions are seen in the center of the image surrounded by epithelial cells, Langhans giant cell and lymphocytes that coalesce into granulomas. Lung parenchyma can be seen in the periphery (C) Lung mucosa biopsy, 10x, Ziehl-Neelsen staining. Acid-resistant bacilli stained bright red on a blue background compatible with M. tuberculosis.(For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)\n\nFig 2\n\nInitial empiric treatment was initiated with rifampicin 600 mg PO q24 h, isoniazid 300 mg PO q24 h, pyrazinamide 1600 mg PO q24 h, and ethambutol 1200 mg PO q24 h all administered on weekdays. Amphotericin B deoxycholate was administered IV (i.e. calculated at 1.0 mg/kg/d the first 7 days and 1.5 mg/kg/d for 23 days) to treat the pulmonary mucormycosis with a total dose of 2.9 g, which was suspended after 30 days of treatment due to nephrotoxicity (i.e. creatinine 3.04 mg/dL) and electrolyte imbalance (i.e. persistent hypokalemia and hypomagnesemia; Table 2) even after adequate reposition. After nephrotoxicity remitted a lobectomy was performed on the right lung (i.e. 35 days after initial hospital admission). The surgical piece biopsy report reported large caseous necrotic regions, surrounded by epithelial cells that cluster into granulomas with lymphocytic infiltrate (Fig. 2b); furthermore, under acid-fast staining acid-resistant bacilli compatible with M. tuberculosis were identified (Fig. 2c). Directly observed therapy (DOT) as previously mentioned was continued and no antifungal medications were administered as no histopathological findings of pulmonary mucormycosis were reported in the surgical piece biopsy report.\n\nAfter 40 days of hospital stay, the patient was discharged due to clinical improvement. The patient continued with the DOT management at her community clinic with rifampicin 600 mg PO q72 h, isoniazid 800 mg PO q72 h completing 45 total doses, without adverse effects and improved kidney function (Table 2). Ninety days after being released from the hospital the patient was clinically asymptomatic and with three consecutive, negative bacilloscopies the patient was discharged from the pulmonary medicine outpatient clinic.\n\n3 Discussion\nConcomitant pulmonary mucormycosis and tuberculosis is very rare and has a poor prognosis. The case presented above describes the rare case of an immunosuppressed patient secondary to uncontrolled diabetes. Only nine previous cases of concomitant mucormycosis and TB (i.e. five cases of pulmonary mucormycosis and TB) have been reported in the literature. While the first case of pulmonary co-infection of TB and mucormycosis reported in the literature is in Japanese, the four other cases available in English are from India [8], [9], [10], [11]. Three cases involved uncontrolled diabetic patients (i.e. one with ketoacidosis and two with previous history and treatment of TB) [8], [9], [10], while the fourth case was an immunocompromised patient with aplastic anemia post allogeneic stem cell transplantation [11]. The case described above is only the sixth case described in the literature of pulmonary co-infection by mucormycosis and TB and the third case involving an uncontrolled DM patient to survive. Furthermore, despite medical and surgical treatment, invasive pulmonary mucormycosis has mortality rates as high as 70% [12]; which highlights the importance of an opportune diagnosis and treatment of concomitant pulmonary mucormycosis and TB in immunocompromised patients.\n\nPulmonary mucormycosis can have a similar presentation to pneumonia, which is often refractory to initial antibiotic treatment and a key feature is hemoptysis. Upon clinical follow-up, arterial aneurysms, pseudoaneurysms, bronchial obstruction, and solitary cavitary lesions are associated with pulmonary mucormycosis [1]. Pulmonary mucormycosis is highly lethal, with mortality ranging between 51–91% [13], [14]. Among the most frequent tomographic findings for pulmonary mucormycosis are consolidation and nodular patterns, as well as intrapulmonary masses with a halo sign [15]. Diagnosis is made through histopathological detection of hyphae ranging 3–25 mm in length, obtained from samples obtained through bronchoscopies or fine needle biopsies [3], [16], [17]. Meanwhile, pulmonary tuberculosis should be suspected in patients with cough and persistent fever greater than two weeks. Other clinical findings associated with pulmonary TB are weight-loss, hemoptysis, and nocturnal diaphoresis [18], [19]. There are three main validated methods for the detection of active tuberculosis: (1) microscopic identification of acid-fast bacilli; (2) nucleic acid amplification tests; and (3) culture from sputum [20].\n\nOur patient underwent three consecutive bacilloscopies, all reported negative. However, due to the persistent clinical picture suggesting TB a bronchoscopy with bronchoalveolar lavage and mucosa biopsy was performed in order to perform an RT-PCR in search of M. tuberculosis mycobacterial ribosomal RNA. Due to the presence of hemoptysis, fever, cough, and the cavitary pulmonary lesions, differential diagnosis was made with vasculitis (e.g., granulomatosis with polyangiitis, eosinophilic granulomatosis polyangiitis, and lupus erythematosus); consequently, requesting immunoassays which were reported as negative. Other differential diagnoses considered where neoplastic processes such as lymphoma and metastasis from an unknown primary but these were ruled out after obtaining the results from the lung biopsy.\n\nPulmonary mucormycosis treatment hinges on the administration of antifungal medication (e.g. amphotericin B deoxycholate, liposomal and lipid complex amphotericin B, isavuconazole, and posaconazole), treatment of underlying risk factors (e.g. metabolic control of DM, glucocorticoid suspension, and interruption of deferoxamine therapy), and surgical management [21]. Furthermore, surgical lobectomy should be considered in the presence of lung cavitation secondary to TB. Surgical success, reduction in mortality rate, ranges between 75 and 98% among TB patients [22]. In the case presented above, the patient responded well to the recommended 4-drug regimen for TB treatment with isoniazid, rifampin, pyrazinamide, and ethambutol. The only adverse reaction noted due to this treatment regimen was the elevation of uric acid, which was related to pyrazinamide. This side effect ceased after pyrazinamide was suspended.\n\n3.1 Limitations\nOne of the limitations of this case report is related to the treatment of mucormycosis. Although the liposomal formulation of amphotericin B is the drug of choice based on efficacy and safety data [21], [23], we only had amphotericin B deoxycholate at our disposal in our hospital. This is a limitation since the deoxycholate formulation is nephrotoxic; consequently, treatment had to be suspended when the total dose reached 2.9 g and the creatinine serum levels reached 3.04 mg/dL in association with electrolyte imbalance. In this regard, although a rare complication, ethambutol can induce nephrotoxicity and could be a contributing factor to the renal insufficiency. Furthermore, the patient's renal function (e.g. creatinine clearance, mean of urea and creatinine clearance, radioisotopic methods) was not quantified before, during or after the administration of tuberculosis and mucormycosis treatment, hence the association with the exact time of renal failure or premorbid renal damage cannot be established. Careful monitoring of renal function is advisable in chronic diabetic patients undergoing treatment with nephrotoxic agents such as ethambutol and amphotericin B. Another limitation to the case presented was the lack of confirmatory assessment of mucormycosis remission after treatment through a follow-up bronchoscopy with bronchoalveolar lavage and mucosa biopsy since the patient refused to undergo this procedure prior to her discharge. However, the patient improved clinically and no new lesions were identified through imaging after medical and surgical treatment.\n\n3.2 Conclusion\nPulmonary mucormycosis and tuberculosis co-infections are very rare. When confronted with an uncontrolled diabetic patient with a clinical picture that includes hemoptysis, fever, and dyspnea, associated with consolidation or cavitary lesions and nodules as imaging findings, we are obligated as clinicians to test for tuberculosis and mucormycosis.\n\nConflict of interest\nThe authors declare that they have no conflict of interest.\n\nAppendix Supplementary materials\nImage, application 1 \n\nAcknowledgments\nThis study was supported by CONACyT (Consejo Nacional de Ciencia y Tecnología) grant #440591. This research did not receive any specific grant from funding agencies in the commercial sector. We would like to commend the work of the medical staff (i.e. specialists, medical residents, and nursing staff) of the Internal Medicine Department and Juana Rosalba García from the Pathology Department at Hospital General León.\n\nAvailability of data and materials\nThe clinical data supporting the conclusions of this article is included in the article.\n\nAuthors’ contributions\nStudy concept and design: O.J.Z. and J.D.M. Acquisition of data: M.M.R., O.J.Z., and M.A.L. Analysis and interpretation of data: J.D.U.A., G.A.F.S., L.N.V.R., and J.D.M. Critical revision of the manuscript for important intellectual content: All authors. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nApproval from the ethical committee was not required due to the nature of this case report. Abiding by the Declaration of Helsinki, patient anonymity was guaranteed.\n\nSupplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jctube.2019.100105.\n==== Refs\nReferences\n1 Farmakiotis D Kontoyiannis D.P. Mucormycoses Infect Dis Clin North Am 30 1 2016 143 163 PMID26897065 26897065 \n2 Hamilos G Samonis G Kontoyiannis D.P Pulmonary mucormycosis Semin Respir Crit Care Med 32 6 2011 693 702 PMID22167397 22167397 \n3 Kontoyiannis D.P Lewis R.E. How I treat mucormycosis Blood 118 5 2011 1216 1224 PMID21622653 21622653 \n4 Petrikkos G Skiada A Lortholary O Roilides E Walsh T.J Kontoyiannis DP Epidemiology and clinical manifestations of mucormycosis Clin Infect Dis 54 Suppl 1 2012 S23 S34 PMID22247442 22247442 \n5 World Health Organization. Global Tuberculosis Report2018. Geneva: World Health Organization; 2018. https://www.who.int/tb/publications/global_report/en/.\n6 Lee J.H Park S.S Lee D.H Shin D.H Yang S.C Yoo B.M Endobronchial tuberculosis. Clinical and bronchoscopic features in 121 cases Chest 102 4 1992 990 994 PMID1395814 1395814 \n7 Siow W.T Lee P. Tracheobronchial tuberculosis: a clinical review J Thorac Dis 9 1 2017 E71 E77 PMID: 28203440 28203440 \n8 Aggarwal D Chander J Janmeja A.K Katyal R Pulmonary tuberculosis and mucormycosis co-infection in a diabetic patient Lung India 32 1 2015 53 55 PMID25624598 25624598 \n9 Dube P Saroa R Palta S Coinfections in intensive care unit with pulmonary tuberculosis and mucormycosis: a clinical dilemma Indian J Crit Care Med 20 3 2016 191 193 PMID27076735 27076735 \n10 Garg R Marak R.S Verma S.K Singh J Sanjay Prasad R Pulmonary mucormycosis mimicking as pulmonary tuberculosis: a case report Lung India 25 3 2008 129 131 PMID20165666 20165666 \n11 Sharma S.K Agarwal N Mukherjee A Seth T Mishra P Xess I Mahapatra M Sharma S Coexisting pulmonary tuberculosis and mucormycosis in a patient with aplastic anemia post allogenic stem cell transplantation Mediterr J Hematol Infect Dis 3 1 2011 e2011036 PMID22084651 \n12 Roden M.M Zaoutis T.E Buchanan W.L Knudsen T.A Sarkisova T.A Schaufele R.L Sein M Sein T Chiou C.C Chu J.H Kontoyiannis D.P Walsh T.J Epidemiology and outcome of zygomycosis: a review of 929 reported cases Clin Infect Dis 41 2005 634 653 PMID16080086 16080086 \n13 Spellberg B Edwards J Jr Ibrahim A Novel perspectives on mucormycosis: pathophysiology, presentation, and management Clin Microbiol Rev 18 3 2005 556 569 PMID16020690 16020690 \n14 Marty F.M Ostrosky-Zeichner L Cornely O.A Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis Lancet Infect Dis 16 7 2016 828 837 PMID26969258 26969258 \n15 Nam B.D Kim T.J Lee K.S Kim T.S Han J Chung M.J Pulmonary mucormycosis: serial morphologic changes on computed tomography correlate with clinical and pathologic findings Eur Radiol 28 2 2018 788 795 PMID28812135 28812135 \n16 He R Hu C Tang Y Cao L Niu R Report of 12 cases with tracheobronchial mucormycosis and a review Clin Respir J 12 4 2018 1651 1660 PMID29028140 29028140 \n17 Chamilos G Luna M Lewis R.E Bodey G.P Chemaly R Tarrand J.J Safdar A Raad I.I Kontoyiannis D.P Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989–2003) Haematologica 91 7 2006 986 989 PMID16757415 16757415 \n18 Miller L.G. Asch SM Yu EI A population-based survey of tuberculosis symptoms: how atypical are atypical presentations? Clin Infect Dis. 30 2 2000 293 299 PMID10671331 10671331 \n19 Lewinsohn D.M Leonard M.K LoBue P.A Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: diagnosis of tuberculosis in adults and children Clin Infect Dis 64 2 2017 111 115 PMID28052967 28052967 \n20 Pai M Nicol M.P Boehme C.C Tuberculosis diagnostics: state of the art and future directions Microbiol Spectr 4 5 2016 1 15 PMID27763258 \n21 Skiada A Lanternier F Groll A.H Pagano L Zimmerli S Herbrecht R Lortholary O Petrikkos GL European Conference on Infections in Leukemia. Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3) Haematologica 98 4 2013 492 504 PMID22983580 22983580 \n22 Yablonskii P.K Kudriashov G.G Avetisyan A.O Surgical resection in the treatment of pulmonary tuberculosis Thorac Surg Clin 29 1 2019 37 46 PMID30454920 30454920 \n23 Spellberg B Walsh T.J Kontoyiannis D.P Edwards J Ibrahim A.S Recent advances in the management of mucormycosis: from bench to bedside Clin Infect Dis 48 12 2009 1743 1751 PMID19435437 19435437\n\n",
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"title": "A case of concomitant pulmonary tuberculosis and mucormycosis in an insulin-dependent diabetic patient.",
"title_normalized": "a case of concomitant pulmonary tuberculosis and mucormycosis in an insulin dependent diabetic patient"
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"abstract": "We report a 64 year old man who developed Candida albicans infection following total knee arthroplasty. A two-stage exchange arthroplasty was performed after an initial swab culture grew Acinobacter sp. A scanty growth of yeast was also found from the tissue culture. Intravenous cefuroxime was instituted for six weeks followed by reimplantation four months after the removal. Three weeks after that revision, the prosthesis became infected and a culture of knee aspirate established the diagnosis of Candida albicans infection. Treatment consisted of thorough debridement of the involved joint and oral fluconazole for a year. Infection was never totally resolved and a secondary infection with methicillin resistant staphylococcus aureus then developed. Excision arthroplasty was done at two and a half years after the initial infection. At five years follow-up the infection was quiescent and he had a range of movement of 30 degrees to 70 degrees. Knee brace was used to control the valgus-varus stability.",
"affiliations": null,
"authors": "Badrul|B|B|;Ruslan|G|G|",
"chemical_list": "D000935:Antifungal Agents; D002511:Cephalosporins; D015725:Fluconazole; D002444:Cefuroxime",
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"mesh_terms": "D000935:Antifungal Agents; D002177:Candidiasis; D002444:Cefuroxime; D002511:Cephalosporins; D020878:Device Removal; D015725:Fluconazole; D006801:Humans; D007275:Injections, Intravenous; D007720:Knee Prosthesis; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012086:Reoperation",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Candida albicans infection of a prosthetic knee replacement: a case report.",
"title_normalized": "candida albicans infection of a prosthetic knee replacement a case report"
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{
"abstract": "We report on a case of nephrotic syndrome with focal and segmental hyalinosis complicated by chylous ascites in a girl of 2 years and 8 months old. This pure nephrotic syndrome in its early stage was initially treated with intensive steroid treatment at 2mg/kg/day orally for 2 months, followed by a bolus of methylprednisolone. The persistence of proteinuria meant corticosteroid resistance. Renal biopsy then revealed focal and segmental hyalinosis. A recurrence of the edema-ascites syndrome was associated with macroscopic hematuria. Blood pressure and serum creatinine remained normal. Protidemia decreased to 28g/L, with severe hypoalbuminemia at 7g/L. The ascites puncture brought 1 L of aseptic and milky fluid, containing 0.22g/L of proteins, 20 IU/L of amylase, and 331g/L of total lipids. The treatment protocol included a hyperprotein diet, prednisone at 0.5mg/kg/day, cyclophosphamide at 2.5mg/kg/day for 1 month, then once every 2 days for 3 months, and repeated ascites punctures. After 12 ascites punctures performed every 15 days, a polyuric episode occurred and the ascites disappeared. Proteinuria persisted at a nephrotic rate up to the 14th month, without impairment in kidney filtration function, and completely disappeared at the 20th month. After 5 years of follow-up, proteinuria remains undetectable and the physical exam is normal. The occurrence of chylous ascites during the nephrotic syndrome is a rare event. The formation of bowel lymphangiectasia, caused by a slowdown in venous return due to the pressure exerted by ascites, is probably the predominant mechanism.",
"affiliations": "Service de pédiatrie nourrissons, CHU de Brazzaville, Brazzaville, Congo; Faculté des sciences de la santé, université Marien Ngouabi, Brazzaville, Congo. Electronic address: jmabialababela@yahoo.fr.;Service de pédiatrie nourrissons, CHU de Brazzaville, Brazzaville, Congo.;Faculté des sciences de la santé, université Marien Ngouabi, Brazzaville, Congo; Service de néphrologie, CHU de Brazzaville, Brazzaville, Congo.;Service de pédiatrie nourrissons, CHU de Brazzaville, Brazzaville, Congo.;Service de pédiatrie nourrissons, CHU de Brazzaville, Brazzaville, Congo; Faculté des sciences de la santé, université Marien Ngouabi, Brazzaville, Congo.",
"authors": "Mabiala Babela|J R|JR|;Ollandzobo Ikobo|L C|LC|;Loumingou|R|R|;Nika|E R|ER|;Mouko|A|A|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.arcped.2016.10.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-693X",
"issue": "24(1)",
"journal": "Archives de pediatrie : organe officiel de la Societe francaise de pediatrie",
"keywords": null,
"medline_ta": "Arch Pediatr",
"mesh_terms": "D002675:Child, Preschool; D002915:Chylous Ascites; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental; D006417:Hematuria; D006801:Humans; D009404:Nephrotic Syndrome; D011507:Proteinuria",
"nlm_unique_id": "9421356",
"other_id": null,
"pages": "24-27",
"pmc": null,
"pmid": "27884537",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nephrotic syndrome complicated by chylous ascites in a girl of 2 years and 8 months old.",
"title_normalized": "nephrotic syndrome complicated by chylous ascites in a girl of 2 years and 8 months old"
} | [
{
"companynumb": "CG-MYLANLABS-2017M1017646",
"fulfillexpeditecriteria": "1",
"occurcountry": "CG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",... |
{
"abstract": "OBJECTIVE\nTo report a case of COVID-19 presenting with acute psychosis, without the hallmark respiratory symptoms of fever, cough, and shortness of breath associated with the novel virus.\n\n\nMETHODS\nA 58 year-old male presented with acute psychosis and no symptoms associated with COVID-19. He denied fever, chills, chest pain, shortness of breath, or gastrointestinal symptoms. The patient had a medical history of coronary artery disease, chronic hepatitis C, polysubstance abuse (including cocaine and alcohol), liver disease, anxiety, and panic disorder. Patient was confused, disruptive, unable to communicate, and admitted to hallucinations. Prior to transfer to a psychiatric facility, the patient developed a cough, triggering COVID-19 testing and a positive result. He was initially treated with hydroxychloroquine before this was discontinued. The patient was treated with haloperidol and lorazepam before returning to baseline. He was discharged home with continued isolation.\n\n\nCONCLUSIONS\nAcute psychosis, with or without other symptoms, appears to be a potential presentation of COVID-19 and should be considered by clinicians as a possible presenting manifestation. Other coronaviruses appear to have also been linked to neurological manifestations, including psychosis. Neurological manifestations of the virus vary widely, but have been reported multiple times. Treatment, as shown in this case report, appears to be supportive and symptom based for the associated psychotic symptoms. Optimal antiviral treatment is still yet to be clearly defined, as research continues on how to best treat the virus itself.",
"affiliations": "Department of Pharmacy, 233484Johnson City Medical Center, Johnson City, TN, USA.;Department of Nursing, 162625Franklin Woods Community Hospital, Johnson City, TN, USA.;Department of Pharmacy, 233484Johnson City Medical Center, Johnson City, TN, USA.;Department of Infectious, Inflammatory and Immunologic Diseases, 12324East Tennessee State University Quillen College of Medicine, Johnson City, TN, USA.;Department of Pharmacy, 233484Johnson City Medical Center, Johnson City, TN, USA.",
"authors": "Lanier|Cameron G|CG|https://orcid.org/0000-0002-4651-2461;Lewis|Stacey A|SA|;Patel|Paras D|PD|;Ahmed|Ahmed Mohamed|AM|;Lewis|Paul O|PO|https://orcid.org/0000-0002-2626-7390",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0897190020977721",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": null,
"journal": "Journal of pharmacy practice",
"keywords": "COVID-19; SARS-CoV-2; acute psychosis; coronavirus",
"medline_ta": "J Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "897190020977721",
"pmc": null,
"pmid": "33280502",
"pubdate": "2020-12-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "An Unusual Case of COVID-19 Presenting as Acute Psychosis.",
"title_normalized": "an unusual case of covid 19 presenting as acute psychosis"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2022-08881",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugad... |
{
"abstract": "Current chemistry analyzers measure ion concentration using ion- selective electrodes; however, may differ in the specific technology at the bedside versus the central laboratory. Instruments utilized for point-of-care testing (POCT) at the bedside use direct ion-selective electrodes, whereas central-laboratory analyzers use indirect ion-selective electrodes. Under most circumstances, these instruments will deliver the same result; however, various substances can cause interferences in one or the other. An 18-year-old Hispanic woman with a history of immune thrombocytopenic purpura (ITP) presented at Children's National Medical Center (CNMC) with a severe headache and required intravenous immunoglobulin (IVIG) therapy. Because a discrepancy developed between her point-of-care and central-laboratory sodium values, another instrument was used to retest the central-laboratory plasma specimens. The results were more in agreement with those from the point-of-care instrument and revealed a unique interference in sodium measurement related to IVIG use.",
"affiliations": "Department of Pathology and Laboratory Medicine, Medstar Georgetown University Hospital, Washington, DC.;Division of Critical Care Medicine, Children's National Medical Center, Washington, DC.;Division of Laboratory Medicine and Hematology, Children's National Medical Center, Washington, DC.",
"authors": "Virk|Mrigender S|MS|;Dean|Nathan P|NP|;Wong|Edward C C|ECC|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D012964:Sodium",
"country": "England",
"delete": false,
"doi": "10.1093/labmed/lmy025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-5027",
"issue": "49(4)",
"journal": "Laboratory medicine",
"keywords": null,
"medline_ta": "Lab Med",
"mesh_terms": "D000293:Adolescent; D003951:Diagnostic Errors; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D016553:Purpura, Thrombocytopenic, Idiopathic; D015203:Reproducibility of Results; D012964:Sodium",
"nlm_unique_id": "0250641",
"other_id": null,
"pages": "372-376",
"pmc": null,
"pmid": "29897485",
"pubdate": "2018-10-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe Underestimation of Serum Na following IVIG Treatment.",
"title_normalized": "severe underestimation of serum na following ivig treatment"
} | [
{
"companynumb": "US-BIOTEST PHARMACEUTICALS CORPORATION-US-2019ADM000005",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
}... |
{
"abstract": "BACKGROUND\nAnti-angiogenic agents are reported to exert clinical activity in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We evaluated the outcomes of the combination of docetaxel plus nintedanib in refractory NSCLC patients harboring EGFR mutations.\n\n\nMETHODS\nWe retrospectively analyzed 19 patients with advanced EGFR-mutant NSCLC who had progressed to EGFR tyrosine kinase inhibitors (TKI) and platinum-based chemotherapy receiving docetaxel and nintedanib at 14 Spanish institutions from January 2013 to December 2019. Kaplan-Meier and log-rank tests were used to evaluate progression-free survival (PFS) and overall survival (OS).\n\n\nRESULTS\nMedian age was 58.9 years (range 42.8-81), 73.7% were female. All patients were Caucasian, and 73.7% were never or light smokers. The baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 94.7% of patients. All patients had adenocarcinoma. Brain and liver metastases were present in 47.4% and 31.6% of patients, respectively. The most common EGFR mutations were exon 19 deletion (52.6%) and exon 21 L858R mutation (36.8%); 47.4% patients presented the EGFR T790M. 94.8% of the patients had received 2-3 previous treatment lines. Docetaxel was administered at 75 mg/m2/3 weeks to 16 patients, at 60 mg/m2 to 2 patients and at 45 mg/m2 to one patient. Nintedanib was given until disease progression or unacceptable toxicity at 200 mg twice daily except in 2 patients who received 150 mg twice daily and one patient who received 100 mg/12 h. With a median follow-up of 11.4 months (1-38), the median PFS was 6.1 months [95% confidence interval (CI), 4.9-7.3] and the median OS 10.1 months (95% CI 5.9-14.3). The objective response rate (ORR) was 44.4% (23.7-66.8%) and the disease control rate (DCR) 72.2% (49.4-88.5%). Efficacy tended to be greater in patients with the acquired T790M who had received osimertinib, with a median PFS of 6.3 (95% CI 2.1-10.5) versus (vs.) 4.8 (95% CI 3.5-6.1) and a median OS of 12.3 months (95% CI 8.6-16.0) vs. 6.7 months (95% CI 3.9-9.4), although this tendency was not statistically significant (p = 0.468 and p = 0.159, respectively). Sixteen patients (84.2%) had a total of 34 adverse events (AEs), with a median of two (0-6) AEs per patient. The most frequent AEs were asthenia (20.6%) and diarrhea (20.6%). One treatment-related death due to portal thrombosis was reported.\n\n\nCONCLUSIONS\nOur data indicate that the combination of docetaxel and nintedanib can be considered to be an effective treatment for EGFR TKI-resistant EGFR-mutant NSCLC.",
"affiliations": "Medical Oncology Department, Hospital de La Santa Creu I Sant Pau, Sant Quintí, 89, 08041, Barcelona, Spain.;Medical Oncology Department, Institut Català d'Oncologia (ICO), Hospital Universitari Dr. Josep Trueta, Girona, Spain.;Medical Oncology Department, Hospital Universitario de Torrejón, Madrid, Spain.;Medical Oncology Department, Complejo Asistencial Universitario de León, León, Spain.;Medical Oncology Department, Institut Català d'Oncologia (ICO), Badalona Applied Research Group in Oncology (B-ARGO Group), Institut Investigació Germans Trias I Pujol (IGTP), Department of Medicine, Universitat Autònoma de Barcelona (UAB), Campus Can Ruti, Badalona, Barcelona, Spain.;Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain.;Medical Oncology Department, Consorci Sanitari de Terrassa, Barcelona, Spain.;Medical Oncology Department, Hospital General de Elda, Alicante, Spain.;Medical Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain.;Medical Oncology Department, Fundación Hospital Universitario de Alcorcón, Madrid, Spain.;Medical Oncology Department, Institut Català d'Oncologia (ICO), Badalona Applied Research Group in Oncology (B-ARGO Group), Institut Investigació Germans Trias I Pujol (IGTP), Department of Medicine, Universitat Autònoma de Barcelona (UAB), Campus Can Ruti, Badalona, Barcelona, Spain.;Medical Oncology Department, Hospital Universitario, 12 de Octubre, Madrid, Spain.;Medical Oncology Department, Hospital de Manacor, Manacor, Spain.;Medical Oncology Department, Hospital Universitario de la Princesa, Madrid, Spain.;Medical Oncology Department, Hospital de La Santa Creu I Sant Pau, Sant Quintí, 89, 08041, Barcelona, Spain. mmajem@santpau.cat.",
"authors": "Riudavets|Mariona|M|;Bosch-Barrera|Joaquim|J|;Cabezón-Gutiérrez|Luís|L|;Diz Taín|Pilar|P|;Hernández|Ainhoa|A|;Alonso|Miriam|M|;Blanco|Remei|R|;Gálvez|Elisa|E|;Insa|Amelia|A|;Mielgo|Xabier|X|;Morán|Teresa|T|;Ponce|Santiago|S|;Roa|Diana|D|;Sánchez|José Miguel|JM|;Majem|Margarita|M|http://orcid.org/0000-0002-9919-7485",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.1007/s12094-021-02661-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1699-048X",
"issue": "23(12)",
"journal": "Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico",
"keywords": "Docetaxel; Epidermal growth factor receptor (EGFR); Nintedanib; Non-small cell lung cancer",
"medline_ta": "Clin Transl Oncol",
"mesh_terms": null,
"nlm_unique_id": "101247119",
"other_id": null,
"pages": "2560-2567",
"pmc": null,
"pmid": "34292495",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": "28017789;29151359;31751012;22285168;19692680;23816960;20022809;20573926;21783417;26105600;24893891;27770386;27959700;27751847;28221867;28577956;26159065;28968167;31591063;25175099;28408243;24411639;30771085;30368503;19097774;31125062",
"title": "Efficacy of nintedanib plus docetaxel in patients with refractory advanced epidermal growth factor receptor mutant lung adenocarcinoma.",
"title_normalized": "efficacy of nintedanib plus docetaxel in patients with refractory advanced epidermal growth factor receptor mutant lung adenocarcinoma"
} | [
{
"companynumb": "ES-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2021-BI-117836",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NINTEDANIB"
},
"... |
{
"abstract": "This phase II study (NCT03469557) assessed safety/tolerability and antitumor activity of first-line tislelizumab, a monoclonal antibody against programmed cell death-1, plus chemotherapy in patients with locally advanced/metastatic esophageal squamous cell carcinoma (ESCC) or gastric/gastroesophageal junction (G/GEJ) adenocarcinoma.\n\n\n\nPatients with ESCC received tislelizumab [200 mg i.v. every 3 weeks (Q3W)] plus cisplatin (80 mg/m² i.v. Q3W for ≤6 cycles) and fluorouracil (800 mg/m²/day i.v., Days 1-5 Q3W for ≤6 cycles); patients with G/GEJ adenocarcinoma received tislelizumab (200 mg i.v. Q3W) plus oxaliplatin (130 mg/m² i.v. Q3W for up to six cycles) and oral capecitabine (1,000 mg/m² twice daily, Days 1-14 Q3W). The safety/tolerability profile of combination therapy was the primary endpoint; secondary endpoints included objective response rate (ORR), duration of response (DoR), disease control rate (DCR), and progression-free survival per RECIST v1.1. Exploratory endpoints included overall survival and potential predictive biomarkers.\n\n\n\nAs of March 31, 2019, 30 patients (n = 15 per cohort) were enrolled. Most common adverse events considered related to tislelizumab and/or chemotherapy were anemia (n = 18), decreased appetite (n = 17), nausea (n = 16), and asthenia (n = 15). One patient experienced fatal hepatic dysfunction, confounded by progressive disease and underlying hepatitis, attributed to treatment by the investigator. Confirmed ORRs and DCRs were 46.7% and 80%, respectively, for both ESCC and G/GEJ adenocarcinoma. In ESCC, median DoR was 12.8 months (95% confidence interval, 3.5-12.8); DoR was not yet mature for the G/GEJ cohort.\n\n\n\nTislelizumab plus chemotherapy demonstrated durable responses with manageable tolerability in patients with advanced ESCC or G/GEJ adenocarcinoma.",
"affiliations": "Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China. jmxu2003@yahoo.com.;Harbin Medical University Cancer Hospital, Harbin, China.;The First Affiliated Hospital of Zhejiang University, Hangzhou, China.;First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.;Northern Jiangsu People's Hospital, Yangzhou, China.;BeiGene (Beijing) Co., Ltd., Beijing, China.;BeiGene (Beijing) Co., Ltd., Beijing, China.;BeiGene (Beijing) Co., Ltd., Beijing, China.;Tongji Hospital, Wuhan, China.",
"authors": "Xu|Jianming|J|;Bai|Yuxian|Y|;Xu|Nong|N|;Li|Enxiao|E|;Wang|Buhai|B|;Wang|Jin|J|;Li|Xiang|X|;Wang|Xin|X|;Yuan|Xianglin|X|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000077150:Oxaliplatin; C000707970:tislelizumab; D000069287:Capecitabine; D002945:Cisplatin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-19-3561",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "26(17)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000230:Adenocarcinoma; D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D002945:Cisplatin; D004334:Drug Administration Schedule; D004938:Esophageal Neoplasms; D000077277:Esophageal Squamous Cell Carcinoma; D004943:Esophagogastric Junction; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077150:Oxaliplatin; D000077982:Progression-Free Survival; D066066:Response Evaluation Criteria in Solid Tumors; D013274:Stomach Neoplasms; D055815:Young Adult",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "4542-4550",
"pmc": null,
"pmid": "32561664",
"pubdate": "2020-09-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Tislelizumab Plus Chemotherapy as First-line Treatment for Advanced Esophageal Squamous Cell Carcinoma and Gastric/Gastroesophageal Junction Adenocarcinoma.",
"title_normalized": "tislelizumab plus chemotherapy as first line treatment for advanced esophageal squamous cell carcinoma and gastric gastroesophageal junction adenocarcinoma"
} | [
{
"companynumb": "CN-HQ SPECIALTY-CN-2021INT000034",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "The retrospective investigation of the exposure to toxic substances by general unknown screening of hair is still a difficult task because of the large number of possible poisons, the low sample amount and the difficult sample matrix. In this study the use of liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) was tested as a promising technique for this purpose. In the optimized procedure, 20mg hair were decontaminated with water and acetone and two times extracted by 18h incubation with 0.5ml of a mixture of methanol/acetonitrile/H(2)O/ammonium formate at 37°C. A mixture of deuterated standards from different drug groups was added for quantification and method control. The united extracts were evaporated to a residue of 0.5ml and 5μl were injected without clean-up for LC-QTOF-MS measurement (instrument Agilent 6530) with positive electrospray ionization and in data dependent acquisition mode. For peak identification the accurate mass data base and spectral library of the authors was used which contains accurate mass CID spectra of more than 2500 and theoretically calculated accurate mass data of more than 7500 toxicologically relevant substances. Validation at the example of 24 illegal drugs, their metabolites and benzodiazepines resulted in limits of detection of 0.003-0.015ng/mg, and limits of quantification of 0.006-0.021ng/mg with good accuracy and intra- and interday reproducibility. The matrix effect by ion suppression/enhancement was 72-107% for basic drugs and 42-75% for benzodiazepines. Yields of the hair extraction above 90% were determined for 59 drugs or metabolites. The method was applied to hair samples from 30 drug fatalities and from 60 death cases with known therapeutic drug intake at life time. Altogether 212 substances were identified with a frequency per drug of 1-40 (mean 4.2) and per case of 2-33 (mean 10.2), between them 35 illegal drug related substances and 154 therapeutic drugs. Comparison with the data known from case histories and from the analysis of blood, urine and gastric content showed only a low agreement, with many unexpected drugs detected and many reported drugs not detected in hair. Basic drugs and metabolites such as opioides, cocaine, amphetamines, several groups of antidepressants, neuroleptics, beta-blockers or the metamizole metabolite noramidopyrine were found with high frequency whereas acidic and several neutral drugs such as cannabinoids, salicylic acid, furosemide, barbiturates, phenprocoumone or cardiac glycosides could not be detected with sufficient sensitivity, mainly because of the low ion yield of positive ESI for these compounds. The advantage of a comprehensive acquisition of all substances is paid by a lower sensitivity in comparison to targeted screening LC-MS/MS procedures. In conclusion, the procedure of sample preparation and LC-QTOF-MS analysis proved to be a robust and sensitive routine method in which the qualitative screening for a wide variety of toxic substances in hair is combined with the quantitative determination of selected illegal drugs.",
"affiliations": "Institute of Legal Medicine, University Hospital Charité, Turmstraße 21, Building N, 10559 Berlin, Germany.",
"authors": "Broecker|Sebastian|S|;Herre|Sieglinde|S|;Pragst|Fritz|F|",
"chemical_list": "D000097:Acetonitriles; D005561:Formates; D009294:Narcotics; D004364:Pharmaceutical Preparations; D012997:Solvents; C030544:formic acid; D001569:Benzodiazepines; D000432:Methanol; C032159:acetonitrile",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2011.10.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "218(1-3)",
"journal": "Forensic science international",
"keywords": null,
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000097:Acetonitriles; D000328:Adult; D001569:Benzodiazepines; D002853:Chromatography, Liquid; D053593:Forensic Toxicology; D005561:Formates; D005766:Gastrointestinal Contents; D006197:Hair; D006801:Humans; D057230:Limit of Detection; D008297:Male; D013058:Mass Spectrometry; D000432:Methanol; D008875:Middle Aged; D009294:Narcotics; D004364:Pharmaceutical Preparations; D012997:Solvents; D013048:Specimen Handling; D015813:Substance Abuse Detection; D014465:Ultrasonics",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "68-81",
"pmc": null,
"pmid": "22036310",
"pubdate": "2012-05-10",
"publication_types": "D016428:Journal Article; D023361:Validation Study",
"references": null,
"title": "General unknown screening in hair by liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF-MS).",
"title_normalized": "general unknown screening in hair by liquid chromatography hybrid quadrupole time of flight mass spectrometry lc qtof ms"
} | [
{
"companynumb": "DE-JNJFOC-20121015984",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": null,
... |
{
"abstract": "A 71-year-old woman who had been treated with methotrexate (MTX) and prednisolone for rheumatoid arthritis since 2010 presented with hematuria. Cystitis was diagnosed. Chest and abdominal CT images revealed a bladder tumor, with lung and bilateral adrenal metastases. Transurethral resection of the bladder tumor (TUR-BT) confirmed these findings in September 2014. Histological findings of the bladder included large atypical lymphoid cells indicating diffuse large B-cell lymphoma. After TUR-BT, CT imaging showed that the tumor had shrunk. Still, MTX was continued. She was diagnosed with MTX-related lymphoproliferative disorders in November 2014 and MTX was discontinued. Fluorodeoxyglucose-positron emission tomography on March 2015 showed a complete response.",
"affiliations": "Dept. of Gastroenterology and Hematology/Clinical Oncology, Internal Medicine, Steel Memorial Muroran Hospital.;Dept. of Gastroenterology and Hematology/Clinical Oncology, Internal Medicine, Steel Memorial Muroran Hospital.;Dept. of Gastroenterology and Hematology/Clinical Oncology, Internal Medicine, Steel Memorial Muroran Hospital.;Dept. of Gastroenterology and Hematology/Clinical Oncology, Internal Medicine, Steel Memorial Muroran Hospital.;Dept. of Gastroenterology and Hematology/Clinical Oncology, Internal Medicine, Steel Memorial Muroran Hospital.;Dept. of Gastroenterology and Hematology/Clinical Oncology, Internal Medicine, Steel Memorial Muroran Hospital.;Dept. of Gastroenterology and Hematology/Clinical Oncology, Internal Medicine, Steel Memorial Muroran Hospital.;Dept. of Gastroenterology and Hematology/Clinical Oncology, Internal Medicine, Steel Memorial Muroran Hospital.;Dept. of Gastroenterology and Hematology/Clinical Oncology, Internal Medicine, Steel Memorial Muroran Hospital.;Dept. of Gastroenterology and Hematology/Clinical Oncology, Internal Medicine, Steel Memorial Muroran Hospital.;Dept. of Gastroenterology and Hematology/Clinical Oncology, Internal Medicine, Steel Memorial Muroran Hospital.;Dept. of Pathology and Clinical Laboratory, Steel Memorial Muroran Hospital.;Dept. of Medical Oncology and Hematology, Internal Medicine, Sapporo Medical University.",
"authors": "Yamada|Michiko|M|;Kuroda|Hiroyuki|H|;Sato|Ken|K|;Miura|Shogo|S|;Ameda|Saki|S|;Sakano|Hiroya|H|;Shibata|Takanori|T|;Uemura|Naoki|N|;Abe|Tomoyuki|T|;Fujii|Shigeyuki|S|;Maeda|Masahiro|M|;Fujita|Miri|M|;Kato|Junji|J|",
"chemical_list": "D018501:Antirheumatic Agents",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.58.287",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "58(4)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Bladder resection; Diffuse large B-cell lymphoma; Infection; Methotrexate",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D009365:Neoplasm Regression, Spontaneous; D001743:Urinary Bladder; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "287-291",
"pmc": null,
"pmid": "28484154",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous regression of methotrexate-related diffuse large B-cell lymphoma following bladder lesion resection.",
"title_normalized": "spontaneous regression of methotrexate related diffuse large b cell lymphoma following bladder lesion resection"
} | [
{
"companynumb": "PHHY2017JP170871",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "1",
"dru... |
{
"abstract": "Left ventricular dysfunction resulting in cardiogenic shock occurs infrequently following organ reperfusion in liver transplantation. The etiology of the cardiogenic shock is often multifactorial and difficult to manage due to the complex nature of the procedure and the patient's baseline physiology. Traditionally, this hemodynamic instability is managed medically using inotropic agents and vasopressor support. If medical treatment is insufficient, the use of an intra-aortic balloon pump for counterpulsation may be employed to improve the hemodynamics and stabilize the patient. Here, we analyze three cases and review the literature.",
"affiliations": "Department of Surgery, Case Western Reserve University, Cleveland, OH, USA.;Division of Transplant Surgery Medical University of South Carolina, Charleston, SC, USA.;Division of Transplant Surgery Medical University of South Carolina, Charleston, SC, USA.;Department of Surgery, College of Medicine, University of Tennessee, Chattanooga, TN, USA.;Department of Gastroenterology & Hepatology, Medical University of South Carolina, Charleston, SC, USA.;Department of Anesthesia and Perioperative Medicine, Medical University of South Carolina, Charleston, SC, USA.;Division of Transplant Surgery Medical University of South Carolina, Charleston, SC, USA.;Department of Surgery, Case Western Reserve University, Cleveland, OH, USA.",
"authors": "Palanisamy|Arun P|AP|0000-0002-7793-0682;Nadig|Satish N|SN|;Chedister|Gabriel R|GR|;Dowden|Jacob E|JE|;Koch|David G|DG|;Stoll|William D|WD|;McGillicuddy|John W|JW|;Chavin|Kenneth D|KD|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.13002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "31(7)",
"journal": "Clinical transplantation",
"keywords": "emergency; hemodynamic instability; liver disease; surgery; ventricular dysfunction",
"medline_ta": "Clin Transplant",
"mesh_terms": "D005260:Female; D006439:Hemodynamics; D006801:Humans; D007423:Intra-Aortic Balloon Pumping; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012307:Risk Factors; D012770:Shock, Cardiogenic",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28489254",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Use of intra-aortic counterpulsation in cardiogenic shock post-liver transplantation.",
"title_normalized": "use of intra aortic counterpulsation in cardiogenic shock post liver transplantation"
} | [
{
"companynumb": "US-PFIZER INC-2017316896",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": null,
... |
{
"abstract": "We describe a rare case of a severe gastric ulcer of a 66-year-old immunocompetent man who was associated with primary Epstein-Barr virus (EBV) infection and temporarily misdiagnosed with gastric lymphoma. A contrast-enhanced computed tomography (CT-scan) of the thorax, abdomen and pelvis followed by EUS revealed a neoplastic infiltrative-ulcerative semicircumferentialgastric mass and a 1 cm large satellite adenopathy, being classified as T3N1M0 gastric neoplasia. The histological analysis of the ¾ distal stomach and lymph node sthat were resected contradicted the initial biopsy report, suggesting EBV gastric ulcer, etiology confirmed by the in situ hybridization technique.",
"affiliations": "Department of Gastroenterology, 1st Medical Clinic, \"Iuliu Hatieganu\" University of Medicine and Pharmacy, Cluj-Napoca, Romania.;Department of Surgery, County Emergency Hospital, Cluj-Napoca, Romania.;Department of Pathology, \"Ion Chiricuță\" Institute of Oncology, Cluj-Napoca, Romania.;Department of Gastroenterology, Regional Institute of Gastroenterology and Hepatology Prof. Dr. Octavian Fodor, Cluj-Napoca, Romania. mezei_anita@yahoo.com.",
"authors": "Catinean|Adrian|A|;Motocu|Radu|R|;Fetica|Bogdan|B|;Mezei|Anita|A|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": "10.11152/mu-1560",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1844-4172",
"issue": "21(1)",
"journal": "Medical ultrasonography",
"keywords": null,
"medline_ta": "Med Ultrason",
"mesh_terms": "D000368:Aged; D003937:Diagnosis, Differential; D019160:Endosonography; D020031:Epstein-Barr Virus Infections; D005743:Gastrectomy; D006801:Humans; D008297:Male; D013274:Stomach Neoplasms; D013276:Stomach Ulcer; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101522985",
"other_id": null,
"pages": "96-98",
"pmc": null,
"pmid": "30779839",
"pubdate": "2019-02-17",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Epstein-Barr virus-associated gastric ulcer mimicking gastric neoplasia: a case report.",
"title_normalized": "epstein barr virus associated gastric ulcer mimicking gastric neoplasia a case report"
} | [
{
"companynumb": "RO-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-022509",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TELMISARTAN"
},
... |
{
"abstract": "BACKGROUND\nResting brain perfusion, measured using the MRI-based arterial spin labelling (ASL) technique, is sensitive to detect central effects of single, clinically effective, doses of pharmacological compounds. However, pharmacological interaction experiments, such as the modulation of one drug response in the presence of another, have not been widely investigated using a task-free ASL approach.\n\n\nOBJECTIVE\nWe assessed the effects of three psychoactive compounds (ketamine, risperidone and lamotrigine), and their interaction, on resting brain perfusion in healthy human volunteers.\n\n\nMETHODS\nA multivariate Gaussian process classification (GPC) and more conventional univariate analyses were applied. The four pre-infusion conditions for each subject comprised risperidone, lamotrigine and two placebo sessions. The two placebo conditions enabled us to evaluate the classification performance in a test-retest setting, in addition to its performance in distinguishing the active oral drugs from placebo (direct effect on brain perfusion). The post ketamine- or saline-infusion scans allowed the effect of ketamine, and its interaction with risperidone and lamotrigine, on brain perfusion to be characterised.\n\n\nRESULTS\nThe pseudo-continuous ASL measurements of perfusion were sensitive to the effects of ketamine infusion and risperidone. The GPC captured consistent changes in perfusion across the group and contextualised the univariate changes with a larger pattern of regions contributing to accurate discrimination of ketamine from placebo.\n\n\nCONCLUSIONS\nThe findings argue against perfusion changes confounding in the previously described evoked BOLD response to ketamine and emphasise the blockade of the NMDA receptor over neuronal glutamate release in determining the perfusion changes induced by ketamine.",
"affiliations": "Tailored Therapeutics - Neuroscience, Eli Lilly and Company, Indianapolis, IN, 46285, USA.;Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.;Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.;Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.;Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.;Tailored Therapeutics - Neuroscience, Eli Lilly and Company, Indianapolis, IN, 46285, USA. a.schwarz@lilly.com.",
"authors": "Shcherbinin|Sergey|S|;Doyle|Orla|O|;Zelaya|Fernando O|FO|;de Simoni|Sara|S|;Mehta|Mitul A|MA|;Schwarz|Adam J|AJ|",
"chemical_list": "D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; D018698:Glutamic Acid; D007649:Ketamine; D018967:Risperidone; D000077213:Lamotrigine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00213-015-4021-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-3158",
"issue": "232(21-22)",
"journal": "Psychopharmacology",
"keywords": "Brain imaging; Drug; MRI; Mapping; Modulation; Patterning; Recognition; Schizophrenia",
"medline_ta": "Psychopharmacology (Berl)",
"mesh_terms": "D000328:Adult; D001921:Brain; D018492:Dopamine Antagonists; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D064368:Healthy Volunteers; D006801:Humans; D007649:Ketamine; D000077213:Lamotrigine; D008297:Male; D016194:Receptors, N-Methyl-D-Aspartate; D018967:Risperidone; D014227:Triazines; D055815:Young Adult",
"nlm_unique_id": "7608025",
"other_id": null,
"pages": "4191-204",
"pmc": null,
"pmid": "26223493",
"pubdate": "2015-11",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "19879364;12044193;25896256;23009959;24938404;25693169;23370794;20066400;25554429;24581548;10528123;15114201;12960545;7459184;17805312;25980482;18250253;22094642;25499958;21317356;25673761;16052107;23684876;15778890;17389691;19025913;15219979;25812945;7690693;11425500;24239590;24933713;21609772;22266414;3677542;16001126",
"title": "Modulatory effects of ketamine, risperidone and lamotrigine on resting brain perfusion in healthy human subjects.",
"title_normalized": "modulatory effects of ketamine risperidone and lamotrigine on resting brain perfusion in healthy human subjects"
} | [
{
"companynumb": "US-JNJFOC-20160311242",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Posttransplant lymphoproliferative disorders are a spectrum of lymphoproliferative disorders seen in recipients of solid-organ, bone marrow, and stem cell allografts. They include polyclonal early lesions mimicking infectious mononucleosis and monoclonal proliferations of B and T cells, indistinguishable from lymphomas occurring in immunocompetent individuals. Although most posttransplant lymphoproliferative disorders are B-cell neoplasms, T-cell posttransplant lymphoproliferative disorders are very rare. Among solid-organ transplants, renal allografts have low risk for development of posttransplant lymphoproliferative disorders. We describe the case of an adult male who developed a T-cell posttransplant lympho?roliferative disorder involving the small intestine after renal transplant, which was diagnosed as peripheral T-cell lymphoma, not otherwise specified.",
"affiliations": "From the Department of Pathology, All India Institute of Medical Sciences, New Delhi, India 110029.",
"authors": "Kakkar|Aanchal|A|;Pradeep|Immanuel|I|;Singh|Geetika|G|;Dinda|Amit|A|;Agarwal|Sanjay K|SK|",
"chemical_list": "D014408:Biomarkers, Tumor",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2016.0042",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "16(5)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D014408:Biomarkers, Tumor; D001706:Biopsy; D006801:Humans; D007150:Immunohistochemistry; D007580:Jejunal Neoplasms; D016030:Kidney Transplantation; D016411:Lymphoma, T-Cell, Peripheral; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "617-619",
"pmc": null,
"pmid": "27915968",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Peripheral T-Cell Lymphoma: A Posttransplant Lymphoproliferative Disorder Presenting as a Jejunal Mass in a Renal Transplant Recipient.",
"title_normalized": "peripheral t cell lymphoma a posttransplant lymphoproliferative disorder presenting as a jejunal mass in a renal transplant recipient"
} | [
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-210322",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"dr... |
{
"abstract": "We present the case of a 53-year-old woman with long-standing ulcerative colitis and severe, steroid-dependent disease course unresponsive to treatment with azathioprine, methotrexate, anti-TNF antibodies (infliximab, adalimumab) and tacrolimus, who refused colectomy as a therapeutic option. As the pro-inflammatory cytokine interleukin-6 (IL-6) had been identified as a crucial regulator in the immunopathogenesis of inflammatory bowel diseases, we treated the patient with biweekly intravenous infusions of an anti-IL-6R antibody (tocilizumab) for 12 wk. However, no clinical improvement of disease activity was noted. In fact, endoscopic, histological and endomicroscopic assessment demonstrated exacerbation of mucosal inflammation and ulcer formation upon anti-IL-6R therapy. Mechanistic studies revealed that tocilizumab treatment failed to suppress intestinal IL-6 production, impaired epithelial barrier function and induced production of pro-inflammatory cytokines such as TNF, IL-21 and IFN-γ. Inhibition of IL-6 by tocilizumab had no clinical benefit in this patient with intractable ulcerative colitis and even led to exacerbation of mucosal inflammation. Our findings suggest that anti-IL-6R antibody therapy may lead to aggravation of anti-TNF resistant ulcerative colitis. When targeting IL-6, the differential responsiveness of target cells has to be taken into account, as IL-6 on the one side promotes acute and chronic mucosal inflammation via soluble IL-6R signaling but on the other side also strongly contributes to epithelial cell survival via membrane bound IL-6R signaling.",
"affiliations": "Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany.;Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany.;Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany.;Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany.;Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany.;Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany.;Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany.",
"authors": "Atreya|Raja|R|;Billmeier|Ulrike|U|;Rath|Timo|T|;Mudter|Jonas|J|;Vieth|Michael|M|;Neumann|Helmut|H|;Neurath|Markus F|MF|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D005765:Gastrointestinal Agents; C508603:IL6R protein, human; D019947:Receptors, Interleukin-6; C502936:tocilizumab",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v21.i45.12963",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "21(45)",
"journal": "World journal of gastroenterology",
"keywords": "Anti-interleukin-6R antibody; Apoptosis; Cytokines; Endomicroscopy; Epithelial barrier; Inflammation; Interleukin-6; Ulcerative colitis",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D001706:Biopsy; D003093:Colitis, Ulcerative; D003113:Colonoscopy; D016207:Cytokines; D018450:Disease Progression; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D019947:Receptors, Interleukin-6; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "12963-9",
"pmc": null,
"pmid": "26668517",
"pubdate": "2015-12-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12190167;19074180;21108178;21377916;21833686;21875498;22115827;22549092;22894574;23489068;24751956;25304132;25567115;10779797;10802717;12858437;15057738;1864537;7683293;10204613;17153445;18566104;12219085",
"title": "First case report of exacerbated ulcerative colitis after anti-interleukin-6R salvage therapy.",
"title_normalized": "first case report of exacerbated ulcerative colitis after anti interleukin 6r salvage therapy"
} | [
{
"companynumb": "DE-ACCORD-036708",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
"drug... |
{
"abstract": "Coronavirus disease-19 caused by severe acute respiratory syndrome Corona virus-2 is characterised by wide heterogeneity in clinical presentation. The typical radiographic findings in COVID-19 include bilateral ground-glass opacities and/or consolidations predominantly affecting the lower lobes and posterior segments of lungs. Other rare abnormal radiographic findings include pneumothorax, pneumomediastinum and pneumopericardium. There has been an increased incidence of pneumomediastinum, a rare but potentially life-threatening complication during this pandemic. It may be spontaneous or secondary. Pneumomediastinum may be due to barotrauma, cytokine storm induced diffuse alveolar injury or direct viral infection of type I and type II pneumocytes. The presence of pneumomediastinum in COVID-19 patients may indicate extensive alveolar membrane destruction and those patients need close monitoring. There are no consensus guidelines in managing COVID-19 patients with pneumomediastinum. Higher mortality rates (70.58%) are reported in intubated COVID-19 patients with pneumomediastinum. The development of pneumomediastinum in COVID-19 should be considered as a poor prognostic factor.",
"affiliations": "Department of Internal Medicine, Apollo Hospitals, Chennai, India.;Department of Internal Medicine, Apollo Hospitals, Chennai, India.;Department of Internal Medicine, Apollo Hospitals, Chennai, India.;Department of Radiology, Apollo Hospitals, Chennai, India.",
"authors": "Machiraju|Phani Krishna|PK|https://orcid.org/0000-0002-9721-6996;Alex|Neetu Mariam|NM|;Safinaaz|||;Baby|Nikita Mary|NM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X211011807",
"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X\nSAGE Publications Sage UK: London, England\n\n10.1177/2050313X211011807\n10.1177_2050313X211011807\nCase Report\nPneumomediastinum in COVID-19: A series of three cases and review of literature\nhttps://orcid.org/0000-0002-9721-6996\nMachiraju Phani Krishna 1\nAlex Neetu Mariam 1\nSafinaaz 1\nBaby Nikita Mary 2\n1 Department of Internal Medicine, Apollo Hospitals, Chennai, India\n2 Department of Radiology, Apollo Hospitals, Chennai, India\nPhani Krishna Machiraju, Department of Internal Medicine, Apollo Hospitals, Greams Road, Chennai 600 006, Tamil Nadu, India. Email: phani940@gmail.com\n29 4 2021\n2021\n9 2050313X21101180713 1 2021\n30 3 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://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).\nCoronavirus disease-19 caused by severe acute respiratory syndrome Corona virus-2 is characterised by wide heterogeneity in clinical presentation. The typical radiographic findings in COVID-19 include bilateral ground-glass opacities and/or consolidations predominantly affecting the lower lobes and posterior segments of lungs. Other rare abnormal radiographic findings include pneumothorax, pneumomediastinum and pneumopericardium. There has been an increased incidence of pneumomediastinum, a rare but potentially life-threatening complication during this pandemic. It may be spontaneous or secondary. Pneumomediastinum may be due to barotrauma, cytokine storm induced diffuse alveolar injury or direct viral infection of type I and type II pneumocytes. The presence of pneumomediastinum in COVID-19 patients may indicate extensive alveolar membrane destruction and those patients need close monitoring. There are no consensus guidelines in managing COVID-19 patients with pneumomediastinum. Higher mortality rates (70.58%) are reported in intubated COVID-19 patients with pneumomediastinum. The development of pneumomediastinum in COVID-19 should be considered as a poor prognostic factor.\n\nPneumomediastinum\nCOVID-19\nSARS CoV-2\npneumopericardium\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nCoronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome Corona virus-2 (SARS CoV-2) is characterised by wide heterogeneity in clinical presentation ranging from asymptomatic infection to critical and fatal illness. The lung is the primary target organ, and hypoxemic respiratory failure is the major complication in COVID-19 patients; other complications include that of cardiac, renal, neurologic, and haematological system. The characteristic haematological abnormalities of COVID-19 patients have prognostic implications, and it is very challenging in managing these haematological complications in COVID-19.1\n\nThere has been a significant increase in the number of intubations and need for mechanical ventilation during this pandemic and studies have shown that approximately 12%–24% of hospitalised patients required endotracheal intubation.2,3 Pneumomediastinum (PM) also known as mediastinal emphysema is defined by the presence of air in the mediastinum. Spontaneous pneumomediastinum (SPM) was first described by Louis Hamman in the year 1939;4 hence, it is called as ‘Hamman Syndrome’. The incidence of SPM is reported to be 1 in 32,896.5 Chest pain, dyspnea, and subcutaneous emphysema are the most common clinical manifestations.6\n\nIt may be spontaneous or secondary to traumatic, non-traumatic and iatrogenic causes. PM has been reported previously in staphylococcal pneumonia, fungal pneumonia, human immunodeficiency virus infection in association with pneumocystis and tuberculosis, cytomegalovirus pneumonitis and in patients with haematological malignancies.7 There has been an increased incidence of this rare but potentially life-threatening complication during this pandemic. We report the clinical course, management, complications and outcome in three cases of COVID-19 complicated by PM.\n\nCase details\n\nPatient: 1\n\nA 51-year-old man with a past medical history of type 2 diabetes mellitus and hypertension, presented with complaints of fever, myalgia and dry cough for 8 days. No history of chronic obstructive pulmonary disease (COPD) and asthma. He denied smoking history. He tested positive for COVID-19 by reverse transcription polymerase chain reaction (RT-PCR), and he was initially treated elsewhere with remdesivir, dexamethasone and antibiotics (co-amoxiclav and doxycycline). On arrival, the patient was conscious, oriented, and febrile (temperature: 101°F) with a pulse rate (PR) of 106/min and blood pressure (BP) of 140/90 mm Hg. Arterial blood gas (ABG) analysis showed metabolic acidosis and type-I respiratory failure. He was hypoxic (SpO2: 86% on room air) and started on high-flow oxygen at 15 L/min.\n\nHis initial investigations revealed severe hyperglycemia (random blood sugar: 493 mg/dL (70–140 mg/dL)), hyperkalemia (6.4 meq/L (3.5–5.5 meq/L)), azotemia (urea: 101 mg/dL (7–20 mg/dL), creatinine: 1.3 mg/dL (0.9–1.3 mg/dL)), and leucocytosis (27,700 cells/mm3 (4000–11,000 cells/mm3)). Urine ketones were positive and serum ketones level was elevated, he was started on insulin infusion. Chest X-ray revealed bilateral patchy consolidations. Inflammatory markers were elevated (lactate dehydrogenase (LDH): 529 U/L (105–333 U/L), ferritin: 2783.4 ng/mL (20–250 ng/mL), interleukin-6 (IL-6): 329.4 pg/mL (5–15 pg/mL), and C-reactive protein (CRP): >199 mg/L (<10 mg/L)).\n\nDue to worsening hypoxemia, he was intubated on the same day of admission and was started on volume control ventilator support. Because of persistent hypoxia, computed tomography scan (CT-scan) chest (Figure 1) done on sixth day of admission revealed PM, pneumopericardium with an extension of air into the fascial planes of the neck and subcutaneous and intermuscular planes of the chest, dense consolidation in the left lower lobe and intraparenchymal septated cavity. He was started on Meropenem, Targocid and voriconazole, and PM was managed conservatively. He had methicillin-resistant Staphylococcus aureus bacteremia, and bronchial wash cultures grew Klebsiella pneumoniae, antibiotics and antifungals were continued. Repeat X-ray done on eighth day of admission showed features of adult respiratory distress syndrome (ARDS), consolidation, subcutaneous emphysema and resolving PM (Figure 2).\n\nFigure 1. CT-scan chest of patient 1 showing pneumomediastinum.\n\nFigure 2. Chest X-ray of patient 1 showing features of ARDS, subcutaneous emphysema and resolving pneumomediastinum.\n\nHis condition further deteriorated, and he went into septic shock for which he was started on inotropes. Because of the need for prolonged ventilator support, he underwent tracheostomy. The patient’s inflammatory markers continued to remain high, and he remained haemodynamically unstable, requiring inotropes and mechanical ventilation. Despite aggressive management, his condition deteriorated, and he died due to his disease on tenth day of hospitalisation.\n\nPatient: 2\n\nA 77-year-old man with a history of hypertension presented with complaints of shortness of breath (SOB) for 1 week. No history of fever, cough or chest pain, and no history of COPD and asthma. He denied smoking history. COVID-19 RT-PCR done elsewhere initially was negative. CT-scan chest done on the day of admission showed multiple confluent areas of ground-glass opacities and crazy paving pattern with a severity score of 26. On arrival in emergency room (ER), he was afebrile and hypoxic (PR: 96/min, BP: 120/80 mm Hg, temperature: 98.4°F, SpO2: 89% on room air). Physical examination was notable for bilateral crepts. ABG revealed type-I respiratory failure, and he was started on high-flow oxygen at 10 L/min. Baseline labs were notable for leucocytosis (16,300 cells/mm3) and hyponatremia (124 meq/L).\n\nInflammatory markers were elevated (LDH: 311 U/l, ferritin: 1403.8 ng/mL, IL-6: 177.8 pg/mL, CRP: >199 mg/L). Blood and urine cultures were sent, and he was started on dexamethasone, enoxaparin, remdesivir and antibiotics (co-amoxiclav and doxycycline). CT chest with pulmonary thromboembolism (PTE) protocol (Figures 3 and 4) was done on day 5 to rule out pulmonary embolism. It did not show evidence of pulmonary embolism, compared to the previous CT, lower lobe consolidation and PM was a new finding. In view of worsening hypoxia and increased work of breathing, he was intubated on the same day and was started on volume control ventilator support. Hyponatremia was managed with dietary and fluid modifications. PM was managed conservatively, and serial X-rays showed resolving PM and pneumopericardium (Figure 5).\n\nFigure 3. CT chest of second patient showing pneumomediastinum with pneumopericardium.\n\nFigure 4. CT chest of second patient showing pneumomediastinum with pneumopericardium.\n\nFigure 5. Chest X-ray of second patient showing features of ARDS, and resolving pneumopericardium and pneumomediastinum.\n\nDuring the course of hospital stay, he had fluctuating haemodynamics requiring inotropes, and antibiotics were escalated to Meropenem and Targocid for new-onset fever. He developed acute kidney injury secondary to sepsis, severe metabolic acidosis and was dialysed. On the 16th day of admission, he had supraventricular tachycardia and was reverted to sinus rhythm with synchronised shock, and he was continued on anti-coagulants, inotropes and ventilator support. Despite aggressive management, his condition deteriorated, and he died due to multi-organ dysfunction syndrome and refractory hypoxemia on 17th day of hospitalisation.\n\nPatient: 3\n\nThis 53-year-old lady with a history of type 2 diabetes mellitus and dyslipidemia, presented with complaints of fever and headache for 5 days. She denied a history of cough, chest pain, giddiness, urinary or gastrointestinal symptoms. No history of COPD, asthma and smoking. She had come in contact with a COVID-19 positive patient. COVID-19 RT-PCR was positive.\n\nShe was conscious, oriented, febrile (PR: 88/min, BP: 110/80 mm Hg, temperature: 101.4°F) at the time of presentation. She was maintaining SpO2 of 98% on room air. Physical examination was unremarkable. Baseline labs were notable for hypokalemia (3.2 meq/L), and inflammatory markers were mildly elevated (ferritin: 301.5 ng/mL and CRP: 13.6 mg/L). She was started on dexamethasone, remdesivir and enoxaparin.\n\nDuring the hospital stay, she had worsening hypoxia for which she was started on oxygen support via nasal prongs. CT chest (Figure 6) done on ninth day of admission revealed no evidence of pulmonary embolism, multiple patchy areas of ground-glass opacities with intralobular septal thickening and subpleural fibrotic bands, moderate PM extending into the subcutaneous planes of the neck with a severity score of 16. She was managed conservatively and continued on anti-coagulants. A repeat chest X-ray (Figure 7) showed resolution of PM. She improved clinically, maintaining oxygen saturation (SpO2) >96% on room air, and was discharged home on 15th day of admission.\n\nFigure 6. CT chest of third patient showing pneumomediastinum.\n\nFigure 7. Chest X-ray of third patient showing resolution of pneumomediastinum.\n\nDiscussion\n\nThe typical abnormal radiographic findings reported in COVID-19 patients are bilateral ground-glass opacities and/or consolidations with peripheral/subpleural distribution, predominantly affecting the lower lobes and posterior segments of lungs. Other rare abnormal radiographic findings include pneumothorax (PTX), PM and pneumopericardium. PM is reported in 4% of the patients with ARDS, and it is found to be a predictive factor for PTX in these patients.8,9\n\nKangas-Dick et al.10 reported PM in 10% of the intubated patients with COVID-19. Similar reports of increased incidence of PM as well as PTX was reported during SARS pandemic in 2003.7 Pneumopericardium is further rare, and very few cases are reported in association with COVID-19.11–13 In our series, first patient had pneumopericardium along with PM, and necrotising pneumonia with cavity formation and second patient had a pre-peritoneal extension of air along with pneumopericardium. All three patients had subcutaneous emphysema.\n\nThe pathophysiology of increased incidence of PM in COVID-19 patients is not clear. Increase in the number of intubations and resultant barotrauma secondary to mechanical ventilation may be a significant factor contributing to this and is usually evident within 24 h of intubation. There are reported cases of PM in COVID-19 patients unrelated to intubation. In our series, first patient developed PM 5 days after intubation, in second patient PM was detected prior to intubation, and third patient was never intubated. Our first patient required high positive end-expiratory pressure (PEEP), as well as high plateau pressure for maintaining oxygenation which might have increased the risk of barotrauma and PM. In a retrospective study by G McGuinness et al.,14 higher rates of barotrauma were seen in patients with COVID-19 infection and invasive mechanical ventilation than patients with ARDS and patients without COVID-19 infection.14\n\nThe structural changes in lungs caused by COVID-19 and lung damage associated with mechanical ventilation may be responsible for PM in these patients. But, a recent study by DHL Lemmers et al.15 have shown that there is significant increase in PM/subcutaneous emphysema in COVID-19 ARDS (13.6%) patients than non-COVID-19 ARDS (1.9%) despite use of low tidal volume and low airway plateau pressure lung protective ventilator strategies in COVID-19 patients. Thus, if barotrauma is eliminated, the underlying lung pathology due to infection should be considered as cause for development of PM. CoV ARDS is associated with increased risk of pulmonary vascular thrombosis, and subsequent necrosis and damage to alveolar membrane that can contribute to barotrauma.\n\nSpontaneous PM in COVID-19 patients may occur as a result of the cytokine storm induced diffuse alveolar injury or direct viral infection of type I and type II pneumocytes makes alveoli more liable to rupture resulting in alveolar membrane rupture, the resultant gush of air circulates through the peri-bronchial and perivascular sheaths to the mediastinum, popularly known as ‘Macklin phenomenon’. Viral infection associated tracheal oedema increasing risk of tracheal injury during intubation, increased alveolar pressure due to violent coughing secondary to viral infections may all attribute to the development of PM in COVID-19 patients.10,16,17\n\nMales seem to be more affected than the females. In our series, two (66%) out of three were male patients and mean age was 60.3 years which is in concordance with results of the study by Kangas-Dick et al.10 Two patients had diabetes, and two patients had hypertension in our series. Mean time from admission to PM was 1 week in all three of our cases. While PM was detected at around third week of illness in SARS pandemic, in most of the reported cases of COVID-19 including ours, it is being detected between 7 and 14 days frequently.7,10\n\nA recent report summarising the outcome of 5279 COVID-19 patients reported a mortality rate of 60.4% in the patient requiring mechanical ventilation.2 Chu et al.7 reported that the presence of PM could complicate SARS and indicate worsening of the disease, requiring more aggressive management. Similarly, Kangas-Dick et al.10 reported higher mortality rate (70.58%) in intubated COVID-19 patients with PM. Two (66%) out of three patients in our series have died, in concordance with the data. COVID-19 patients may have a higher susceptibility to compressive effects of PM, due to significant loss of physiological reserve of the lung, especially in severe cases.17\n\nPM is usually self-limiting and is managed conservatively. Treatment of the underlying causes and least damaging ventilator settings possible to achieve adequate oxygenation are the mainstays in managing PM. But, PM can lead to worsening respiratory acidosis and failure. COVID-19 patients with PM seem to have a more complicated clinical course and poor outcome. There are no consensus guidelines in managing COVID-19 patients with PM. Wali et al.17 managed patients aggressively by placing chest drains, whereas Volpi et al.18 successfully managed two patients of PM by conservative approach. Hamad et al.19 suggested inserting a unilateral intrapleural chest drain to protect at least one side against potential pneumothorax. All three patients in our series were managed conservatively – one patient recovered, and the other two patients died due to multi-organ failure. Barotrauma appears to be marker for worsening clinical condition and is an independent risk factor for increased mortality and length of hospital stay.\n\nIn the retrospective analysis by Kangas-Dick et al.,10 more than half of the patients with PM were managed conservatively, and there was no significant difference in the mortality rates between those managed with tube thoracostomy and those managed by conservative approach. In the absence of mediastinal compressive symptoms, conservative approach to these patients is suggested, and approach should be decided case-to-case basis.\n\nConclusion\n\nPM is a rare but potentially life-threatening complication which is being increasingly reported in association with COVID-19. PM may be spontaneous or secondary. The presence of PM in COVID-19 patients may indicate extensive alveolar membrane destruction and those patients need close monitoring. The development of PM in COVID-19 should be considered as a poor prognostic factor. Furthermore, more extensive studies are required to establish the association between the presence of PM and outcomes in COVID-19.\n\nAuthor contributions: All the authors contributed equally to this study.\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\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s)/a legally authorised representative(s) for their anonymised information to be published in this article. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nORCID iD: Phani Krishna Machiraju https://orcid.org/0000-0002-9721-6996\n==== Refs\nReferences\n\n1 Sahu KK Cerny J. A review on how to do hematology consults during COVID-19 pandemic. Blood Rev. Epub ahead of print 8 November 2020. DOI: 10.1016/j.blre.2020.100777.\n2 Christopher MP Jones SA Yang J , et al . Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ 2020; 369 : m1966.32444366\n3 Richardson S Hirsch JS Narasimhan M , et al . Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalised with COVID-19 in the New York City area. JAMA 2020; 323 : 2052–2059.32320003\n4 Hamman L. Spontaneous mediastinal emphysema. Bull Johns Hopkins Hospital 1939; 64 : 1–21.\n5 Bodey GP. Medical mediastinal emphysema. Ann Intern Med 1961; 54 : 46–56.\n6 Macia I Moya J Ramos R , et al . Spontaneous pneumomediastinum: 41 cases. Eur J Cardiothorac Surg 2007; 31 (6 ): 1110–1114.17420139\n7 Chu CM Leung YY Hui JY , et al . Spontaneous pneumomediastinum in patients with severe acute respiratory syndrome. Eur Respir J 2004; 23 (6 ): 802–804.15218989\n8 Weg JG Anzueto A Balk RA , et al . The relation of pneumothorax and other air leaks to mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338 : 341–346.9449726\n9 Gammon RB Shin MS Buchalter SE. Pulmonary barotrauma in mechanical ventilation. Chest 1992; 102 : 568–572.1643949\n10 Kangas-Dick A Gazivoda V Ibrahim M , et al . Clinical characteristics and outcome of pneumomediastinum in patients with COVID-19 pneumonia. J Laparoendosc Adv Surg Tech A 2021; 31 : 273–278.32936034\n11 Li S Chau E Ghasem W , et al . Air should not be there: a case of pneumomediastinum and pneumopericardium in COVID-19. Cureus 2020; 12 (11 ): e11696.33391929\n12 Sahu KK Mishra AK Goldman Y. A rare case of pneumopericardium secondary to COVID-19. Heart Lung 2020; 49 (6 ): 679–680.32861883\n13 Ghods K Aghaamoo S Amini Fooladi N , et al . Spontaneous massive pneumopericardium in a patient with COVID-19. Eur J Cardiothorac Surg. Epub ahead of print 26 December 2020. DOI: 10.1093/ejcts/ezaa465.\n14 McGuinness G Zhan C Rosenberg N , et al . Increased incidence of barotrauma in patients with COVID-19 on invasive mechanical ventilation. Radiology 2020; 297 (2 ): E252–E262.32614258\n15 Lemmers DHL Abu Hilal M Bnà C , et al . Pneumomediastinum and subcutaneous emphysema in COVID-19: barotrauma or lung frailty? ERJ Open Res 2020; 6 (4 ): 00385-2020.33257914\n16 Joshi S Bhatia A Singh P , et al . Pneumomediastinum as a Presenting Feature of COVID-19-an Observation. J Assoc Physicians India 2020; 68 (10 ): 81–82.\n17 Wali A Rizzo V Bille A , et al . Pneumomediastinum following intubation in COVID-19 patients: a case series. Anaesthesia 2020; 75 (8 ): 1076–1081.32375200\n18 Volpi S Ali JM Suleman A , et al . Pneumomediastinum in COVID-19 patients: a case series of a rare complication. Eur J Cardiothorac Surg 2020; 58 : 646–647.32754730\n19 Hamad AM Elmahrouk AF Abdulatty OA. Alveolar air leakage in COVID-19 patients: Pneumomediastinum and/or pneumopericardium. Heart Lung 2020; 49 (6 ): 881–882.32980170\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-313X",
"issue": "9()",
"journal": "SAGE open medical case reports",
"keywords": "COVID-19; Pneumomediastinum; SARS CoV-2; pneumopericardium",
"medline_ta": "SAGE Open Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101638686",
"other_id": null,
"pages": "2050313X211011807",
"pmc": null,
"pmid": "34017591",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32320003;32444366;32861883;1643949;32978932;33367679;15218989;32980170;33199084;9449726;33257914;17420139;32754730;32614258;33391929;32375200;32936034",
"title": "Pneumomediastinum in COVID-19: A series of three cases and review of literature.",
"title_normalized": "pneumomediastinum in covid 19 a series of three cases and review of literature"
} | [
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"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-303027",
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"abstract": "BACKGROUND\nDeceased organ donations are rare in Japan, with most kidney transplants performed from a limited number of living donors. Researchers have thus developed highly successful ABO-incompatible transplantation procedures, emphasizing preoperative desensitization and postoperative immunosuppression. A recent open-label, single-arm, multicenter clinical study prospectively examined the efficacy and safety of rituximab/mycophenolate mofetil desensitization in ABO-incompatible kidney transplantation without splenectomy.\n\n\nMETHODS\nMycophenolate mofetil and low dose steroid were started 28 days pretransplant, followed by two doses of rituximab 375 mg/m2 at day -14 and day -1, and postoperative immunosuppression with tacrolimus or ciclosporin and basiliximab. The primary endpoint was the non-occurrence rate of acute antibody-mediated rejection. Patient survival and graft survival were monitored for 1 year posttransplant.\n\n\nRESULTS\nEighteen patients received rituximab and underwent ABO-incompatible kidney transplantation. CD19-positive peripheral B cell count decreased rapidly after the first rituximab infusion and recovered gradually after week 36. The desensitization protocol was tolerable, and most rituximab-related infusion reactions were mild. No anti-A/B antibody-mediated rejection occurred with this series. One patient developed anti-HLA antibody-mediated rejection (Banff 07 type II) on day 2, which was successfully managed. Patient and graft survival were both 100 % after 1 year.\n\n\nCONCLUSIONS\nOur desensitization protocol was confirmed to be clinically effective and with acceptable toxicities for ABO-I-KTx (University Hospital Medical Information Network Registration Number: UMIN000006635).",
"affiliations": "Niigata Organ Transplant Foundation, Niigata, Japan. takahashi-kouta@image.ocn.ne.jp.;Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.;Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan.;Department of Surgery, Tokyo Women's Medical University, Tokyo, Japan.;Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Tochigi, Japan.;Department of Nephrology, Toho University, Tokyo, Japan.;Transplant Surgery, Nagoya Daini Red Cross Hospital, Aichi, Japan.;Department of Organ Transplant and General Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.;Department of Nephrology, Masuko Memorial Hospital, Aichi, Japan.;Department of Digestive and Transplantation Surgery, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan.",
"authors": "Takahashi|Kota|K|;Saito|Kazuhide|K|;Takahara|Shiro|S|;Fuchinoue|Shohei|S|;Yagisawa|Takashi|T|;Aikawa|Atsushi|A|;Watarai|Yoshihiko|Y|;Yoshimura|Norio|N|;Tanabe|Kazunari|K|;Morozumi|Kunio|K|;Shimazu|Motohide|M|;|||",
"chemical_list": "D000017:ABO Blood-Group System; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D000069283:Rituximab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10157-016-1321-5",
"fulltext": null,
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"issn_linking": "1342-1751",
"issue": "21(4)",
"journal": "Clinical and experimental nephrology",
"keywords": "ABO incompatibility; Antibody-mediated rejection; Desensitization therapy; Kidney transplantation; Plasma exchange; Rituximab",
"medline_ta": "Clin Exp Nephrol",
"mesh_terms": "D000017:ABO Blood-Group System; D000293:Adolescent; D000328:Adult; D000368:Aged; D001787:Blood Group Incompatibility; D003888:Desensitization, Immunologic; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006680:HLA Antigens; D006648:Histocompatibility; D006801:Humans; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D007564:Japan; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9709923",
"other_id": null,
"pages": "705-713",
"pmc": null,
"pmid": "27534951",
"pubdate": "2017-08",
"publication_types": "D000068397:Clinical Study; D016428:Journal Article; D016448:Multicenter Study",
"references": "16623804;24932811;17593512;15196066;12451255;12973118;20559108;21297552;3321614;21175849;1989153;16623803;3892322;16623808;22054413;25894122;22902167;18941430",
"title": "Results of a multicenter prospective clinical study in Japan for evaluating efficacy and safety of desensitization protocol based on rituximab in ABO-incompatible kidney transplantation.",
"title_normalized": "results of a multicenter prospective clinical study in japan for evaluating efficacy and safety of desensitization protocol based on rituximab in abo incompatible kidney transplantation"
} | [
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"companynumb": "JP-ROCHE-1817642",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
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"abstract": "An 81-year-old man with a large hepatocellular carcinoma was referred in our institution for Y radioembolization (RE). The preliminary arteriography using Tc-macroaggregate albumin demonstrated an important hepatopulmonary shunt. It was an exclusion criterion for RE due to high risks of lung radiations. Then, the patient was treated with sorafenib during 4 months, stopped because of grade 3 toxicity. A second liver arteriography was performed, and Tc-macroaggregate albumin imaging showed an important reduction of the lung shunt. Transient therapy with sorafenib permitted to close the lung shunt and was a bridge for RE.",
"affiliations": "From the Departments of Nuclear Medicine.;Gastroenterology, and.;Interventional Radiology, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium.;Interventional Radiology, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium.;From the Departments of Nuclear Medicine.",
"authors": "dʼAbadie|Philippe|P|;Borbath|Ivan|I|;Goffette|Pierre|P|;Amini|Nadia|N|;Lhommel|Renaud|R|",
"chemical_list": "D000970:Antineoplastic Agents; D019275:Radiopharmaceuticals; D013668:Technetium Tc 99m Aggregated Albumin; D015021:Yttrium Radioisotopes; D000077157:Sorafenib",
"country": "United States",
"delete": false,
"doi": "10.1097/RLU.0000000000002369",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-9762",
"issue": "44(1)",
"journal": "Clinical nuclear medicine",
"keywords": null,
"medline_ta": "Clin Nucl Med",
"mesh_terms": "D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D006528:Carcinoma, Hepatocellular; D059248:Chemoradiotherapy; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D019275:Radiopharmaceuticals; D000077157:Sorafenib; D013668:Technetium Tc 99m Aggregated Albumin; D015021:Yttrium Radioisotopes",
"nlm_unique_id": "7611109",
"other_id": null,
"pages": "70-71",
"pmc": null,
"pmid": "30394928",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sorafenib Reduced Significantly Heptopulmonary Shunt in a Large Hepatocelullar Carcinoma.",
"title_normalized": "sorafenib reduced significantly heptopulmonary shunt in a large hepatocelullar carcinoma"
} | [
{
"companynumb": "BE-BAYER-2019-003975",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SORAFENIB"
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"abstract": "Arrhythmias or conduction system disease are not the most common manifestation of COVID-19 infection in patients requiring hospital admission. Torsade de pointes typically occurs in bursts of self-limiting episodes with symptoms of dizziness and syncope. However, it may occasionally progress to ventricular fibrillation and sudden death. In this article, we report a case of COVID-19 patient who developed polymorphic ventricular tachycardia with torsade de pointes morphology with normal QTc interval in the setting of fever. An 81-year-old woman was admitted with symptoms of COVID-19. She was treated with hydroxychloroquine, azithromycin, and doxycycline at an outside facility and finished the treatment 5 days prior to admission to our facility. Her course was complicated by atrial fibrillation with rapid ventricular response requiring cardioversion. Later, she developed two episodes of polymorphic ventricular tachycardia with TdP morphology with normal QTc. There was a correlation with fever triggering the ventricular tachycardia. We advocated aggressive fever control given the QTc was normal and stable. Following fever control, the patient remained stable and had no abnormal rhythm. COVID-19 patients are prone to different arrhythmias including life-threatening ventricular arrhythmias with normal left ventricular systolic function and normal QTc, and they should be monitored for fever and electrolyte abnormality during their hospital stay.",
"affiliations": "Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141 USA.;Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141 USA.;Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141 USA.;Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141 USA.;Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141 USA.",
"authors": "Babapoor-Farrokhran|Savalan|S|0000-0002-9898-2895;Port|Zachary|Z|;Wiener|Philip C|PC|;Amanullah|Aman|A|;Mainigi|Sumeet K|SK|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s42399-020-00531-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2523-8973",
"issue": null,
"journal": "SN comprehensive clinical medicine",
"keywords": "Arrhythmias; COVID-19; Polymorphic ventricular tachycardia; Severe acute respiratory syndrome coronavirus-2; Torsade de pointes",
"medline_ta": "SN Compr Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101740833",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "32989427",
"pubdate": "2020-09-24",
"publication_types": "D016428:Journal Article",
"references": "32901230;32838177;32838153;2757893;32927023;7900661;26183037;32838188;28638664;32360126",
"title": "Polymorphic Ventricular Tachycardia with a Normal QTc Interval in a Patient with COVID-19 and Fever: Case Report.",
"title_normalized": "polymorphic ventricular tachycardia with a normal qtc interval in a patient with covid 19 and fever case report"
} | [
{
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"abstract": "More active therapies are needed for older and unfit patients with chronic lymphocytic leukemia (CLL) who are not eligible for chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The phosphyotidylinositol-3-kinase δ inhibitor idelalisib is effective in patients with treatment-naive and relapsed/refractory CLL as monotherapy and in combination with rituximab, but it can be associated with treatment-limiting adverse events, particularly diarrhea/colitis. The outcomes for patients who cease treatment for adverse events have not been previously described.\n\n\n\nThe authors analyzed long-term follow-up data from 40 treatment-naïve patients aged ≥65 years who received treatment at The University of Texas MD Anderson Cancer Center on a phase 2 study of idelalisib plus rituximab for CLL.\n\n\n\nIn patients who permanently ceased treatment because of toxicity, the time to subsequent disease progression was analyzed according to baseline characteristics. Fifteen patients permanently ceased therapy (PCT) because of toxicity (PCTTOX ), most commonly diarrhea/colitis (n = 7), at a median of 11 months after commencing treatment. PCTTOX was associated with a higher risk of subsequent disease progression (hazard ratio, 6.61; 95% confidence interval, 1.77-16.15) relative to that observed in patients who remained on therapy. Ten patients subsequently progressed, and 7 required salvage therapy; 5 patients remained progression-free at a median of 23.3 months (range, 8.5-28.6 months). Patients who were positive for ζ-associated protein-70 had more rapid disease progression after treatment cessation (P = .048). There were no CLL-related deaths.\n\n\n\nPCTTOX is the major determinant of PFS in patients who receive first-line idelalisib-based treatment. However, a subgroup of patients with favorable biologic characteristics has prolonged PFS, even after PCTTOX . The absence of CLL-related deaths indicates that salvage treatment is generally successful after PCTTOX . Cancer 2016;122:2505-11. © 2016 American Cancer Society.",
"affiliations": "Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.;The University of California Irvine Chao Family Comprehensive Cancer Center, Orange, California.",
"authors": "Thompson|Philip A|PA|;Stingo|Francesco|F|;Keating|Michael J|MJ|;Ferrajoli|Alessandra|A|;Burger|Jan A|JA|;Wierda|William G|WG|;Kadia|Tapan M|TM|;O'Brien|Susan M|SM|0000-0003-3386-6540",
"chemical_list": "D011687:Purines; D052999:Quinazolinones; D000069283:Rituximab; C552946:idelalisib",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.30069",
"fulltext": null,
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"issn_linking": "0008-543X",
"issue": "122(16)",
"journal": "Cancer",
"keywords": "chronic lymphocytic leukemia (CLL); disease-free survival; idelalisib; remission; rituximab; toxicity",
"medline_ta": "Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D009367:Neoplasm Staging; D011687:Purines; D052999:Quinazolinones; D000069283:Rituximab; D016019:Survival Analysis; D016896:Treatment Outcome; D028761:Withholding Treatment",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "2505-11",
"pmc": null,
"pmid": "27182988",
"pubdate": "2016-08-15",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "26472751;18216293;831755;25634683;20888994;24615777;24450857;12235209;12130661;12446777",
"title": "Outcomes of patients with chronic lymphocytic leukemia treated with first-line idelalisib plus rituximab after cessation of treatment for toxicity.",
"title_normalized": "outcomes of patients with chronic lymphocytic leukemia treated with first line idelalisib plus rituximab after cessation of treatment for toxicity"
} | [
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"activesubstancename": "IDELALISIB"
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{
"abstract": "Thrombotic microangiopathy is a rare haematological emergency which encompasses the conditions of haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). It is an unusual but recognised complication of chemotherapy. It has not previously been described in conjunction with docetaxel or trastuzumab therapy. We report a 47-year-old patient with localised breast cancer who developed thrombotic microangiopathy (HUS/TTP) acutely following concurrent neoadjuvant therapy with trastuzumab and docetaxel. We demonstrate from our case that mild confusion occurring on a background of mild anaemia and thrombocytopenia may sometimes be the only clue to the diagnosis. Clinicians should be aware of the possibility of thrombotic microangiopathy associated with trastuzumab and docetaxel therapy, as early intervention can improve clinical outcome.",
"affiliations": "Department of Medicine, Great Western Hospital, SN3 6BB, Swindon, UK. keith@siau.org",
"authors": "Siau|Keith|K|;Varughese|Mohini|M|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D043823:Taxoids; D000077143:Docetaxel; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": "10.1007/s12032-009-9333-6",
"fulltext": null,
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"issn_linking": "1357-0560",
"issue": "27(4)",
"journal": "Medical oncology (Northwood, London, England)",
"keywords": null,
"medline_ta": "Med Oncol",
"mesh_terms": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D015996:Survival Rate; D043823:Taxoids; D057049:Thrombotic Microangiopathies; D000068878:Trastuzumab; D016896:Treatment Outcome",
"nlm_unique_id": "9435512",
"other_id": null,
"pages": "1057-9",
"pmc": null,
"pmid": "19847680",
"pubdate": "2010-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19507208;3923162;19054690;15255125;8448753;12978378",
"title": "Thrombotic microangiopathy following docetaxel and trastuzumab chemotherapy: a case report.",
"title_normalized": "thrombotic microangiopathy following docetaxel and trastuzumab chemotherapy a case report"
} | [
{
"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-110144",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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"activesubstancename": "DOCETAXEL"
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{
"abstract": "Hyponatraemia is the most common electrolyte disturbance in the elderly. It can be asymptomatic or produce a spectrum of symptoms, particularly in the central nervous system, such as altered state of consciousness, lethargy, headache, seizures and gait disturbances, all of which are a common reason for consultation in this population. This condition has a high impact on the functionality of the patient given the need for multiple hospital stays, as well as on mortality. Its aetiology is multifactorial and its most common causes include low salt intake, chronic diseases such as kidney disease and heart failure, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH), which is commonly caused by the chronic use of certain drugs, such as antidepressants, diuretics and antipsychotics, which are the most forgotten in clinical practice. The following clinical case presents the diagnostic approach of hyponatraemia and the importance of the medical history as a key tool to detect the aetiology of this clinical entity.",
"affiliations": "Instituto de Envejecimiento, Facultad de Medicina, Pontificia Universidad Javeriana, Bogotá, Colombia. Electronic address: samiraruachan@javeriana.edu.co.;Instituto de Envejecimiento, Facultad de Medicina, Pontificia Universidad Javeriana, Bogotá, Colombia.;Unidad de Geriatría, Hospital Universitario San Ignacio, Bogotá, Colombia.",
"authors": "Aruachán|Samir|S|;Morales|Sergio|S|;Caicedo|Sandra Milena|SM|",
"chemical_list": "D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.rcp.2019.03.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2530-3120",
"issue": "49(4)",
"journal": "Revista Colombiana de psiquiatria (English ed.)",
"keywords": "Anciano; Elderly; Hiponatremia; Hyponatraemia; Psicofármacos; Psychotropic drugs; Quetiapina; Quetiapine",
"medline_ta": "Rev Colomb Psiquiatr (Engl Ed)",
"mesh_terms": "D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D006801:Humans; D007010:Hyponatremia; D008297:Male; D008487:Medical History Taking; D000069348:Quetiapine Fumarate",
"nlm_unique_id": "101778593",
"other_id": null,
"pages": "297-300",
"pmc": null,
"pmid": "33328024",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Hyponatraemia Associated with the Use of Quetiapine: Case Report.",
"title_normalized": "hyponatraemia associated with the use of quetiapine case report"
} | [
{
"companynumb": "CO-ACCORD-127271",
"fulfillexpeditecriteria": "1",
"occurcountry": "CO",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PRAZOSIN"
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{
"abstract": "Although sodium nitroprusside (SNP) is often used in pediatric intensive care units, cyanide toxicity can occur after SNP treatment. To treat SNP-induced cyanide poisoning, antidotes such as amyl nitrite, sodium nitrite, sodium thiosulfate, and hydroxycobalamin should be administered immediately after diagnosis. Here, we report the first case of a very young infant whose SNP-induced cyanide poisoning was successfully treated by exchange transfusion. The success of this alternative method may be related to the fact that exchange transfusion not only removes the cyanide from the blood but also activates detoxification systems by supplying sulfur-rich plasma. Moreover, exchange transfusion replaces cyanide-contaminated erythrocytes with fresh erythrocytes, thereby improving the blood's oxygen carrying capacity more rapidly than antidote therapy. Therefore, we believe that exchange transfusion might be an effective therapeutic modality for critical cases of cyanide poisoning.",
"affiliations": "Department of Pediatrics, Gyeongsang National University School of Medicine, Jinju, Korea.",
"authors": "Baek|Jong Geun|JG|;Jeong|Hoar Lim|HL|;Park|Ji Sook|JS|;Seo|Ji Hyun|JH|;Park|Eun Sil|ES|;Lim|Jae Young|JY|;Park|Chan Hoo|CH|;Woo|Hyang Ok|HO|;Youn|Hee Shang|HS|;Yeom|Jung Sook|JS|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.3345/kjp.2010.53.8.805",
"fulltext": "\n==== Front\nKorean J PediatrKJPKorean Journal of Pediatrics1738-10612092-7258The Korean Pediatric Society 10.3345/kjp.2010.53.8.805Case ReportSuccessful treatment by exchange transfusion of a young infant with sodium nitroprusside poisoning Baek Jong Geun M.D.Jeong Hoar Lim M.D.Park Ji Sook M.D.Seo Ji Hyun M.D.Park Eun Sil M.D.Lim Jae Young M.D.Park Chan Hoo M.D.Woo Hyang Ok M.D.Youn Hee Shang M.D.Yeom Jung Sook M.D.Department of Pediatrics, Gyeongsang National University School of Medicine, Jinju, Korea.Corresponding author: Jung Sook Yeom, M.D. Department of Pediatrics, Gyeongsang National University School of Medicine, 92 Chilam-dong, Jinju 660-751, Korea. Tel: +82.55-750-8161, Fax: +82.55-752-9339, polo96@daum.net8 2010 31 8 2010 53 8 805 808 23 3 2010 19 4 2010 25 5 2010 Copyright © 2010 by The Korean Pediatric Society2010This 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.Although sodium nitroprusside (SNP) is often used in pediatric intensive care units, cyanide toxicity can occur after SNP treatment. To treat SNP-induced cyanide poisoning, antidotes such as amyl nitrite, sodium nitrite, sodium thiosulfate, and hydroxycobalamin should be administered immediately after diagnosis. Here, we report the first case of a very young infant whose SNP-induced cyanide poisoning was successfully treated by exchange transfusion. The success of this alternative method may be related to the fact that exchange transfusion not only removes the cyanide from the blood but also activates detoxification systems by supplying sulfur-rich plasma. Moreover, exchange transfusion replaces cyanide-contaminated erythrocytes with fresh erythrocytes, thereby improving the blood's oxygen carrying capacity more rapidly than antidote therapy. Therefore, we believe that exchange transfusion might be an effective therapeutic modality for critical cases of cyanide poisoning.\n\nNitroprussideExchange transfusionCyanidesPoisoningDetoxificationInfant\n==== Body\nIntroduction\nThe sodium nitroprusside (SNP) is often used in pediatric intensive care units because of its strongly antihypertensive properties1) and various pharmacokinetic advantages2). However, cyanide toxicity, the most lethal complication, can occur after SNP treatment. Antidotal therapy is the treatment of choice in cases of cyanide poisoning. In general, exchange transfusion can be useful in poisoning cases because it activates the detoxification systems and removes some of the toxic agents from the blood more rapidly than does antidote therapy. Here, we report the first case of a 2-month-old infant whose SNP-induced cyanide poisoning was successfully treated by exchange transfusion rather than by the use of antidotes.\n\nCase report\nA 2-month-old male infant was brought to the emergency room due to cough, fever, and dyspnea. At the time of presentation to the emergency room, the following vital signs were recorded: blood pressure, 95/40 mmHg; pulse rate, 187/min; respiration rate, 66/min; and body temperature, 37.8℃. Oxygen saturation was 80% in room air. A chest X-ray revealed consolidation in the right lung. Venous blood gas analysis showed the following results: pH, 7.23; carbon dioxide partial pressure (pCO2), 65 mmHg; and oxygen partial pressure (pO2), 18 mmHg. The white blood cell (WBC) count and hemoglobin level were 8,300/mm3 and 10.7 g/dL, respectively. The C-reactive protein (CRP) level was markedly increased (111 mg/L). The infant developed serious dyspnea and failed to maintain oxygen saturation; he subsequently underwent mechanical ventilation after being hospitalized in the intensive care unit. He was diagnosed to have aspiration pneumonia and was treated with antibiotics and an anti-inflammatory dose of steroids.\n\nSeveral hours after admission, his blood pressure increased to 110/70 mmHg. To control his blood pressure, treatment with nitroglycerin was started. However, 2 days after admission, the infant's blood pressure further increased to 120/80 mmHg after methylprednisolone pulse therapy, which was administered to control pneumonia that had worsened and progressed to acute respiratory distress syndrome. Despite nitroglycerin infused to its maximal level, the infant's blood pressure failed to normalize. Thus, SNP was started and maintained with 2.4 µg/(kg·min) until SNP-induced cyanide poisoning was diagnosed (on the ninth day of hospitalization). In an evaluation study for hypertension, there was no evidence of kidney or heart disease. On the seventh day after admission, extubation was performed, and arterial blood gas analysis finding was within the normal range. By the eighth day of hospitalization, SNP continued to be infused at a rate of 2 µg/(kg·min), and arterial blood gas analysis revealed high anion gap metabolic acidosis with compensatory respiratory alkalosis (pH, 7.44; pCO2, 19 mmHg; pO2, 120 mmHg; and bicarbonate level, 11 mmol/L); however, respiratory distress symptoms were not observed.\n\nHowever, 1 day later, on the ninth day of admission, the respiratory rate increased gradually, and the patient showed symptoms of air hunger, moaning sound, nasal flaring, and irritability. The heart rate increased to 190/min. And the patient had myoclonic seizures. The infant's skin was cherry-red in color, and arterial blood gas analysis revealed a worsening of the high anion gap metabolic acidosis (pH, 7.27; pCO2, 12 mmHg; pO2, 281 mmHg; and bicarbonate level, 5 mmol/L). Although the plasma lactic acid level exhibited a marked increase to 122 mmol/L, lung sounds were normal, and a chest X-ray revealed improvement in the pneumonic infiltration. No evidence of sepsis or severe sepsis was found; there was no fever, normal WBC count (7,280/mm3) and hypertension rather than hypotension. The infection or inflammation was controlled (CRP was markedly decreased to 3.5 mg/dL). Thus, SNP toxicity was diagnosed, and SNP infusion was stopped. Since a suitable antidote drug was not available, we performed an exchange transfusion immediately after SNP toxicity was diagnosed. After one volume of exchange transfusion, the acidosis improved to a pH of 7.44, a pCO2 of 25 mmHg, a pO2 of 118 mmHg, and a bicarbonate level of 17 mmol/L. However, tachypnea was still observed and the pCO2 level was low. Plasma lactate was markedly decreased but not yet normalized (40 mmol/L). Consequently, a second volume of exchange transfusion was administered. Thereafter, the blood gas and plasma bicarbonate levels normalized (pH, 7.43; pCO2, 35 mmHg; and bicarbonate level, 23 mmol/L), plasma lactate was further decreased (31 mmol/L), the respiratory rate stabilized, and the patient improved clinically (Fig. 1). The infant was discharged from the hospital on the 20th day after hospitalization without any neurological deficits.\n\nDiscussion\nAlthough SNP has been used safely to treat many neonates3), infants4) and children5), cyanide intoxication should be considered if unexplained tachypnea, tachycardia, lactic acidosis, irritability, and seizures occur after SNP administration6). Reported risk factors associated with cyanide toxicity from SNP administration include prolonged infusion duration and/or high doses of SNP7), as indicated by several cases of cyanide toxicity in patients who had received more than 2 µg/(kg·min) SNP or had been infused for more than 24 hours5, 8). Moreover, children and neonates may be more susceptible to cyanide toxicity because of lower thiosulfate storage levels9). In the present case, the infant had several risk factors for SNP infusion-associated cyanide toxicity; specifically, he was very young (2 months old) and had received a high dose [>2 µg/(kg·min)] of SNP for several days.\n\nIn this case, the infant showed the classical symptoms and signs of cyanide toxicity, i.e., tachycardia, tachypnea without respiratory problems, unexplained metabolic acidosis, irritability, and seizures. It was not possible to measure the blood cyanide concentrations in our hospital, but the plasma lactate concentrations were 122 mmol/L. Plasma lactate concentrations that exceed 10 mmol/L correlate with blood cyanide concentrations that exceed 40 µmol/L10), and it has been shown that clinical toxicity appears when the blood cyanide concentration exceeds 40 µmol/L11). In adults, the fatal level of cyanide is generally considered to exceed 100-115 µmol/L10). Although nitroglycerin induced lactic acidosis might contribute to some portions of the patient's plasma lactate, his symptoms and sings were very typical to cyanide toxicity, we made a diagnosis of SNP-induced cyanide toxicity consequently. A key strategy to manage cyanide poisoning is to administer sulfur donors; sodium thiosulfate is usually used in clinical practice12). However, antidotes were not immediately available to us. Albumin can exhibit enzyme-like behavior and use bound elemental sulfur to detoxify cyanide13, 14). Thus, to supply sulfur donors and remove the cyanide and thiocyanate, we performed exchange transfusion.\n\nSince exchange transfusion activates the detoxification systems and can clear some toxins from the blood more rapidly than antidotes, it can be useful for poisoning cases. Exchange transfusion has been used successfully to treat neonates or infants who have been poisoned with salicylate15), theophyllin16), phenobarbital17), and other agents. A study in cats revealed that blood exchange transfusion is also an effective way to treat acute cyanide poisoning18). While the usefulness of blood exchange transfusion for pediatric cases of cyanide or nitroprusside poisoning has not yet been reported, we reasonably assumed that exchange transfusion would also be efficacious for cyanide poisoning. This is because exchange transfusion not only removes cyanide and thiocyanide from the blood but also activates the detoxification systems by supplying blood with abundant amounts of sulfur moieties. More importantly, exchange transfusion replaces cyanide-contaminated erythrocytes with fresh erythrocytes, thereby improving the blood's oxygen carrying capacity more rapidly than does antidote therapy. Therefore, we believe that exchange transfusion might be an effective therapeutic modality in a critical case of cyanide poisoning.\n\nCyanide poisoning causes cessation of oxidative phosphorylation and induces histotoxic anoxia, especially of the central nervous and cardiovascular systems; at high levels, it can lead to death. Exchange transfusion causes complications in 5% to 10% of infants even though the risk of death from the procedure is only 0.3/100 procedures19). In weighing the risks and benefits of using exchange transfusion therapy, we considered our patient to be at a serious risk from cyanide poisoning (based on classic cyanide poisoning signs and a markedly high level of plasma lactate without renal or heart problems or evidence of sepsis) and concluded that exchange transfusion provided more benefits than risks. Therefore, the infant received two rounds of exchange transfusion, after which his plasma lactic acid levels dropped markedly, the irritability and seizures disappeared, and his blood pCO2 levels and vital signs normalized. No complications of exchange transfusion were observed.\n\nIn summary, while exchange transfusion is not considered as the primary treatment option for treating SNP infusion-associated cyanide poisoning, it may be an effective alternative modality for treating this condition if antidotes are not available.\n\nFig. 1 Changes in vital signs and blood gas analysis findings during hospitalization. Sodium nitroprusside poisoning was diagnosed after 9 days of hospitalization. At that time, the patient showed unexplained tachypnea, tachycardia, irritability, and seizures. PaO2 was extremely high and PaCO2 was lower than the normal range. The plasma lactic acid level exhibited a marked increase to 122 mmol/L. These were recognized as the classical symptoms and signs of cyanide toxicity. The patient was stabilized after exchange transfusion. Abbreviations: HR, heart rate; RR, respiratory rate; BT, body temperature; BP, blood pressure; PaO2, partial arterial oxygen pressure; PaCO2, partial arterial carbon dioxide pressure.\n==== Refs\n1 Moffett BS Price JF Evaluation of sodium nitroprusside toxicity in pediatric cardiac surgical patients Ann Pharmacother 2008 42 1600 1604 18957627 \n2 Gilboa N Urizar RE Severe hypertension in newborn after pyeloplasty of hydronephrotic kidney Urology 1983 22 179 182 6879892 \n3 Benitz WE Malachowski N Cohen RS Stevenson DK Ariagno RL Sunshine P Use of sodium nitroprusside in neonates: Efficacy and safety J Pediatr 1985 106 102 110 3917495 \n4 Linakis JG Lacouture PG Woolf A Monitoring cyanide and thiocyanate concentrations during infusion of sodium nitroprusside in children Pediatr Cardiol 1991 12 214 218 1946009 \n5 Schulz V Clinical pharmacokinetics of nitroprusside, cyanide, thiosulphate and thiocyanate Clin Pharmacokinet 1984 9 239 251 6375932 \n6 Friederich JA Butterworth JF 4th Sodium nitroprusside: twenty years and counting Anesth Analg 1995 81 152 162 7598246 \n7 Thomas C Svehla L Moffett BS Sodium-nitroprusside-induced cyanide toxicity in pediatric patients Expert Opin Drug Saf 2009 8 599 602 19645589 \n8 Przybylo HJ Stevenson GW Schanbacher P Backer C Dsida RM Hall SC Sodium nitroprusside metabolism in children during hypothermic cardiopulmonary bypass Anesth Analg 1995 81 952 956 7486083 \n9 Schulz V Bonn R Kindler J Kinetics of elimination of thiocyanate in 7 healthy subjects and in 8 subjects with renal failure Klin Wochenschr 1979 57 243 247 431033 \n10 Kulig K Cyanide antidotes and fire toxicology N Engl J Med 1991 325 1801 1802 1944486 \n11 Baud FJ Barriot P Toffis V Riou B Vicaut E Lecarpentier Y Elevated blood cyanide concentrations in victims of smoke inhalation N Engl J Med 1991 325 1761 1766 1944484 \n12 Geller RJ Barthold C Saiers JA Hall AH Pediatric cyanide poisoning: Causes, manifestations, management, and unmet needs Pediatrics 2006 118 2146 2158 17079589 \n13 Way JL Cyanide intoxication and its mechanism of antagonism Annu Rev Pharmacol Toxicol 1984 24 451 481 6428300 \n14 Fasco MJ Iii CR Stack RF O'hehir C Barr JR Eadon GA Cyanide adducts with human plasma proteins: Albumin as a potential exposure surrogate Chem Res Toxicol 2007 20 677 684 17373827 \n15 Manikian A Stone S Hamilton R Foltin G Howland MA Hoffman RS Exchange transfusion in severe infant salicylism Vet Hum Toxicol 2002 44 224 227 12136972 \n16 Shannon M Wernovsky G Morris C Exchange transfusion in the treatment of severe theophylline poisoning Pediatrics 1992 89 145 147 1728001 \n17 Sancak R Kucukoduk S Tasdemir HA Belet N Exchange transfusion treatment in a newborn with phenobarbital intoxication Pediatr Emerg Care 1999 15 268 270 10460084 \n18 Tauberger G Karzel K Roezel V The efficacy of blood exchange transfusions in the treatment of acute cyanide poisoning (author's transl) Arch Toxicol 1974 32 189 197 4479742 \n19 Stoll BJ Kliegman RM Jenson HB Behrman RE Stanton BF Anemia in the newborn infant Nelson textbook of pediatrics 2007 18th ed Philadelphia Saunders Co 771 772\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1061",
"issue": "53(8)",
"journal": "Korean journal of pediatrics",
"keywords": "Cyanides; Detoxification; Exchange transfusion; Infant; Nitroprusside; Poisoning",
"medline_ta": "Korean J Pediatr",
"mesh_terms": null,
"nlm_unique_id": "101215374",
"other_id": null,
"pages": "805-8",
"pmc": null,
"pmid": "21189979",
"pubdate": "2010-08",
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"title": "Successful treatment by exchange transfusion of a young infant with sodium nitroprusside poisoning.",
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"abstract": "Medication-related osteonecrosis of the jaw (MRONJ) is a relatively infrequent but very well-known adverse effect of bisphosphonates. This rare complication of bisphosphonates is rarest with the use of certain drugs. Tyrosine kinase inhibitors (TKIs), particularly used in renal cell carcinoma or gastrointestinal tumors as a chemotherapeutic agent, can precipitate this particular medical condition of bone when it is associated with either radiation or bisphosphonates, though, monodrug therapy with TKIs rarely causes MRONJ. This article describes a rare case of necrosis of the jawbone in a patient with a myeloproliferative neoplasm who was receiving the TKI imatinib and had no history of bisphosphonate or radiation therapy to head and neck region.",
"affiliations": "Assistant Professor, Department of Dental and Prosthetic Surgery, Mahamana Pandit Madan Mohan Malaviya Cancer Center, Unit of Tata Memorial Center, Varanasi, Uttar Pradesh, India.;Professor, Department of Dental and Prosthetic Surgery, Tata Memorial Hospital, Tata Memorial Center (TMC), Homi Bhabha National Institute (HBNI) Mumbai, Maharashtra, India.;Former Assistant Professor, Department of Dental and Prosthetic Surgery, Homi Bhabha Cancer Hospital and Research Center, Unit of Tata Memorial Center, Vizag, Andhra Pradesh, India.;Professor, Department of Dental and Prosthetic Surgery, Tata Memorial Hospital, Tata Memorial Center (TMC), Homi Bhabha National Institute (HBNI) Mumbai, Maharashtra, India. Electronic address: drsandeepgurav@gmail.com.",
"authors": "Gupta|Lokendra|L|;Dholam|Kanchan|K|;Janghel|Yogesh|Y|;Gurav|Sandeep V|SV|",
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"title": "Osteonecrosis of the jaw associated with imatinib therapy in myeloproliferative neoplasm: a rare case report.",
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"abstract": "A 76-year-old woman was diagnosed with lung tuberculosis. On the second day of anti-tuberculosis treatment, she became unconscious and developed status epilepticus accompanied by hyponatremia. The hyponatremia was caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Detailed examinations revealed that the patient's status epilepticus had occurred due to hyponatremia, which was caused by lung tuberculosis-associated SIADH. Previous case reports noted that patients with tuberculosis-associated SIADH showed mild clinical manifestations. They also reported that extensive lung involvement was associated with SIADH development. We herein report a rare case of SIADH complicated with status epilepticus that was caused by tuberculosis with mild lung involvement.",
"affiliations": "Division of Respiratory Disease, Department of Internal Medicine, The Jikei University School of Medicine, Japan.",
"authors": "Hashimoto|Mitsuo|M|;Kuriiwa|Saki|S|;Kojima|Ayako|A|;Shinhuku|Kyota|K|;Sato|Akihito|A|;Sasaki|Ryoko|R|;Hasegawa|Tsukasa|T|;Ito|Akihiko|A|;Utsumi|Hirofumi|H|;Yanagisawa|Haruhiko|H|;Wakui|Hiroshi|H|;Minagawa|Shunsuke|S|;Kojima|Jun|J|;Numata|Takanori|T|;Hara|Hiromichi|H|;Araya|Jun|J|;Kaneko|Yumi|Y|;Nakayama|Katsutoshi|K|;Kuwano|Kazuyoshi|K|",
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"fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.56.7224Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 28202866Case ReportMild Lung Tuberculosis in a Patient Suffering from Status Epilepticus Caused by the Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) Hashimoto Mitsuo 1Kuriiwa Saki 1Kojima Ayako 1Shinhuku Kyota 1Sato Akihito 1Sasaki Ryoko 1Hasegawa Tsukasa 1Ito Akihiko 1Utsumi Hirofumi 1Yanagisawa Haruhiko 1Wakui Hiroshi 1Minagawa Shunsuke 1Kojima Jun 1Numata Takanori 1Hara Hiromichi 1Araya Jun 1Kaneko Yumi 1Nakayama Katsutoshi 1Kuwano Kazuyoshi 11 Division of Respiratory Disease, Department of Internal Medicine, The Jikei University School of Medicine, JapanCorrespondence to Dr. Mitsuo Hashimoto, mitsuoha-georgetown@live.jp\n\n15 2 2017 56 4 429 433 3 2 2016 27 6 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/).A 76-year-old woman was diagnosed with lung tuberculosis. On the second day of anti-tuberculosis treatment, she became unconscious and developed status epilepticus accompanied by hyponatremia. The hyponatremia was caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Detailed examinations revealed that the patient's status epilepticus had occurred due to hyponatremia, which was caused by lung tuberculosis-associated SIADH. Previous case reports noted that patients with tuberculosis-associated SIADH showed mild clinical manifestations. They also reported that extensive lung involvement was associated with SIADH development. We herein report a rare case of SIADH complicated with status epilepticus that was caused by tuberculosis with mild lung involvement. \n\nlung tuberculosisSIADHstatus epilepticushyponatremia\n==== Body\nIntroduction\nHyponatremia is one of the most common electrolyte imbalances. It is important that healthcare professionals recognize the imbalance promptly to prevent potential morbidity or mortality, since it is often a marker of underlying disease (1). The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is the most common cause of hyponatremia in patients suffering from pulmonary diseases. The main causes of SIADH are central neurological diseases, malignant diseases, medication-related adverse effects, and pulmonary diseases such as pneumonia and pulmonary tuberculosis (2). Several cases of pulmonary tuberculosis complicated with SIADH have been documented (3-5). Minami et al. summarized eight case reports of tuberculosis-associated SIADH and showed that seven of the reports were caused by severe tuberculosis, implying that extensive lung involvement is associated with the development of SIADH in patients with pulmonary tuberculosis (4). Furthering this finding, Nishizawa et al. summarized five case reports of tuberculosis with SIADH and showed that SIADH associated with pulmonary tuberculosis resulted in mild symptoms, including headache, nausea and vertigo (5). We herein report a rare case of SIADH complicated with status epilepticus that was caused by tuberculosis with mild lung involvement.\n\nCase Report\nA 75-year-old woman was admitted to the Jikei University Hospital due to impaired consciousness and status epilepticus. She was referred to the hospital's outpatient clinic 24 days before admission to investigate a progressive mass-like lesion with a maximum diameter of 30 mm that was located on her left upper lung. Positive results from an interferon-gamma-release assay (T-spot.TB assay, Oxford Immunotec Ltd. Marlborough, MA, USA) and a tuberculosis polymerase chain reaction (PCR) led to a diagnosis of pulmonary tuberculosis 16 days before admission. A sputum culture showed that the patient was positive for tuberculosis, and the diagnosis was later confirmed. The patient was prescribed four anti-tuberculosis medications (isoniazid, rifampicin, ethambutol, and pyramide). She did not start taking full doses of the medications until two days prior to her admission due to anxiety over the side effects. Her medical history included hypertension, gastric ulcer and hyperlipidemia, but she had been healthy until admission. On the day of admission, she was found lying on the floor at her home and was transported to the hospital. At the emergency room, she developed generalized seizures five times and was admitted to the intensive care unit to undergo treatment for statue epilepticus.\n\nOn admission, the patient was unconscious (Glasgow Coma Scale, E1V1M3) with a body temperature of 37℃, a heart rate of 108/min, a respiratory rate of 18 breaths/min, a saturation level of 99% on room air and a blood pressure of 160/90 mmHg. Physical examinations showed normal breath and heart sounds and no swelling of her extremities. Neurological examinations revealed an increase of muscle tonus, especially in the lower limbs. Biochemical examinations showed hyponatremia (120 mEq/L) with low serum osmolality (253 mOsm/kg), high urinary osmolality (458 mOsm/kg), and a normal urinary sodium concentration (81 mEq/L) (Table). Despite the patient's severe hyponatremia, her serum antidiuretic hormone (ADH) level was not decreased (3.3 pg/mL); it was close to the upper limit of the normal range (0.3-4.2 pg/mL). The patient's thyroid, kidney, and adrenal functions were normal. The fact that her blood urea nitrogen (BUN) to creatinine (Cr) ratio was 6.6 and the fact that she did not experience severe diarrhea or vomiting implied that she was clinically euvolemic. Based on these laboratory findings, this patient met the criteria for SIADH, which were as follows: decreased effective osmolality; urinary osmolality, >100 mOsm/kg of water; clinical euvolemia; urinary sodium concentration, >40 mmol/L; and normal thyroid and adrenal functions (2). Chest radiography and computed tomography (CT) showed a wedge-shaped infiltrative shadow with small tree-in-bud satellite lesions in the left upper lobe of the lung (Fig. 1). With the exception of pulmonary tuberculosis, contrast-enhanced CT of the whole body did not reveal any malignant or infectious diseases. Brain magnetic resonance imaging (MRI) revealed no abnormalities and electroencephalograms, which were taken three times, were all normal. A cerebrospinal fluid examination (CSF) showed no increase in the cell count (0 cells/uL) or the total protein level (47 mg/dL), no decrease in the glucose (102 mg/dL), and was culture-negative for tuberculosis and bacteria. Repeated blood cultures were also negative for bacteria. She was not taking any medicines that have previously been reported as a potential cause of SIADH. It was therefore concluded the patient's SIADH was caused by pulmonary tuberculosis. Among the prescribed medications, only isoniazid has the potential to lead to seizures. However, this possibility was excluded due to a lack of complications during re-administration. Accordingly, we concluded that the patient's status epilepticus could be attributed to hyponatremia, which had caused by pulmonary tuberculosis-associated SIADH.\n\nTable. Laboratory Data on Admission.\n\nHematology\tSerology\tEndocrinology\t\nWBC\t15,900\t/uL\tCRP\t0.29\tmg/dL\tTSH\t0.7\tuIU/mL\t\nHb\t14\tg/dL\tPCT\t0.1\tmg/dL\tFT4\t0.92\tpg/mL\t\nHt\t40.6\t%\t\t\t\tACTH\t32.3\tpg/mL\t\nPlt\t25.9×104\t/uL\t\t\t\tCortisol\t21.4\tug/mL\t\n\t\t\tTumor markers\tPAC\t73.4\tpg/mL\t\nBiochemistry\tsIL-2R\t388\tU/mL\tPRA\t1.2\tng/mL/hr\t\nAST\t24\tU/L\tCEA\t1.1\tng/mL\tAd\t63\tpg/mL\t\nALT\t12\tU/L\tSLX\t34\tU/mL\tNA\t527\tpg/mL\t\nCK\t247\tU/L\tProGRP\t26.2\tpg/mL\tADH\t3.3\tpg/mL\t\nBUN\t3\tmg/dL\tKL-6\t155\tU/mL\t\t\t\t\nCr\t0.45\tmg/dL\t\t\t\tUrinalysis\t\nNa\t120\tmEq/L\tBlood Gas Analysis (room air)\tNa\t81\tmEq/L\t\nK\t3.5\tmEq/L\tPH\t7.416\t\t\t\t\t\nCl\t87\tmEq/L\tPaCO2\t30.4\tTorr\tOsmolality\t\t\nVit. B6\t5.8\tug/dL\tPaO2\t73.8\tTorr\tSerum\t253\tmOsm/kg\t\nBS\t164\tmg/dL\tHCO3-\t19.6\tmEq/L\tUrine\t458\tmOsm/kg\t\nPCT: Procalcitonin, PAC: Plasma Aldosterone Concentration, PRA: Plasma Renin Activity, CRP: C-Reactive Protein, sIL-2R: soluble interleukin-2 receptor\n\nFigure 1. A: chest radiography on admission showed mass-like shadow in the left upper lung field. B: CT on admission showed wedge-shaped infiltrative shadow with small tree-in-bud satellite lesions in the left upper lobe.\n\n\nThe patient did not develop seizures after infusion of fosphenytoin sodium hydrate. Her level of consciousness improved after an infusion of saline to treat her abnormal serum sodium concentration, and she became conscious on the second day after admission (Fig. 2). Rhabdomyolysis occurred due to the patient's status epilepticus, and her creatine kinase (CK) levels increased (6,630 IU/L). SIADH did not recur after the patient resumed taking the anti-tuberculosis medicines and she was discharged from the hospital on the 22nd day after admission. The fact that she improved with treatment verified our diagnosis.\n\nFigure 2. \n Clinical Course. INH: isoniazid, RFP: rifampicin, EB: ethambutol, PZA: pyrazinamide, JCS: Japan coma scale, Cons: consciousness, P-Osmo: Plasma osmolality\n\nDiscussion\nSIADH is characterized by the excessive release of ADH, which results in dilutional hyponatremia and an increase in the blood volume. This form of hyponatremia is associated with neurological symptoms such as headaches, confusion, weakness, seizures, and coma (2). The causes of SIADH include, but are not limited to, central nervous system diseases, malignant diseases, drug-induced diseases, and pulmonary diseases. It is estimated that about 2.1% of pulmonary disease-related SIADH cases can be attributed to pulmonary tuberculosis (3).\n\nHyponatremia is commonly associated with tuberculosis. It has been reported that 10.7% of patients with newly diagnosed active pulmonary tuberculosis have hyponatremia (6). Although it is not clear what percentage of hyponatremia cases are associated with SIADH, Nakamata et al. reported that approximately 29% of lung tuberculosis patients had high plasma ADH, suggesting the existence of a potential causal relationship between pulmonary tuberculosis and SIADH (7). ADH is released from the posterior pituitary in response to a decrease in the intravascular volume or an increase in the serum osmolality (8); however the cause of the inappropriate release of ADH in patients with pulmonary tuberculosis is not fully understood.\n\nThere are several possible mechanisms for abnormal ADH levels in patients with tuberculosis. First, although our patient was not suffering from tuberculous meningitis, ADH production may be triggered by cerebral insults, including infections and malignancies, which suggests that non-specific inflammation may stimulate the release of ADH from the posterior pituitary (1,9). Moreover, recent reports have suggested that interleukin-6 (IL-6) has an important role in the release of ADH in response to inflammatory diseases such as pneumonia and tuberculosis (10). Ogawa et al. reported that the monocytes or macrophages of tuberculosis patients showed higher levels of IL-6-production than those of healthy subjects (11). These reports suggest that IL-6 could play important roles in causing hyponatremia in tuberculosis patients. However, our patient's C reactive protein level was only slightly increased, implying that there was low inflammation. Secondly, decreased blood flow in the intrathoracic vessels due to the destruction of the lung by extensive pulmonary tuberculosis can be sensed by the mechanoreceptors in the left ventricle, leading to the non-osmotic release of ADH (12). However, in the present case, the patient's pulmonary tuberculosis was limited. Finally, another intriguing possibility is the direct release of ADH from lungs infected with tuberculosis. Vorherr et al. detected high concentrations of ADH in tuberculous lung tissue, suggesting the production of ADH in the local lung or that the tuberculous lung tissue had adsorbed an inappropriately released hormone from the posterior pituitary (13). Moreover, Lee et al. reported a case of tuberculosis and proven diabetes insipidus in a patient who had an elevated ADH level in the presence of hyponatremia even without using desmopressin, which suggested ectopic ADH production (14). In our case, SIADH occurred two days after the initiation of anti-tuberculosis treatment. The bactericidal property of the medications might have affected the integrity of the tuberculous lung tissue, which may have resulted in the release of ADH. Thus, although it is still not clear whether ADH is produced in tuberculous lung tissue or whether it accumulates there, we hypothesize that the accelerated temporary release of ADH from tuberculous lung tissue due to anti-tuberculosis medications may have caused SIADH in the present case.\n\nSeveral cases of tuberculosis-associated SIADH have been reported in Japan. However, most of the cases were caused by severe lung tuberculosis or tuberculous meningitis and the symptoms were generally mild (5). In contrast, our patient had mild lung tuberculosis complicated with SIADH, which caused serious symptoms such as impaired consciousness and status epilepticus. The manifestations of hyponatremia are more prominent when a patient's serum sodium concentration rapidly decreases (15); we therefore assumed that the severe symptoms in our case occurred due to a rapid decrease in the serum sodium concentration. This rapid decrease in the serum sodium concentration could be explained by a rapid release of ADH. We hypothesize that the accelerated and temporary release of ADH was from the tuberculous lung tissue, and that it was induced by the bactericidal property of the anti-tuberculosis medicines.\n\nWe believe that close observation is required to detect symptoms of SIADH, even in cases of mild lung tuberculosis, especially when a patient begins to take anti-tuberculosis medications.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Esposito P , Piotti G , Bianzina S , et al \nThe syndrome of inappropriate antidiuresis: pathophysiology, clinical management and new therapeutic options . Nephron Clin Pract \n119 : c62 -c73 , 2011 .21677440 \n2. Ellison DH , Berl T \nThe syndrome of inappropriate antidiuresis . N Engl J Med \n356 : 2064 -2072 , 2007 .17507705 \n3. Saito T \nThe syndrome of inappropriate secretion of antidiuretic hormone . J Jpn Soc Int Med \n85 : 1705 -1710 , 1996 .\n4. Minami T , Wakamatsu K , Kumazoe H , et al \nA case of mild lung tuberculosis complicated with the syndrome of inappropriate antidiuretic hormone secretion which caused impaired consciousness . AJRS \n49 : 607 -611 , 2011 .\n5. Nishizawa Y , Yamamori C , Nishimura Y , et al \nA case of lung tuberculosis initially presented with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) . Kekkaku \n78 : 27 -31 , 2003 (in Japanese, Abstract in English).12655703 \n6. Chung DK , Hubbard WW \nHyponatremia in untreated active lung tuberculosis . Am Rev Res Dis \n99 : 595 -597 , 1969 .\n7. Nakamata M , Tsukioka K , Kondo A , Hashimoto T \nPlasma ADH in patients with lung tuberculosis . Kekkaku \n62 : 635 -639 , 1987 (in Japanese).3448347 \n8. Verbalis JG , Goldsmith SR , Greenberg A , Schrier RW , Sterns RH \nHyponatremia treatment guidelines 2007: expert panel recommendations . Am J Med \n120 (11 Suppl 1 ): S1 -S21 , 2007 .17981159 \n9. Park SJ , Shin JI \nInflammation and hyponatremia: an underrecognized condition? \nKorean J Pediatr \n56 : 519 -522 , 2013 .24416046 \n10. Swart RM , Hoorn EJ , Betjes MG , Zietse R \nHyponatremia and inflammation: the emerging role of interleukin-6 in osmoregulation . Nephron Physiol \n118 : 45 -51 , 2011 .21196778 \n11. Ogawa T , Uchida H , Kusumoto Y , Mori Y , Yamamura Y , Hamada S \nIncrease in tumor necrosis factor alpha- and interleukin-6-secreting cells in peripheral blood mononuclear cells from subjects infected with Mycobacterium tuberculosis . Infect Immune \n59 : 3021 -3025 , 1991 .\n12. Reddy P , Mooradian AD \nDiagnosis and management of hyponatraemia in hospitalized patients . Int J Clin Pract \n63 : 1494 -1508 , 2009 .19769706 \n13. Vorherr H , Massry SG , Fallet R , et al \nAntidiuretic principle in tuberculous lung tissue of a patient with lung tuberculosis and hyponatremia . Ann Intern Med \n72 : 383 -387 , 1970 .5415421 \n14. Lee P , Ho KK \nHyponatremia in pulmonary TB: evidence of ectopic antidiuretic hormone production . Chest \n137 : 207 -208 , 2010 .20051406 \n15. Luis CG , Maria DC , Jose MLC , et al \nElectrolytes disturbances and seizures . Epilepsia \n47 : 1990 -1998 , 2006 .17201695\n\n",
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"title": "Mild Lung Tuberculosis in a Patient Suffering from Status Epilepticus Caused by the Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH).",
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"abstract": "Invasive aspergillosis in immunosuppressed people has been well documented, but to diagnose and treat in an immunocompetent individual after near drowning, it requires early suspicion and proper empirical treatment. We report a case diagnosed to have invasive aspergillosis with systemic dissemination of the infection to the brain, gluteal muscles, and kidneys after a fall in a chemical tank of a paper manufacturing company. He was ventilated for acute respiratory distress syndrome and managed with antibiotics and vasopressors. Due to nonresolving pneumonia and positive serum galactomannan, trans-tracheal biopsy was performed which confirmed invasive aspergillosis and was treated with antifungals. With the availability of galactomannan assay and better radiological investigative modalities, occurrence of such invasive fungal infections in cases of drowning patients should be considered early in such patients and treated with appropriate antifungals.",
"affiliations": "Department of Critical Care, Yashoda Hospital, Nampally, Hyderabad, Telangana, India.;Department of Critical Care, Care Hospital, Nampally, Hyderabad, Telangana, India.;Department of Pulmonology, Apollo Health City, Jubilee Hills, Hyderabad, Telangana, India.",
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"fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XMedknow Publications & Media Pvt Ltd India IJCCM-19-73910.4103/0972-5229.171413Case ReportInvasive aspergillosis in near drowning nonneutropenic patient Munta Kartik Gopal Palepu B. N. 1Vigg Ajit 2From: Department of Critical Care, Yashoda Hospital, Nampally, Hyderabad, Telangana, India1 Department of Critical Care, Care Hospital, Nampally, Hyderabad, Telangana, India2 Department of Pulmonology, Apollo Health City, Jubilee Hills, Hyderabad, Telangana, IndiaCorrespondence: Dr. Kartik Munta, Yashoda Hospital, Somajiguda, Hyderabad, Telangana, India. E-mail: kartikmunta@yahoo.com12 2015 19 12 739 742 Copyright: © Indian Journal of Critical Care Medicine2015This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Invasive aspergillosis in immunosuppressed people has been well documented, but to diagnose and treat in an immunocompetent individual after near drowning, it requires early suspicion and proper empirical treatment. We report a case diagnosed to have invasive aspergillosis with systemic dissemination of the infection to the brain, gluteal muscles, and kidneys after a fall in a chemical tank of a paper manufacturing company. He was ventilated for acute respiratory distress syndrome and managed with antibiotics and vasopressors. Due to nonresolving pneumonia and positive serum galactomannan, trans-tracheal biopsy was performed which confirmed invasive aspergillosis and was treated with antifungals. With the availability of galactomannan assay and better radiological investigative modalities, occurrence of such invasive fungal infections in cases of drowning patients should be considered early in such patients and treated with appropriate antifungals.\n\nAcute respiratory distress syndromeinvasive aspergillosisnear drowningvoriconazole\n==== Body\nIntroduction\nInvasive infections by fungi have been described in immunocompetent hosts after submersion and near drowning.[1] Fungi known to cause invasive diseases in cases of near drowning patient are Pseudallescheria boydii and, to a much lesser degree, Aspergillus species.\n\nCase Report\nA 28-year-old male presented to casualty posttreatment at a local hospital from near drowning in a paper factory. He was ventilated there in view of acute respiratory distress syndrome for 5 days. He received ceftriaxone as empiric antibiotic along with other therapies.\n\nThe patient presented with high-grade fever, tachypnea, and oxygen saturation of 87% on 15 L oxygen through a tracheal tube in situ. Lab investigations revealed leukocytosis (17,200/cumm), hemoglobin 11.1 g%, normal electrolytes, and creatinine of 1.8 mg/dl. Endotracheal secretions, blood and urine samples were sent for gram, fungal, acid-fast stain, and cultures. Antibiotic coverage was changed to cefoperazone + sulbactam.\n\nChest X-ray revealed bilateral alveolar shadows and a cystic lesion in the lung parenchyma [Figure 1]. Computed tomography (CT) brain showed multiple ill-defined, round hypodense lesions in bilateral cerebral hemispheres with surrounding edema [Figure 2]. CT chest with contrast [Figure 3] showed multiple, well-defined, round, variable sized nodular lesions scattered in both lungs, with few of them showing central cavitation. CT scan abdomen revealed patchy hypodensities in both kidneys and patchy hypodensities in the gluteal muscles bilaterally. Echocardiography was normal. Bronchoalveolar lavage (BAL) and transbronchial biopsy were performed, and antibiotic for bacterial coverage was escalated to meropenem in view of patient's unstable condition.\n\nFigure 1 Chest X-ray showing alveolar shadows\n\nFigure 2 Computed tomography scan brain with contrast showing lesions\n\nFigure 3 Computed tomography scan chest with contrast showing cavitary lesions\n\nOn the 2nd day of Intensive Care Unit (ICU) admission, all the microbiological laboratory reports were negative, but for serum galactomannan (1.5) they were raised and endotracheal aspirate for fungal stain showed Aspergillus species. Voriconazole and caspofungin combination were started with suspicion of invasive aspergillosis with hemodynamic unstability. The patient meanwhile developed hemoptysis, tachycardia, and desaturation, which were controlled with fresh frozen plasma and tranexamic acid.\n\nThe patient developed septic shock requiring vasopressors and worsening respiratory acidosis with leukopenia (2200/cumm). Transbronchial biopsy report revealed neutrophilic exudates and foci of fungal broad hyphae, broad angle branching [Figure 4]. These features were suggestive of fungal infection due to Aspergillus. BAL specimen on culture revealed Aspergillus fumigatus growth. The patient expired on day 5 of ICU admission due to severe multiorgan organ dysfunction.\n\nFigure 4 Transbronchial biopsy showing branching Aspergillus hyphae\n\nDiscussion\nUnfortunate incidents such as drowning and near drowning can lead to catastrophic outcomes in young and healthy individuals. Aspergillus species have been shown to be present in soil, sewage, and polluted waters.\n\nSigns and symptoms of invasive pulmonary aspergillosis (IPA) are often missed due to low index of suspicion causing delayed additional diagnostic examination. However, if the patient is slow to respond to broad-spectrum antibiotic therapy, develops pneumonia few days to several weeks after the submersion event or develops brain abscess and/or meningitis, a diagnosis of invasive fungal disease should be aggressively pursued. These should include chest CT, direct microscopy, and culture of sputum or BAL sample.\n\nSpecific fluorescent stain of sputum or BAL with chitin is easy, rapid to read, and improves the sensitivity of microbiological examination.[23] Visualization of septate (e.g., Aspergillus, Fusarium, and Scedosporium) and nonseptate (e.g., Mucorales) molds can be made easily on direct microscopic examination.\n\nChest radiological signs include “halo sign,” which is relatively frequent in the early stages and air crescent sign.[45678910] Together these two signs, increase the sensitivity to more than 80% and specificity to 60–98%.[7] Galactomannan is a major Aspergillus cell-wall component released during the growth phase of the fungus.[11] Its specificity in diagnosing IPA is at least 85%, but the sensitivity varied considerably between 29% and 100%. A recent meta-analysis on serum galactomannan showed median sensitivity in proven cases of 71% and specificity of 89%. In probable cases, it was 61% and 93%, respectively.[12] A prospective study in adult allogeneic stem cell transplant recipients demonstrated that positive galactomannan titers preceded fever by 3.5 days, positive chest high-resolution CT by 6 days, positive chest radiograph by 8 days, positive cultures by 9 days, and a definitive diagnosis by 14 days (all values are medians).[13]\n\nCT scan and magnetic resonance imaging brain should be high on priority for near drowning patients with neurological abnormalities with proven/probable cases of aspergillosis due to preferential central nervous system (CNS) localization of this disease, secondary to high vascular tropism. The determination of serum galactomannan, with two positive results, coupled with typical radiological findings, is highly sensitive and specific to support the diagnosis.[14] Extension of invasive aspergillosis to the CNS is associated with an exceedingly high mortality which approaches 100%.[15]\n\nProphylactics antifungals should not be administered in all individuals of near drowning.[1] Amphotericin B deoxycholate had been the standard therapy for IPA. Due to an increasing antifungal resistance and nephrotoxicity of this compound, in particular nephrotoxicity, various studies have tried to find an alternative.[16] In a large multi-center trial, voriconazole provided better survival and lesser drug-related adverse events than amphotericin B in the treatment of “probable or proven” IPA among patients with hematological diseases.[17] Consequently, voriconazole is increasingly recommended as initial therapy for IPA.[18] At present, out of three approved echinocandins, caspofungin has demonstrated efficacy for the treatment of IPA. In general, there is no conclusive evidence that extended-spectrum triazoles are superior to echinocandins or polyenes or vice versa for monotherapy of IPA in ICU patients.\n\nFactors responsible for the fatal course in this particular case could have a higher concentration of Aspergillus inoculum in the pulp extract, lack of early suspicion of invasive aspergillosis along with the injury sustained by the lungs, and hypoxic damage to the blood-brain barrier, which caused proliferation and invasion of Aspergillus in these organs.\n\nConclusion\nNonspecific signs and symptoms, low clinical suspicion, and time delay due to high risks involved in invasive procedures to obtain histopathological evidence for diagnosing IPA are some of the reasons for the lack of timely diagnosis. Persistent pulmonary infection despite broad-spectrum antibiotics should trigger further diagnostic exploration. If galactomannan is not available, endotracheal cultures, CT scan, and lung biopsy must be considered early in the management of non-neutropenia patients with pulmonary involvement due to near drowning.\n\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Ender PT Dolan MJ Pneumonia associated with near-drowning Clin Infect Dis 1997 25 896 907 9356805 \n2 Levy H Horak DA Tegtmeier BR Yokota SB Forman SJ The value of bronchoalveolar lavage and bronchial washings in the diagnosis of invasive pulmonary aspergillosis Respir Med 1992 86 243 8 1620912 \n3 Andreas S Heindl S Wattky C Möller K Rüchel R Diagnosis of pulmonary aspergillosis using optical brighteners Eur Respir J 2000 15 407 11 10706512 \n4 Collins J CT signs and patterns of lung disease Radiol Clin North Am 2001 39 1115 35 11699664 \n5 Greene R The radiological spectrum of pulmonary aspergillosis Med Mycol 2005 43 Suppl 1 S147 54 16110807 \n6 Horger M Einsele H Schumacher U Wehrmann M Hebart H Lengerke C Invasive pulmonary aspergillosis: Frequency and meaning of the “hypodense sign” on unenhanced CT Br J Radiol 2005 78 697 703 16046420 \n7 Kami M Kishi Y Hamaki T Kawabata M Kashima T Masumoto T The value of the chest computed tomography halo sign in the diagnosis of invasive pulmonary aspergillosis. An autopsy-based retrospective study of 48 patients Mycoses 2002 45 287 94 12572717 \n8 Lee YR Choi YW Lee KJ Jeon SC Park CK Heo JN CT halo sign: The spectrum of pulmonary diseases Br J Radiol 2005 78 862 5 16110114 \n9 Pasmans HL Loosveld OJ Schouten HC Thunnissen F van Engelshoven JM Invasive aspergillosis in immunocompromised patients: Findings on plain film and (HR)CT Eur J Radiol 1992 14 37 40 1563402 \n10 Won HJ Lee KS Cheon JE Hwang JH Kim TS Lee HG Invasive pulmonary aspergillosis: Prediction at thin-section CT in patients with neutropenia - A prospective study Radiology 1998 208 777 82 9722859 \n11 Maertens J Verhaegen J Lagrou K Van EJ Boogaerts M Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: A prospective validation Blood 2001 97 1604 10 11238098 \n12 Pfeiffer CD Fine JP Safdar N Diagnosis of invasive aspergillosis using a galactomannan assay: A meta-analysis Clin Infect Dis 2006 42 1417 27 16619154 \n13 Maertens J Van Eldere J Verhaegen J Verbeken E Verschakelen J Boogaerts M Use of circulating galactomannan screening for early diagnosis of invasive aspergillosis in allogeneic stem cell transplant recipients J Infect Dis 2002 186 1297 306 12402199 \n14 Denning DW Early diagnosis of invasive aspergillosis Lancet 2000 355 423 4 10841117 \n15 Schwartz S Theil E CNS aspergillosis: Are there new treatment options? Mycoses 2003 46 8 14 15055138 \n16 Imhof A Walter RB Schaffner A Continuous infusion of escalated doses of amphotericin B deoxycholate: An open-label observational study Clin Infect Dis 2003 36 943 51 12684904 \n17 Herbrecht R Denning DW Patterson TF Bennett JE Greene RE Oestmann JW Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis N Engl J Med 2002 347 408 15 12167683 \n18 Böhme A Ruhnke M Buchheidt D Karthaus M Einsele H Guth S Treatment of fungal infections in hematology and oncology - Guidelines of the Infectious diseases working party (AGIHO) of the German society of hematology and oncology (DGHO) Ann Hematol 2003 82 Suppl 2 S133 40 13680170\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0972-5229",
"issue": "19(12)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Acute respiratory distress syndrome; invasive aspergillosis; near drowning; voriconazole",
"medline_ta": "Indian J Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "101208863",
"other_id": null,
"pages": "739-42",
"pmc": null,
"pmid": "26816451",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports",
"references": "10841117;16046420;16110114;16110807;9722859;13680170;15055138;11238098;1563402;16619154;10706512;12402199;12167683;11699664;9356805;1620912;12572717;12684904",
"title": "Invasive aspergillosis in near drowning nonneutropenic patient.",
"title_normalized": "invasive aspergillosis in near drowning nonneutropenic patient"
} | [
{
"companynumb": "IN-PFIZER INC-2020149760",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Vilazodone hydrochloride is the first member in a new class of antidepressants called indolealkylamines and was approved for use in the United States in 2011 for major depressive disorder. It has a combined mechanism of action of a selective serotonin reuptake inhibitor and a partial agonist of serotonin 5-HT1A receptors. It has not been approved for use in the pediatric population, and toxicity from exploratory vilazodone ingestion has been rarely described to date. We describe 2 children with laboratory-confirmed vilazodone ingestions that led to significant toxicity including refractory status epilepticus in 1 patient and likely transient seizure activity in the other. Both patients required multiple doses of benzodiazepines; in the more severe case, barbiturates were added to control seizure activity. These children returned to baseline and had no prolonged neurologic complications. Pediatric experience with vilazodone is limited; however, the literature demonstrates 3 additional case reports of children experiencing seizure after vilazodone ingestion. With the 2 new cases presented here, it seems prudent to educate prescribers and families of the potential dangers of ingestion of vilazodone tablets by young children.",
"affiliations": null,
"authors": "Del Pizzo|Jeannine|J|;Fernandez|Elon K|EK|;Kopec|Kathryn T|KT|;Wenger|Jesse|J|;Noyes|Erin M|EM|;Salzman|Matthew|M|;Henretig|Fred M|FM|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D001569:Benzodiazepines; D000069503:Vilazodone Hydrochloride",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000001174",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "34(3)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D001569:Benzodiazepines; D002675:Child, Preschool; D004636:Emergency Service, Hospital; D006801:Humans; D008297:Male; D012640:Seizures; D017367:Serotonin Uptake Inhibitors; D000069503:Vilazodone Hydrochloride",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "e51-e54",
"pmc": null,
"pmid": "28590988",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Seizures After Pediatric Vilazodone Ingestion: A Case Series.",
"title_normalized": "seizures after pediatric vilazodone ingestion a case series"
} | [
{
"companynumb": "US-OTSUKA-2018_012980",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Sub arachnoid block (SAB) is often perceived safe by many anesthesiologists and other faculties but is also not completely safe choice especially in pregnant females, as the incidence of complications and local anaesthetic agent toxicity is high in these groups of patients. Here we present four such cases out of the seventeen patients over a period of six months, who developed apnea and transient loss of consciousness after spinal anesthesia for lower segment caesarean section. Typically all these patients after spinal anesthesia developed difficulty in breathing, became apnoea and had loss of consciousness for about a minute or two. The apnea was relieved with bag and mask ventilation following which the patient regained consciousness and start breathing normally. The rest of the procedure was uneventful. We presented these cases with aim of sharing similar experiences, and to aware about the possibility of such events as these events do occur frequently but case reports and literatures are unavailable.",
"affiliations": "Department of Anesthesiology, Institute of Medicine, Maharajgunj, Nepal. drsuvash@gmail.com",
"authors": "Acharya|S P|SP|;Marhatta|M N|MN|;Amatya|R|R|",
"chemical_list": null,
"country": "Nepal",
"delete": false,
"doi": "10.3126/kumj.v7i4.2766",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1812-2027",
"issue": "7(28)",
"journal": "Kathmandu University medical journal (KUMJ)",
"keywords": null,
"medline_ta": "Kathmandu Univ Med J (KUMJ)",
"mesh_terms": "D000328:Adult; D001049:Apnea; D001340:Autonomic Nerve Block; D002585:Cesarean Section; D005260:Female; D006801:Humans; D011247:Pregnancy; D020127:Recovery of Function; D018570:Risk Assessment; D012494:Sampling Studies; D016896:Treatment Outcome; D014474:Unconsciousness; D055815:Young Adult",
"nlm_unique_id": "101215359",
"other_id": null,
"pages": "419-22",
"pmc": null,
"pmid": "20502086",
"pubdate": "2009",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Unexplained apnoea and loss of consciousness during sub arachnoid block for caesarean section.",
"title_normalized": "unexplained apnoea and loss of consciousness during sub arachnoid block for caesarean section"
} | [
{
"companynumb": "NP-FRESENIUS KABI-FK202104476",
"fulfillexpeditecriteria": "1",
"occurcountry": "NP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CALCIUM CHLORIDE\\POTASSIUM CHLORIDE\\SODIUM LACTATE"
... |
{
"abstract": "Levodopa-carbidopa intestinal gel (LCIG) has shown to be efficacious in motor and non-motor symptoms (NMS). Nevertheless, studies with patient Quality of Life (QoL) as a primary endpoint are scarce. To assess the effect of LCIG on Advanced Parkinson's Disease (APD) patients QoL. Secondarily, the impact on motor symptoms and NMS, emotional well-being, treatment satisfaction, and caregiver QoL, stress, disease burden, anxiety, depression, and work impairment were also investigated. In this prospective, 6-month multicenter postmarketing observational study, LCIG was administered to 59 patients with APD. Endpoints were assessed using validated scales and questionnaires. LCIG significantly improved patient QoL (PDQ-39 mean change ± standard deviation from baseline, -12.8 ± 14.6; P < 0.0001), motor symptoms (UPDRS-III in \"On,\" -6.5 ± 11.8; P = 0.0002), NMS (NMSS, -35.7 ± 31.1; P < 0.0001), mood (Norris/Bond-Lader VAS, -6.6 ± 21.1; P = 0.0297), fatigue (PFS-16, -0.6 ± 1.0; P = 0.0003), depression (BDI-II, -5.1 ± 9.4; P = 0.0002), anxiety (BAI, -6.2 ± 9.6; P < 0.0001), and patient treatment satisfaction (SATMED-Q, 16.1 ± 16.8; P < 0.0001). There were significant correlations between the change from baseline to 6 months between PDQ-39 and UPDRS-IV, NMSS, BAI, BDI-II, AS, and PFS-16 scores, and Norris/Bond-Lader alertness/sedation factor. Caregiver anxiety also improved (Goldberg anxiety scale, -1.1 ± 1.0; P = 0.0234), but the clinical relevance of this finding is questionable. The serious adverse events reported were similar to those previously described for LCIG. In patients with APD, LCIG improves QoL, motor symptoms and NMS, emotional well-being, and satisfaction with the treatment. Improvement in patient QoL is associated with improvements in motor complications, NMS, anxiety, depression, apathy and fatigue. Improvements in patients' QoL does not correspond with improvements in caregivers' QoL or burden.",
"affiliations": "Movement Disorders Unit, Neurology Service, Clínic Hospital, 170, Villarroel St., 08036, Barcelona, Spain. fvallde@clinic.cat.;Neurology Service, Clínico San Carlos Hospital, Profesor Martín Lagos St., 28040, Madrid, Spain.;Movement Disorders Unit. Neurology Service, Virgen de las Nieves University Hospital, \"Biohealth Investigation Institute. Ibs, Granada, Spain.;Neurology Service, Elche University General Hospital, 11, Camino Almazara St., 03203, Elche, Alicante, Spain.;Neurology Service, Torrecárdenas Hospital Center, Hermandad de Donantes de Sangre St., 04009, Almería, Spain.;Neurology Service, Burgos University Hospital, 3, Islas Baleares Av., 09006, Burgos, Spain.;Department of Neurology, A Coruña University Hospital Center (CHUAC), A Coruña, Spain.;Neurology Service, Bellvitge University Hospital, Feixa Llarga St., 08907L'Hospitalet de Llobregat, Barcelona, Spain.;National Center of Epidemiology and Center for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Carlos III Institute of Health, 5, Monforte de Lemos Av., 28029, Madrid, Spain.;AbbVie Spain, S.L.U., 91, De Burgos Av., 28050, Madrid, Spain.;AbbVie Spain, S.L.U., 91, De Burgos Av., 28050, Madrid, Spain.;Neurology Service, Insular of Gran Canaria University Hospital, Marítima del Sur Av., 35016, Las Palmas, de Gran Canaria, Spain.",
"authors": "Valldeoriola|Francesc|F|http://orcid.org/0000-0002-8680-4274;Catalán|María José|MJ|;Escamilla-Sevilla|Francisco|F|http://orcid.org/0000-0003-2149-2668;Freire|Eric|E|;Olivares|Jesús|J|;Cubo|Esther|E|;García|Diego Santos|DS|http://orcid.org/0000-0002-3126-5111;Calopa|Matilde|M|;Martínez-Martín|Pablo|P|;Parra|Juan Carlos|JC|;Arroyo|Gloria|G|;Arbelo|José Matías|JM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1038/s41531-021-00246-y",
"fulltext": "\n==== Front\nNPJ Parkinsons Dis\nNPJ Parkinsons Dis\nNPJ Parkinson's Disease\n2373-8057\nNature Publishing Group UK London\n\n246\n10.1038/s41531-021-00246-y\nArticle\nPatient and caregiver outcomes with levodopa-carbidopa intestinal gel in advanced Parkinson’s disease\nhttp://orcid.org/0000-0002-8680-4274\nValldeoriola Francesc fvallde@clinic.cat\n\n1\nCatalán María José 2\nhttp://orcid.org/0000-0003-2149-2668\nEscamilla-Sevilla Francisco 3\nFreire Eric 4\nOlivares Jesús 5\nCubo Esther 6\nhttp://orcid.org/0000-0002-3126-5111\nGarcía Diego Santos 7\nCalopa Matilde 8\nMartínez-Martín Pablo 9\nParra Juan Carlos 10\nArroyo Gloria 10\nArbelo José Matías 11\n1 Movement Disorders Unit, Neurology Service, Clínic Hospital, 170, Villarroel St., 08036 Barcelona, Spain\n2 Neurology Service, Clínico San Carlos Hospital, Profesor Martín Lagos St., 28040 Madrid, Spain\n3 grid.411380.f 0000 0000 8771 3783 Movement Disorders Unit. Neurology Service, Virgen de las Nieves University Hospital, “Biohealth Investigation Institute. Ibs, Granada, Spain\n4 grid.411089.5 0000 0004 1768 5165 Neurology Service, Elche University General Hospital, 11, Camino Almazara St., 03203 Elche, Alicante Spain\n5 grid.413486.c 0000 0000 9832 1443 Neurology Service, Torrecárdenas Hospital Center, Hermandad de Donantes de Sangre St., 04009 Almería, Spain\n6 grid.23520.36 0000 0000 8569 1592 Neurology Service, Burgos University Hospital, 3, Islas Baleares Av., 09006 Burgos, Spain\n7 grid.411066.4 0000 0004 1771 0279 Department of Neurology, A Coruña University Hospital Center (CHUAC), A Coruña, Spain\n8 grid.411129.e 0000 0000 8836 0780 Neurology Service, Bellvitge University Hospital, Feixa Llarga St., 08907L’Hospitalet de Llobregat, Barcelona, Spain\n9 grid.413448.e 0000 0000 9314 1427 National Center of Epidemiology and Center for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Carlos III Institute of Health, 5, Monforte de Lemos Av., 28029 Madrid, Spain\n10 AbbVie Spain, S.L.U., 91, De Burgos Av., 28050 Madrid, Spain\n11 Neurology Service, Insular of Gran Canaria University Hospital, Marítima del Sur Av., 35016 Las Palmas, de Gran Canaria Spain\n30 11 2021\n30 11 2021\n2021\n7 1087 4 2020\n7 6 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.\nLevodopa-carbidopa intestinal gel (LCIG) has shown to be efficacious in motor and non-motor symptoms (NMS). Nevertheless, studies with patient Quality of Life (QoL) as a primary endpoint are scarce. To assess the effect of LCIG on Advanced Parkinson’s Disease (APD) patients QoL. Secondarily, the impact on motor symptoms and NMS, emotional well-being, treatment satisfaction, and caregiver QoL, stress, disease burden, anxiety, depression, and work impairment were also investigated. In this prospective, 6-month multicenter postmarketing observational study, LCIG was administered to 59 patients with APD. Endpoints were assessed using validated scales and questionnaires. LCIG significantly improved patient QoL (PDQ-39 mean change ± standard deviation from baseline, −12.8 ± 14.6; P < 0.0001), motor symptoms (UPDRS-III in “On,” −6.5 ± 11.8; P = 0.0002), NMS (NMSS, −35.7 ± 31.1; P < 0.0001), mood (Norris/Bond-Lader VAS, −6.6 ± 21.1; P = 0.0297), fatigue (PFS-16, −0.6 ± 1.0; P = 0.0003), depression (BDI-II, −5.1 ± 9.4; P = 0.0002), anxiety (BAI, −6.2 ± 9.6; P < 0.0001), and patient treatment satisfaction (SATMED-Q, 16.1 ± 16.8; P < 0.0001). There were significant correlations between the change from baseline to 6 months between PDQ-39 and UPDRS-IV, NMSS, BAI, BDI-II, AS, and PFS-16 scores, and Norris/Bond-Lader alertness/sedation factor. Caregiver anxiety also improved (Goldberg anxiety scale, −1.1 ± 1.0; P = 0.0234), but the clinical relevance of this finding is questionable. The serious adverse events reported were similar to those previously described for LCIG. In patients with APD, LCIG improves QoL, motor symptoms and NMS, emotional well-being, and satisfaction with the treatment. Improvement in patient QoL is associated with improvements in motor complications, NMS, anxiety, depression, apathy and fatigue. Improvements in patients’ QoL does not correspond with improvements in caregivers’ QoL or burden.\n\nSubject terms\n\nParkinson's disease\nOutcomes research\nhttps://doi.org/10.13039/100006483 AbbVie (AbbVie Inc.) issue-copyright-statement© The Author(s) 2021\n==== Body\npmcIntroduction\n\nParkinson disease (PD) is characterized not only by the presence of “classical” motor symptomatology, but also by multiple non-motor symptoms (NMS) of different nature, which cause disability and impact quality of life (QoL), especially in the advanced stage of the disease1. At this stage, when oral medication no longer controls motor fluctuations but patients still respond to levodopa, three device-aided therapies (DATs) may be considered: deep brain stimulation (DBS), levodopa-carbidopa intestinal gel (LCIG) or apomorphine injection and infusion. LCIG and DBS have shown to improve patient’s QoL in clinical trials2,3, but no apomorphine that failed to show this effect in a placebo-controlled study4. LCIG is a valid option for most patients who are considered for DBS and for many of the patients for whom DBS is contraindicated. However, all 3 DATs have demonstrated significant improvements in motor fluctuations2–4. So, in the absence of randomized controlled clinical trials among them, the best available evidence (efficacy, contraindications and possible adverse reactions) should be combined with the professional’s expertise and the patient’s preferences to make a decision.\n\nHealth-related QoL is a patient-reported outcome considered to be a key measure of patient global status1, and should be the main purpose of any PD symptomatic treatment. Disease-specific instruments, such as the 39-item Parkinson’s Disease Questionnaire (PDQ-39)5, are valuable in assessing disease-specific problems and measuring the success of treatment in altering QoL over time6. The PDQ-39 has been shown to be feasible, reliable, valid, and responsive to change in patients with PD.\n\nLCIG has demonstrated benefits controlling motor fluctuations and NMS in patients with advanced PD (APD) in randomized, controlled, clinical trials2,7 and observational studies8–19. QoL has been assessed in some of them2,8,10–19 as a secondary objective, showing significant improvements; however, data on the impact of LCIG on patient’s mood and behavior are scarce. In addition, in most of the studies the questionnaire used was the PDQ-88,10,12,14,15,17. PDQ-8 is a short form of the PDQ-39 and, although it has been validated, it has the disadvantage that it does not offer the possibility to assess individual domains but just a simplified index and, for this reason, PDQ-8 is more convenient for using in clinical settings rather than in clinical research.\n\nWe conducted this study to assess, the effect of 6-month treatment with LCIG on the QoL of patients with APD using the self-reported PDQ-39. Additionally, we assessed patient’s NMS related to emotional well-being and satisfaction with treatment, as well as caregiver QoL, burden, and other symptoms/aspects related with his/her role as caregivers of a patient with APD. We hypothesized that LCIG will significantly improve the patient’s QoL, and this improvement will correlate with the improvements in motor and non-motor symptoms, and patient’s emotional well-being, as well as in the caregiver QoL.\n\nResults\n\nBaseline characteristics\n\nSixty-two patients and caregivers from 23 Spanish centers were enrolled; 59 were evaluable and constituted the intent-to-treat and safety populations. Three patients were non-evaluable because they did not reach the nasoduodenal test phase.\n\nThe mean age of patients was 67.9 ± 7.5 years and 61.0% were male; the mean age of caregivers was 58.8 ± 11.7 years and 64.4% were female. The clinical and sociodemographic characteristics of patients and caregivers are shown in Tables 1 and 2, respectively.Table 1 Clinical and socio-demographic characteristics of the patients, at baseline.\n\nBaseline characteristics\t\nAge, years (mean ± SD)\t67.9 ± 7.5\t\nSex male, n (%)\t36 (61.0)\t\nRace Caucasian, n (%)\t59 (100)\t\nMarital status, n (%)\t\t\nSingle\t2 (3.4)\t\nMarried/Couple’s relationship\t45 (76.3)\t\nSeparated/Divorced\t5 (8.5)\t\nWidower/Widow\t7 (11.9)\t\nHighest level of education, n (%)\t\nNone\t12 (22)\t\nPrimary school\t34 (57.6)\t\nSecondary school\t3 (5.1)\t\nVocational education\t3 (5.1)\t\nUniversity\t6 (10.2)\t\nDuration of the disease, years (mean ± SD)\t12.7 ± 6.0\t\nUPDRS-IV (mean ± SD)\t3.6 ± 2.0\t\nHoehn & Yahr during “On”, n (%)\t\nStage 1\t27 (45.7)\t\nStage 2\t25 (42.4)\t\nStage 3\t6 (10.2)\t\nStage 4\t1 (1.7)\t\nHoehn & Yahr during “Off”, n (%)\t\nStage 1\t1 (1.7)\t\nStage 2\t8 (13.6)\t\nStage 3\t35 (59.3)\t\nStage 4\t15 (25.4)\t\nSchawb&England ADL during “On” (mean ± SD)\t70.3 ± 23.1\t\nSchawb&England ADL during “Off” (mean ± SD)\t31.0 ± 18.6\t\nPDQ-39 (mean ± SD)\t46.7 ± 13.6\t\nUPDRS-III during “On” (mean ± SD)\t30.1 ± 14.2\t\nOff-time, h per day (mean ± SD)\t5.8 ± 3.0\t\nOn-time with dyskinesias, h per day (mean ± SD)\t4.6 ± 4.8\t\nNMSS (mean ± SD)\t83.2 ± 32.6\t\nNorris/Bond-Lader VAS (mean ± SD)\t42.6 ± 17.6\t\nPFS-16 (mean ± SD)\t3.7 ± 0.8\t\nAS (mean ± SD)\t11.4 ± 6.4\t\nBDI-II (mean ± SD)\t18.1 ± 9.7\t\nBAI (mean ± SD)\t19.8 ± 9.4\t\nSATMED-Q (mean ± SD)\t52.8 ± 15.7\t\nDaily levodopa dosea, mg (mean ± SD)\t1099.0 ± 538.2\t\nPrior antiparkinsonian medication use, n (%)\t\nDopamine agonist\t59 (100)\t\nCOMT inhibitor\t7 (11.9)\t\nMAO-B inhibitor\t24 (40.7)\t\nAmantadine\t12 (20.3)\t\nOther\t13 (22.0)\t\naIncludes levodopa dose and levodopa equivalent daily dose of concomitant antiparkinsonian medications. ADL Activity of Daily Living, AS Apathy Scale, BAI Beck Anxiety Inventory, BDI Beck Depression Inventory, COMT Catechol-O-methyl transferase, MAO-B Monoamine oxidase B, NMSS Non-Motor Symptom Scale, PDQ-39 Parkinson’s Disease Questionnaire 39-item, PFS-16 Parkinson’s Fatigue Scale 16-item, SATMED-Q Satisfaction with the Medication Questionnaire, UPDRS Unified Parkinson’s Disease Rating Scale (part III, motor examination; part IV, motor complications), VAS Visual Analogue Scale.\n\nTable 2 Baseline sociodemographic characteristics of caregivers and global scores of SQLC, ZBI, CSI, Goldberg Anxiety Scale, Goldberg Depression Scale, and WPAI.\n\nBaseline characteristics\t\nAge, years*(mean ± SD)\t58.8 ± 11.7\t\nSex (female), n (%)\t38 (64.4)\t\nRace (Caucasian),* n (%)\t54 (91.5)\t\nMarital status, n (%)\t–\t\nSingle\t4 (6.8)\t\nMarried/couple’s relationship\t46 (78.0)\t\nSeparated/divorced\t3 (5.1)\t\nWidower/widow\t1 (1.7)\t\nMissing\t5 (8.5)\t\nHighest level of education, n (%)\t\nNone\t5 (8.5)\t\nPrimary school\t23 (39.0)\t\nSecondary school\t9 (15.2)\t\nVocational education\t5 (8.5)\t\nUniversity\t12 (20.3)\t\nMissing\t5 (8.5)\t\nEmployment status, n (%)\t\nNever worked\t6 (10.2)\t\nEmployed\t13 (22.0)\t\nUnemployed\t6 (10.2)\t\nRetired\t16 (27.1)\t\nOn sick leave\t3 (5.1)\t\nAnother situation\t10 (16.9)\t\nMissing\t5 (8.5)\t\nFull time care,*n (%)\t25 (42.4)\t\nSQLC* (mean ± SD)\t63.6 ± 26.4\t\nZBI* (mean ± SD)\t24.9 ± 13.5\t\nCSI* (mean ± SD)\t5.0 ± 3.3\t\nGoldberg Anxiety Scale** (mean ± SD)\t7.2 ± 1.3\t\nGoldberg Depression Scale*** (mean ± SD)\t5.7 ± 1.9\t\nWPAI\t\n• Outcome score 1 (mean ± SD)\t12.0 ± 27.5\t\n• Outcome score 2 (mean ± SD)\t26.4 ± 28.2\t\n• Outcome score 3 (mean ± SD)\t36.1 ± 33.9\t\n• Outcome score 4 (mean ± SD)\t25.6 ± 25.3\t\nMissing subjects *n = 5; **n = 31; ***n = 34.\n\nAPD advanced Parkinson’s disease, CSI Caregiver Strain Index, SQLC Scales of Quality of Life for Caregivers, WPAI Work Productivity and Activity Impairment (assessed in 16 caregivers that were employed during the study; Outcome 1: percent work time missed due to APD; Outcome 2: percent impairment while working due to APD; Outcome 3: percent overall work impairment due to APD; and Outcome 4: percent activity impairment due to APD), ZBI Zarit Burden Inventory.\n\nChanges from baseline to last visit\n\nThe mean dose of LCIG administered to the patients increased from 75.52 ± 94.24 mL, at hospital discharge (after LCIG dose titration), to 84.45 ± 70.73 mL at the final visit, corresponding to 1510.33 ± 1,884.73 mg and 1689.00 ± 1,414.62 mg of levodopa, respectively. The mean LEDD increased from baseline (1099.04 ± 538.16 mg) to the final visit (1861.43 ± 1389.97 mg; P < 0.0002), the dopamine agonists LEDD gradually reduced from 225.18 ± 125.20 mg at baseline to 125.00 ± 77.01 mg at the final visit (P < 0.0001), and the rest of the antiparkinsonian drugs remain constant throughout the study.\n\nPatients´ QoL, represented by the PDQ-39 Summary Index as a whole, significantly improved throughout the study (Figs. 1 and 2). Changes were also statistically significant in all PDQ-39 domains, except in the “social support” domain.Fig. 1 PDQ-39, 39-item Parkinson’s Disease Questionnaire.\n\nA Summary index. B Domain scores. White bars: data at baseline, black bars: data at final visit. P values for PDQ-39 score comparison between final visit and baseline. Values are given as mean ± SD.\n\nFig. 2 PDQ-39 summary index evolution from baseline to final visit.\n\nViolin plots representing the frequency and box plots representing the interquartile range containing 50% of the data, the median and the 95% confidence interval.\n\nCompared with baseline scores, motor symptoms (UPDRS III) and motor complications (UPDRS IV) were also significantly improved throughout the study visits. The mean daily hours of “Off” time were reduced from 5.78 ± 3.00 to 2.34 ± 2.84 at the final visit (P < 0.0001). The mean total daily “On” time with dyskinesia decreased from 4.6 ± 4.8 at baseline to 3.5 ± 4.0 at the final visit although this reduction didn’t reach the statistical significance level (P = 0.077). The mean UPDRS-IV score was reduced from 3.58 ± 1.97 to 1.47 ± 1.31 at the final visit (P < 0.0001). There were no statistical differences in activities of daily living (ADL) assessed using the S&E scale in the “On” state (from 70.3 ± 23.1 to 75.5 ± 18.2; P = 0.29). NMS improved after 6 months of treatment with LCIG. Changes in NMSS scores, both total score and all domain scores, were significantly improved from baseline to the final visit (difference, 35.75 ± 31.12, P < 0.0001; percentage relative change, 41.41 ± 34.22, P < 0.0001; Figs. 3 and 4). Sleep/fatigue and gastrointestinal domains were the most improved domains (percentage relative change, 51.51 ± 39.52 and 34.01 ± 62.90, respectively).Fig. 3 NMSS, Nonmotor symptom scale.\n\nA Total score. B Domain scores. White bars: data at baseline, black bars: data at final visit. P-values for NMSS score comparison between final visit and baseline. Values are given as mean ± SD.\n\nFig. 4 NMSS total score evolution from baseline to final visit.\n\nViolin plots representing the frequency and box plots representing the interquartile range containing 50% of the data, the median and the 95% confidence interval.\n\nAt the end of the study, patients had a statistically significant positive change in mood. When the Norris/Bond-Lader factors were analyzed, there was a statistically significant improvement in alertness/sedation and calmness/relaxation, with mean scores changing from 44.8 ± 19.7 to 37.7 ± 17.3 (P = 0.028) and from 53.9 ± 23.2 to 45.2 ± 23.6 (P = 0.005), respectively. The improvement observed in the content/discontent factor (from 34.2 ± 18.5 to 30.9 ± 17.8) was not significant (P = 0.27). By contrast, no significant differences were observed in caregivers’ outcomes, except for anxiety.\n\nTable 3 shows the mean changes observed in all primary and secondary endpoints. The comparisons of primary and secondary variables per visits (mixed model) were not statistically significant.Table 3 Mean change ± SD from baseline to final visit (6 months ± 15 days) in the primary and secondary study endpoints (final score—baseline score).\n\nPrimary variable\tn\tBaseline\tn\tFinal\tn\tRelative change (%)\tP value\tEffect size (CI 95%)\t\nPDQ-39\t58\t46.7 ± 13.6\t53\t33.7 ± 16.9\t52\t−27.3 ± 30.6\t<0.0001\t0.87 (0.55,1.19)\t\nSecondary variables (patients)\t\t\t\t\t\t\t\t\t\nUPDRS-III (ON)\t59\t30.1 ± 14.2\t53\t22.9 ± 11.6\t53\t−22.7 ± 23.6\t0.0002\t0.55 (0.26,0.84)\t\nNMSS total\t59\t83.2 ± 32.6\t52\t48.1 ± 29.8\t52\t−41.4 ± 34.2\t<0.0001\t1.15 (0.79,1.50)\t\nVAS Norris/Bond-Lader total\t57\t42.6 ± 17.6\t53\t36.6 ± 16.6\t51\t−12.9 ± 17.1\t0.0297\t0.31 (0.03,0.59)\t\nPFS-16\t57\t3.77 ± 0.77\t53\t3.11 ± 0.90\t51\t−12.7 ± 17.7\t0.0003\t0.55 (0.25,0.84)\t\nAS\t58\t11.4 ± 6.40\t53\t12.3 ± 6.52\t52\t0.5 ± 6.9\t0.5877\t−0.08 (−0.20,0.35)\t\nBDI-II\t58\t18.1 ± 9.75\t53\t13.2 ± 10.2\t52\t−31.3 ± 32.7\t0.0002\t0.55 (0.25,0.84)\t\nBAI\t58\t19.8 ± 9.36\t53\t13.8 ± 10.1\t52\t−26.9 ± 27.1\t<0.0001\t0.65 (0.35,0.95)\t\nSATMED-Q\t58\t52.8 ± 15.7\t53\t68.9 ± 11.9\t52\t26.3 ± 16.8\t<0.0001\t−0.96 (−0.63, −1.29)\t\nSecondary variables (caregivers)\t\t\t\t\t\t\t\t\t\nSQLC total\t54\t63.6 ± 26.4\t48\t66.1 ± 28.7\t47\t1.7 ± 1.6\t0.3126\t−0.15 (−0.44,0.14)\t\nZBI\t54\t24.9 ± 13.6\t48\t24.4 ± 14.3\t47\t−0.4 ± 8.7\t0.8321\t0.03 (−0.26,0.32)\t\nCSI\t54\t5.02 ± 3.33\t48\t4.46 ± 3.25\t47\t−4.2 ± 9.0\t0.1945\t0.20 (−0.14,0.38)\t\nGoldberg depression scale\t25\t5.68 ± 1.95\t13\t6.00 ± 1.41\t10\t2.2 ± 2.3\t0.7937\t–\t\nGoldberg anxiety scale\t28\t7.18 ± 1.33\t15\t6.40 ± 1.24\t10\t−12.9 ± 12.8\t0.0234\t–\t\nWPAI\t\t\t\t\t\t\t\t\t\nOutcome score 1 (mean ± SD)\t16\t12.0 ± 27.5\t10\t10.6 ± 14.0\t9\t−1.4 ± 0.7\t0.5222\t–\t\nOutcome score 2 (mean ± SD)\t16\t26.4 ± 28.2\t10\t15.4 ± 18.1\t9\t−10.8 ± 12.4\t1.0000\t–\t\nOutcome score 3 (mean ± SD)\t16\t36.1 ± 33.9\t10\t25.4 ± 21.8\t9\t−10.7 ± 12.3\t0.6481\t–\t\nOutcome score 4 (mean ± SD)\t16\t25.6 ± 25.3\t10\t24.0 ± 17.1\t9\t−1.6 ± 2.9\t0.6741\t–\t\nUPDRS Unified Parkinson’s Disease Rating Scale (part III, motor examination), ADL Activity of Daily Living, PDQ-39 Parkinson’s Disease Questionnaire 39-item, NMSS Nonmotor Symptom Scale, VAS Visual Analogue Scale, PFS-16 Parkinson’s Fatigue Scale 16-item, AS Apathy Scale, BDI Beck Depression Inventory, BAI Beck Anxiety Inventory, SATMED-Q Satisfaction with the Medication Questionnaire, SQLC Scales of Quality of Life for Caregivers, ZBI Zarit Burden Inventory, CSI Caregiver Strain Index, WPAI Work Productivity And Activity Impairment (Outcome 1: percent work time missed due to APD; Outcome 2: percent impairment while working due to APD; Outcome 3: percent overall work impairment due to APD; and Outcome 4: percent activity impairment due to APD).\n\nDue to the low number of valid data, the effect size of some of the scales/questionnaires haven’t been calculated.\n\nAt baseline, 27.1% of patients (16/59) were also receiving concomitant treatments for PD-related symptoms, including anxiety (n = 14), depression (n = 12), insomnia (n = 6), psychosis (n = 5), constipation (n = 5), or pain (n = 4). At the end of the study, half of these patients discontinued ≥1 concomitant treatment. In general, there was a reduction in all concomitant medications decreasing in a 19.0, 18.5, 16.7, 14.3, and 12.5 in anxiolytic, antidepressant, antipsychotic, insomnia, and constipation drug uses, respectively. No pain treatments were discontinued during the study.\n\nCorrelations related with Quality of Life improvements\n\nSignificant correlations were observed between improvement in patient QoL and improvements in motor complications, NMS, anxiety, depression, apathy, fatigue, and the Norris/Bond-Lader alertness/sedation factor. After consideration of multicollinearity of possible independent predictors, a multivariate regression analysis showed that the variables that had the highest contributions to the model were PFS-16, NMSS, and SQLC (adjusted R2 = 0.43, F = 9.41, P < 0.001) (Table 4).Table 4 Multivariate analysis with PDQ-39 as dependent variable and the most relevant predictor variables as independent variables.\n\nVariable\twith Variable\tCoefficient\tStandard Error\tP value\t\nPDQ-39\tNMSS total\t0.17\t0.06\t0.0072\t\nPDQ-39\tPFS-16\t4.91\t1.96\t0.0166\t\nPDQ-39\tBDI-II\t0.21\t0.24\t0.3911\t\nPDQ-39\tSQCL\t−0.21\t0.24\t0.0148\t\nPDQ-39 Parkinson’s Disease Questionnaire 39-item, NMSS Nonmotor symptom scale, PFS-16 Parkinson’s fatigue scale 16-item, BDI-II Beck depression inventory-II, SQCL Scale of Quality of Life of Caregivers.\n\nSafety data\n\nOverall, 13 patients reported 18 SAEs. Three were reported in the nasoduodenal phase of study; of these SAEs, only 1 (pneumoperitoneum) was related to LCIG use. In the post-PEG phase, 15 SAEs were reported, seven were related to LCIG (ventricular tachycardia, gastrointestinal ulcer, paralytic ileus, pneumoperitoneum, infection, peripheral sensory neuropathy, and substance-induced psychotic disorder). Six (10.17%) out of the 59 patients prematurely discontinued the study, three during the nasoduodenal test phase (due to lack of efficacy in two cases, and due to a very narrow therapeutic margin in one case); and three after the PEG intervention phase (in one case due to lack of efficacy, due to exitus in other case, and due to patient’s decision in the third case). In addition, none of deaths were related to LCIG.\n\nDiscussion\n\nIn our study, after 6 months of treatment with LCIG administered in daily clinical practice, the QoL of patients with APD improved significantly, which is consistent with results obtained in other interventional2,7 and observational8–17,20–34 studies in which QoL was assessed as a secondary endpoint. There was a 28% reduction in PDQ-39 scores after 6 months of treatment, which is a relevant result; the conclusions of the Society for Medical Decision-Making states that patients appear to be able to detect and value benefits when changes are >7 to 10% on QoL instruments or pain scales35. In our study, there was a statistically significant improvement in all domains except social support, which is in line with results from previous studies. Interestingly, social support only improved significantly in the Zibetti et al. study; 7 of 17 participants in this study had probable dementia, and the improvement in the social support domain was prominent in this subgroup of patients33. The results of the studies of patients receiving LCIG treatment are similar to the results for other second-line therapies (SLTs) in PD. Results from the OPTIPUMP study, which was similar to the ADEQUA study in terms of population and design, for patients receiving continuous subcutaneous apomorphine infusion, noted a reduction in the total score of the PDQ-39, although half of the domains did not have statistically significant reductions (4 out of 8), with social support being one of them36. Recently, Dafsari et al. investigated whether results in QoL outcomes after bilateral subthalamic nucleus deep brain stimulation are dependent on age. In this study, an improvement in the social support domain of the PDQ-39 was only observed in the youngest subgroup of patients (≤59 years old)37.\n\nWhen motor symptoms and motor complications were assessed in our study, a significant improvement was noted in UPDRS III and IV scores, as observed in other studies7,8,11–13,15–17,20,21,24,26,29,30,32,33,38. Similarly, regarding NMS, there was a statistically significant improvement in NMSS total score in our study that corresponds with the results of other studies, in which NMSS total score improved significantly8,10–16,34,38. We also saw a significant improvement in all NMSS domains. When compared with other studies, sleep/fatigue and gastrointestinal tract were the NMSS domains that most frequently showed a statistically significant improvement (seven out of nine)8,11,12,14–16,34. In our study, the greatest benefit from LCIG treatment was observed in the NMSS score, which could explain the relevant result we found in PDQ-39 score6.\n\nTreatment with LCIG also had a positive impact in patient emotional well-being, with improvements in mood, fatigue, depression, and anxiety. There were no statistically significant effects in apathy after 6 months of treatment. This could be related to dopamine agonist withdrawal39. It has been showed that depression40–44, fatigue41,45–48, apathy45,49, anxiety42,50, and mood46,51,52 have an impact on QoL in patients with PD; thus, it is not surprising that the improvements in these symptoms observed in our study correspond with the improvement noted in patient QoL.\n\nThus, patients in this study generally improved in relation to all aspects of APD. However, there were no statistically significant improvements in ADL as measured using the S&E scale, although improvements of the ADL domain in the PDQ-39 were noted. The S&E scale has been used extensively in patients with PD in recent years. While the clinimetric properties of this scale have never been established53, the International Parkinson and Movement Disorder Society Task Force in 2016 recommended its use in PD, both for clinical and research purposes54. Although the inter-rater reliability between patient and physician ratings seems to be high54, in our study, the S&E scale was completed by the neurologist. It is possible, therefore, that the physician rating could differ from the patient rating, based on results observed in the ADL domain of the PDQ-39. It should be noted that the PDQ-39 requested information from the past month (“Off” and “On”), whereas the S&E scale was evaluated at baseline and the final visit in the “On” state.\n\nSpecial attention should be given to the caregiver results. We did not find a statistically significant effect in caregiver QoL, which is in concordance with the results of Sensi et al.17, but in contradiction with the results of Ciurleo et al.19. Surprisingly, except for anxiety, there was no improvement in a single scale in caregiver status. The stress index and depression of caregivers were unaffected. This is somewhat striking, as patient’s depression has been found to be related to caregiver’s depression55. Regarding caregiver’s anxiety, despite the fact that the reduction observed in the Goldberg anxiety scale was statistically significant, clinical relevance might be minimal as the final total score (6.4) was still above the cut-off point for anxiety (≥4). In some studies, caregiver’s burden improved;19,24,31 in others, no improvement was noted2,11,18. In our study, the ZBI score was low at baseline; therefore, there was little margin for improvement. This may be related to the exclusion of patients with dementia, a factor that contributes negatively to caregiver burden56,57. Similarly, other studies have not observed improvements in caregiver’s burden in patients with APD treated with an SLT58. There was also no improvement in WPAI scores in caregivers due to patient disability. There could be a few hypotheses of why patients improved motor symptoms, NMS, emotional well-being, and QoL but caregivers seemed not to be benefit from it. First, it is possible that the sample size for caregivers was too small to provide the appropriate statistical power (specifically for the WPAI questionnaire, where the number of currently employed caregivers was only 16 [of 59 caregivers in the study]). Another possible explanation was that study period (6 months) was not long enough of a timeline for caregivers of chronic, disabled, and advanced patients to observe a change (a statistically significant effect has been found in prospective long-term studies24,31), when a strong relation of dependence, with certain resistance to change, has already been established between the patient and the caregiver. If this is the case, it should not be assumed that an improvement in the quality of life of patients with advanced Parkinson’s disease corresponds to an immediate improvement in the quality of life of their caregivers. Finally, LCIG is an invasive treatment and a device-aid therapy that requires care and learning, which could negatively impact the caregiver, mainly during the first months that follow the beginning of LCIG therapy. The fact that patients receiving LCIG infusions are more active from the motor point of view probably requires more intense caregiver attention. All these factors could cause difficulties for caregivers after the PEG procedure at home. We should not forget that, based on Santos-García et al. study59, the main factors contributing to burden and stress in caregivers are mood (BDI-II) and ADL, which improved in our study according to the PDQ-39, but remained unchanged in the S&E scale.\n\nImprovements in patient QoL (PDQ-39) correlated with improvements in UPDRS-IV; NMSS total score; BAI, BDI-II, AS, and PFS scores; and the Norris/Bond-Lader alertness/sedation factor, though the correlations were not strong. Nevertheless, none of the improvements observed in patient variables correlated with any of the caregiver variables, which is in contrast with the results obtained by Santos-García et al., which found a correlation between PDQ-39 scores and caregiver burden (ZBI)31. In the post hoc multivariate analysis, the QoL questionnaire for caregivers (SQLC) was one of the main variables that showed greater relation to the improvement in patient QoL (PDQ-39)31.\n\nThis study provides important clinical data related to the use of LCIG and how treatment improves motor symptoms, NMS, and overall QoL in patients with APD. This study also showed improvement in fatigue, depression, and anxiety in non-selected patients with PD under routine care treated with LCIG, using validated questionnaires. One of the study’s strengths was the assessments on caregivers. There are also inherent limitations associated with this study’s design, namely that it was an observational non-controlled study. Firstly, the potential contribution of unknown/unmeasured confounding factors when the correlation between patient and caregiver QoL was assessed against the other variables. Secondly the potential contribution of a placebo effect overestimating response, particularly when subjective variables are analyzed. Thirdly, the QoL evaluation was assessed using a health-related QoL tool, which was not accompanied by a generic QoL tool, such as the EuroQoL-5 Dimensions questionnaire. And, finally, although per inclusion criteria all patients at baseline had to score at least 26 at the MMSE, an even mild cognitive decline might have affected the reported outcomes.\n\nTo end, the safety profile of LCIG described in this study and the rate of discontinuations are comparable to the data published previously in the literature2,8 and collected in the Summary of Product Characteristics. In our study, 13 out of 62 patients reported 18 SAEs, of those, only 8 SAEs were related with LCIG and of those 5 SAEs were related to the percutaneous endoscopic gastrostomy. To this regard, comparisons with other SLTs are difficult to make due to different studies methodologies and follow-up periods. However, we can find that most of the SAEs reported by patients treated with SLTs are related to the surgery or the device. Thus, in the study of Dafsari et al. in which 54 patients who underwent bilateral STN-DBS and were followed-up for an approximately 5 months after surgery, 5 patients reported SAEs related to surgery or device or to stimulation37. Regarding apomorphine pump, in the study of Drapier et al. 143 patients were enrolled, of them 42 patients withdrew from the study due to drug intolerance, lack of efficacy or other reasons. Out of 100 patients who finally completed the study and had available data at 6 months, 13 reported 17 SAEs, being the most common those affecting patients’ skin36.\n\nIn summary, 6-month treatment with LCIG administered in routine clinical practice improved the QoL of patients with APD, as well as motor symptoms and NMS, emotional well-being, and caregiver anxiety. Improvements in PDQ-39 were associated with improvements in UPDRS-IV, NMSS, BAI, BDI-I, AS, and PFS-16 scores, and the Norris/Bond-Lader alertness/sedation factor. However, patients’ QoL improvements do not correspond with improvements in caregivers’ burden or caregivers’ QoL. Further studies focused on the correlation between patients’ motor symptoms, non-motor symptoms, and QoL with burden and QoL of caregivers may be warranted.\n\nMethods\n\nADEQUA was a multicenter, postmarketing, observational, prospective, 6-month single-arm study conducted with APD patients treated with LCIG, prescribed in routine clinical practice in accordance with the terms of the local marketing authorization, from October 2014 to November 2016 at 23 Spanish hospitals.\n\nThe study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, with the protocol, and with standard operating procedures that guaranteed compliance with Good Clinical Practice, as described in the ICH guidelines. Following local regulations, the study was evaluated by the Spanish Agency of Medicines and Medical Devices and was approved by the Spanish Autonomous Communities and the ethics committees of the participating hospitals. All patients provided written informed consent before enrollment in the study.\n\nPatients\n\nEligible participants were outpatients aged ≥18 years with advanced levodopa-responsive PD with a diagnosis of idiopathic PD according to the UK Parkinson’s Disease Society Brain Bank Diagnosis Criteria60, with at least 2 h of daily “Off” time or 2 h of daily dyskinesia (assessed following MDS UPDRS-IV instructions). All patients had no dementia criteria, and had a Mini-Mental State Examination score ≥26, following Movement Disorders Society taskforce on dementia in PD recommendations61. Patients were excluded if they had any LCIG’s contraindication included in the Summary of Product Characteristics or product label. Information about the principal caregiver was collected when possible. The principal caregiver was the person in charge of the patient’s care most of the daytime.\n\nEfficacy assessments were collected at baseline before LCIG treatment initiation with temporary nasojejunal (concomitant PD medications were administered at the discretion of treating physician), at discharge from hospital following Percutaneous Endoscopy Gastrostomy (PEG) placement, and at months 1, 3, and 6.\n\nAssessments\n\nThe primary endpoint was the mean change in PDQ-3962 score from baseline (before LCIG initiation at PEG placement) to final visit (month 6 ± 15 days after hospital discharge). PDQ-39 summary index was standardized from 0 to 100, with a lower summary index indicating a better QoL.\n\nSecondary endpoints for patients included the mean change from baseline to final visit in i) Unified Parkinson’s Disease Rating Scale-Part III (UPDRS-III) score to evaluate motor impairment, measured during the best “On” time;63 ii) Non-Motor Symptoms Scale (NMSS) score;64 iii) Norris/Bond-Lader Visual Analog Scale (VAS) score (to evaluate the patient’s emotional well-being65); iv) 16-item Parkinson’s Fatigue Scale (PFS-16) score (cut-off of ≥3.30 was used to identify those perceiving fatigue to be a problem66); v) Apathy Scale (AS) score (patients with AS scores ≥14 were considered apathetic67); vi) Beck Depression Inventory-II (BDI-II) score;68 vii) Beck Anxiety Inventory (BAI) score;69 and viii) Treatment Satisfaction with Medicines-Questionnaire (SATMED-Q) score70.\n\nFor caregivers, endpoints included the mean change from baseline to final visit in i) Scale of Quality of Life of Caregivers (SQLC) score;71 ii) Zarit Burden Inventory (ZBI) score;72 iii) Caregiver Strain Index score;73 iv) Goldberg Anxiety and Depression Scale score;74,75 and v) Work Productivity and Activity Impairment (WPAI) score76.\n\nSafety measures\n\nSafety data were collected using ad-hoc forms for Serious Adverse Events (SAEs). The physician notified AbbVie (as the sponsor of the study) within 24 h of the physician becoming aware of the event. An adverse event was considered serious if resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or caused congenital anomaly/birth defect. Nonserious adverse events were not collected for analysis and were communicated by the clinicians following usual clinical practice.\n\nStatistical analysis\n\nFor sample size calculation, a minimal difference was assumed to detect 10% over a baseline score of 75.0 points in PDQ-39 based on the study of Lezcano et al.77. Assuming a standard deviation of 18.377, accepting an alpha risk of 0.05 and beta risk of 0.2 in a two-sided, 48 patients were needed to detect a difference equal to or greater than 7.5 units. Assuming a loss to follow up rate of 23% 59.2 patients are needed, so 60 patients are needed. Sample size calculation was performed with v GRANMO. 7.10. Statistical analyses were conducted using SAS® V9.4 software (SAS Institute, Cary, NC). For all analyses, a significance alpha (α) value equal to 0.05 was assumed. Continuous variables are presented as means and standard deviations (SD). The Shapiro-Wilk test was used to test whether variables followed a normal distribution. Categorical variables are reported using frequencies and percentages. Confidence intervals (95%) for the percentage were calculated, when required. The magnitude of change is represented as the relative change and paired Cohen’s effect size (0.20–0.49 = small effect; 0.50–0.79 = moderate effect; and 0.80 = large effect).\n\nDescriptive statistics were calculated for demographic and clinical characteristics. Contrast statistics were used for intra-patient comparisons using repeated measures. In the case of continuous variables, the repeated measures Student t test or the Wilcoxon rank-sum test was used, depending on the normality of the data. In the case of binary qualitative variables, the chi-square test or the McNemar test was used. A mixed model of repeated measures was used for comparisons between visits.\n\nUnivariate analysis and multivariate linear regression analysis were used to assess the association between the change in PDQ-39 (dependent variable) and other variables (independent variables) UPDRS III, Unified Parkinson’s Disease Rating Scale-Part IV (UPDRS IV), NMSS, S&E, VAS, PFS-16, AS, BDI-II, BAI, SATMED-Q, SQCL and ZBI from baseline to 6 months (±15 days) after hospital discharge. Correlations have been evaluated using Pearson test (in case of continuous variables) or Spearman test (in case of ordinal variables). Those independent variables with P < 0.1 in the univariate analysis (all of them except UPDRS III, S&E and ZBI) without multicollinearity were included in the multivariate linear regression model. Statistical analyses were performed with the intent-to-treat and safety populations. Levodopa equivalent daily dose (LEDD), including levodopa daily dose plus all antiparkinsonian therapies, were calculated according to Tomlinson et al.78.\n\nStudy populations\n\nThe statistical analyses were performed in the following study populations:Per Protocol population (PP): included those patients (and caregivers) who met all inclusion criteria and were classified as suitable on the levodopa/carbidopa continuous nasoduodenal catheter infusion test. Those patients had to complete the 6-month period of treatment, and at least, they had the quality of life data collected with the PDQ-39 questionnaire at baseline and after 6 months (±15 days) of treatment.\n\nIntent-To-Treat (ITT) and Safety population: included those patients (and caregivers) that made up the PP population, those who were classified as not suitable on the levodopa/carbidopa continuous nasoduodenal catheter infusion test, and those that after undergoing the percutaneous endoscopic gastrostomy did not complete the 6-month treatment period.\n\nAs no significant differences were found between the two populations, only the results obtained in the ITT population are presented.\n\nReporting Summary\n\nFurther information on research design is available in the Nature Research Reporting Summary linked to this article.\n\nSupplementary information\n\nReporting Summary\n\nSupplementary information\n\nThe online version contains supplementary material available at 10.1038/s41531-021-00246-y.\n\nAcknowledgements\n\nWe thank Vanesa Vera at Pivotal, S.L.U. (Madrid, Spain) for statistical analysis assistance, and Angel Burgos at Pivotal, S.L.U. for editing the manuscript and editorial writing assistance. These services were funded by AbbVie S.L.U. We would like to recognize the contributions of the principal investigators: Son Espases Hospital: Bárbara Vives; Santa Creu i Sant Pau Hospital: Berta Pascual; San Pedro Alcántara Hospital: Gonzalo Gámez-Leyva; La Fe Hospital: Irene Martínez; Valladolid Hospital: Javier Marco; Virgen Macarena Hospital: José Manuel García; Santa Lucía Hospital: Juan José Soria; Navarra Hospital Center: Pedro Luis Clavero, Mª Iciar Gastón; Elche General Hospital: María Álvarez; San Pedro Alcántara Hospital: Montserrat Gómez; Vall D´Hebron Hospital: Oriol de Fàbregues; Puerta del Mar Hospital: Miguel Moya, Raúl Espinosa; Parc Tauli Hospital: Tania Delgado. The study was sponsored by AbbVie, S.L.U. The design, study conduct, and financial support for the ADEQUA study were provided by AbbVie. AbbVie participated in the research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication.\n\nAuthor contributions\n\nAuthors’ roles include but are not restricted to: 1. Research project: A. Conception, B. Organization, C. Execution. 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique. 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. Francesc Valldeoriola: 2C, 3B M.J.C.: 2C, 3B. E.F.: 2C, 3B. J.O.: 2C, 3B. E.C.: 2C, 3B. D.S.G.: 2C, 3B. M.C.: 2C, 3B. P.M-M.: 2C, 3B. J.C.P.: 1A, 1B, 1C, 2C, 3B. G.A.: 1A, 1B, 1C, 2C, 3B. J.M.A.: 2C, 3B.\n\nData availability\n\nAbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and Clinical Study Reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.\n\nThis clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html.\n\nCompeting interests\n\nThe author declares no competing interests. The disclosures of the authors are: F. Valldeoriola has received honoraria for speaking services and advisory boards from AbbVie, Zambon, Teva, Medtronic, and Boston Scientific. M.J. Catalán has received honoraria for consulting, advisory services, speaking services, and research from AbbVie Laboratories and Merz. F. Escamilla-Sevilla has received honoraria for advisory services, consulting, lecturing, support in assisting scientific meetings, and research from AbbVie, Italfarmaco, Medtronic, Merz, Teva, UCB Pharma, and Zambon. E. Freire has received honoraria from AbbVie, UCB, Zambon, Bial, and Eisai. J. Olivares has received honoraria in 2016 from AbbVie, UCB, Zambon, Teva, and Eisai. E. Cubo has received honoraria from AbbVie and Zambon. D. Santos Garcia has received honoraria from AbbVie, UCB Pharma, Teva, Zambon, KRKA, and Lundbeck. M. Calopa has received honoraria from AbbVie and Zambon. P. Martínez-Martín has received honoraria from National School of Public Health (ISCIII), Britannia, and Editorial Viguera for lecturing in courses; International Parkinson and Movement Disorder Society for management of the Program on Rating Scales; Bial, and Zambon for advice in clinical-epidemiological studies. Financial support by the International Parkinson and Movement Disorder Society for attending the IPMDS International Congress 2019. Grant for Research: International Parkinson and Movement Disorder Society, for development and validation of the MDS-NMS. J.C. Parra is an employee of AbbVie and holds AbbVie stock and/or stock options. G. Arroyo is an employee of AbbVie. J.M. Arbelo has received honoraria from AbbVie, Zambon, Bial, and Teva.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Chapuis S Ouchchane L Metz O Gerbaud L Durif F Impact of the motor complications of Parkinson’s disease on the quality of life Mov. Disord. 2005 20 224 230 15384126\n2. Olanow CW Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomised, controlled, double-blind, double-dummy study Lancet Neurol. 2014 13 141 149 24361112\n3. Deuschl G A randomized trial of deep-brain stimulation for Parkinson’s disease N. Engl. J. Med. 2006 355 896 908 16943402\n4. 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(Hoboken) 2011 63 Suppl 11 S337 349 22588755\n77. Lezcano E Improvement in quality of life in patients with advanced Parkinson’s disease following bilateral deep-brain stimulation in subthalamic nucleus Eur. J. Neurol. 2004 11 451 454 15257682\n78. Tomlinson CL Systematic review of levodopa dose equivalency reporting in Parkinson’s disease Mov. Disord. 2010 25 2649 2653 21069833\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2373-8057",
"issue": "7(1)",
"journal": "NPJ Parkinson's disease",
"keywords": null,
"medline_ta": "NPJ Parkinsons Dis",
"mesh_terms": null,
"nlm_unique_id": "101675390",
"other_id": null,
"pages": "108",
"pmc": null,
"pmid": "34848716",
"pubdate": "2021-11-30",
"publication_types": "D016428:Journal Article",
"references": "15384126;24361112;16943402;30055903;7613534;10634243;15668416;29037498;16275852;26618531;24477490;19425079;28185758;28631218;25382161;22821063;31134377;29951701;17661426;18322402;26777085;19253412;28828219;22338551;25545465;23476888;18547273;27318707;19762271;22248261;25588353;22772358;29242809;27060084;29266613;26085378;26071817;25025280;23916654;18543333;16797028;20833572;19514014;26806538;18325024;25918077;23970460;22191074;23890935;25529173;12360535;27193358;10203202;23172765;27925292;27443241;25212106;1564476;18098298;9351479;19025984;19901251;15619463;1627973;3204199;18494753;9617723;7203086;6841931;3140969;8218816;15257682;21069833",
"title": "Patient and caregiver outcomes with levodopa-carbidopa intestinal gel in advanced Parkinson's disease.",
"title_normalized": "patient and caregiver outcomes with levodopa carbidopa intestinal gel in advanced parkinson s disease"
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"companynumb": "A1-Avion Pharmaceuticals, LLC-2128718",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "CARBIDOPA\\LEVODOPA"
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{
"abstract": "BACKGROUND\nThe management of skin toxicity is crucial for efficient afatinib treatment, but the role of tetracycline class antibiotics (TCs) in managing these rashes is relatively unknown.\n\n\nMETHODS\nWe reviewed the clinical records of patients who were administered afatinib for the treatment of non-small cell lung cancer harboring epidermal growth factor receptor mutations between October 2014 and November 2016. Twenty-five patients, who received TCs for the management of afatinib-related skin disorders, were enrolled.\n\n\nRESULTS\nMinocycline was administered orally to participants. Afatinib-related toxic effects, such as rash, diarrhea, and paronychia, were observed in 92%, 92%, and 40% of cases, respectively. Although 24% of diarrhea and 4% of paronychia cases were rated grade 3 or higher, no severe cases of rash were observed during afatinib treatment. Of the 18 afatinib dose reductions, 14 (78%), three (17%), and one (6%) resulted from diarrhea, paronychia, and stomatitis, respectively; no patients required a dose reduction because of rash. When minocycline treatment started, 21 patients (84%) had a rash of grade 1 or less, and three patients had a grade 2 rash. A response to afatinib was observed in 18 patients (72%) and the median duration of afatinib administration was 501 days. An adverse event related to minocycline (grade 1 nausea) was observed in one patient.\n\n\nCONCLUSIONS\nA large proportion of the study patients started minocycline before grade 2 rash development and the severity of afatinib-related rash was lower than that previously reported. Oral TCs may be beneficial, especially if started early.",
"affiliations": "Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, 3453 Mikatahara, Kita Ward, Hamamatsu, Shizuoka 433-8558, Japan. Electronic address: a.goto@sis.seirei.or.jp.;Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, 3453 Mikatahara, Kita Ward, Hamamatsu, Shizuoka 433-8558, Japan. Electronic address: u1.ozawa@sis.seirei.or.jp.;Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, 3453 Mikatahara, Kita Ward, Hamamatsu, Shizuoka 433-8558, Japan. Electronic address: koudakeigokouda@yahoo.co.jp.;Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, 3453 Mikatahara, Kita Ward, Hamamatsu, Shizuoka 433-8558, Japan. Electronic address: daisuke_a_813@yahoo.co.jp.;Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, 3453 Mikatahara, Kita Ward, Hamamatsu, Shizuoka 433-8558, Japan. Electronic address: tak.koyauchhi@gmail.com.;Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, 3453 Mikatahara, Kita Ward, Hamamatsu, Shizuoka 433-8558, Japan. Electronic address: soccerya0706@yahoo.co.;Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, 3453 Mikatahara, Kita Ward, Hamamatsu, Shizuoka 433-8558, Japan. Electronic address: takuya32k@yahoo.co.jp.;Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, 3453 Mikatahara, Kita Ward, Hamamatsu, Shizuoka 433-8558, Japan. Electronic address: yoccherry_o4o5_blossom@i.softbank.jp.;Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, 3453 Mikatahara, Kita Ward, Hamamatsu, Shizuoka 433-8558, Japan. Electronic address: h-hasegawa@sis.seirei.or.jp.;Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, 3453 Mikatahara, Kita Ward, Hamamatsu, Shizuoka 433-8558, Japan. Electronic address: t-matsui@sis.seirei.or.jp.;Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, 3453 Mikatahara, Kita Ward, Hamamatsu, Shizuoka 433-8558, Japan. Electronic address: yo.koshi@sis.seirei.or.jp.;Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192, Japan. Electronic address: suda@hama-med.ac.jp.",
"authors": "Goto|Ayano|A|;Ozawa|Yuichi|Y|;Koda|Keigo|K|;Akahori|Daisuke|D|;Koyauchi|Takashi|T|;Amano|Yusuke|Y|;Kakutani|Takuya|T|;Sato|Yoshiko|Y|;Hasegawa|Hirotsugu|H|;Matsui|Takashi|T|;Yokomura|Koshi|K|;Suda|Takafumi|T|",
"chemical_list": "D000900:Anti-Bacterial Agents; D011725:Pyridines; D013844:Thiazoles; C545733:fatostatin; D004815:Epidermal Growth Factor; D008911:Minocycline",
"country": "Netherlands",
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"issue": "56(2)",
"journal": "Respiratory investigation",
"keywords": "Afatinib; Epidermal growth factor inhibitor; Minocycline; Rash; Tetracycline",
"medline_ta": "Respir Investig",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D002289:Carcinoma, Non-Small-Cell Lung; D003967:Diarrhea; D004815:Epidermal Growth Factor; D005076:Exanthema; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D008911:Minocycline; D009154:Mutation; D010304:Paronychia; D011725:Pyridines; D012720:Severity of Illness Index; D013844:Thiazoles",
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"pages": "179-183",
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"pmid": "29548657",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical impact of minocycline on afatinib-related rash in patients with non-small cell lung cancer harboring epidermal growth factor receptor mutations.",
"title_normalized": "clinical impact of minocycline on afatinib related rash in patients with non small cell lung cancer harboring epidermal growth factor receptor mutations"
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"abstract": "Intravenous trimethoprim-sulfamethoxazole therapy was evaluated in 11 consecutive patients with documented Pneumocystis carinii pneumonia and the results compared to those from previously published studies of trimethoprim-sulfamethoxazole therapy for P. carinii pneumonia. Although six patients needed mechanical ventilation, intravenous therapy was successful in seven of 11 patients (64%), and seven of nine patients (78%) receiving 4 or more days of intravenous trimethoprim-sulfamethoxazole therapy were cured. Side effects occurred in two patients (skin rash in one, nausea and vomiting in one). A review of 80 reported cases of confirmed P. carinii pneumonia initially treated with trimethoprim-sulfamethoxazole alone revealed response rates of 67.5% in all treated patients and 85.5% in patients treated for 9 or more days. The clinical response was similar in adults (63.2%) and children (68.9%). Side effects were noted in only 11 of 80 patients (13.8%). Compared to pentamidine, trimethoprim-sulfamethoxazole has a narrower toxic-therapeutic ratio and should be preferred treatment for P. carinii pneumonia in adults as well as children.",
"affiliations": null,
"authors": "Winston|D J|DJ|;Lau|W K|WK|;Gale|R P|RP|;Young|L S|LS|",
"chemical_list": "D004338:Drug Combinations; D010419:Pentamidine; D014295:Trimethoprim; D013420:Sulfamethoxazole",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D008297:Male; D008875:Middle Aged; D010419:Pentamidine; D011020:Pneumonia, Pneumocystis; D013420:Sulfamethoxazole; D014295:Trimethoprim",
"nlm_unique_id": "0372351",
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"pages": "762-9",
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"pubdate": "1980-06",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Trimethoprim-sulfamethoxazole for the treatment of Pneumocystis carinii pneumonia.",
"title_normalized": "trimethoprim sulfamethoxazole for the treatment of pneumocystis carinii pneumonia"
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"abstract": "Hypokalemia can cause abnormalities in multiple systems. Long term use of antipsychotic medications can lead to electrolyte imbalance, including hypokalemia. We report a 49-year-old female patient with schizophrenia who developed hypokalemia after oral quetiapine and risperidone treatments. Her blood potassium became normal after she switched to another antipsychotic drug (amisulpride). In addition, we discuss the potential mechanism of antipsychotic drugs leading to hypokalemia and clinical cautions.",
"affiliations": "First-episode Schizophrenia and Early Psychosis Program, Division of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;First-episode Schizophrenia and Early Psychosis Program, Division of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;First-episode Schizophrenia and Early Psychosis Program, Division of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.",
"authors": "Yang|Qiongwei|Q|;Guo|Xiaoyun|X|;Liu|Dengtang|D|",
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"doi": "10.11919/j.issn.1002-0829.217168",
"fulltext": "\n==== Front\nShanghai Arch PsychiatrySAPShanghai Archives of Psychiatry1002-0829Shanghai Municipal Bureau of Publishing 10.11919/j.issn.1002-0829.217168Case ReportHypokalemia Caused by Quetiapine and Risperidone Treatment in Schizophrenia: A Case Report 奎硫平合并利培酮治疗精神分裂症导致低血钾1 例 YANG Qiongwei 杨 琼玮 12*GUO Xiaoyun 郭 晓云 1*LIU Dengtang 刘 登堂 1*1 First-episode Schizophrenia and Early Psychosis Program, Division of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China2 Minkang Hospital of Ningxia Civil Affairs Department, Ningxia, China* Mailing address: 600 South Wanping RD, Shanghai, China. Postcode: 200030. xiaoyunguo@163.com* Mailing address: 600 South Wanping RD, Shanghai, China. Postcode: 200030. erliu110@126.com25 6 2018 25 6 2018 30 3 204 206 © Shanghai Municipal Bureau of Publishing2018This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/Summary\nHypokalemia can cause abnormalities in multiple systems. Long term use of antipsychotic medications can lead to electrolyte imbalance, including hypokalemia. We report a 49-year-old female patient with schizophrenia who developed hypokalemia after oral quetiapine and risperidone treatments. Her blood potassium became normal after she switched to another antipsychotic drug (amisulpride). In addition, we discuss the potential mechanism of antipsychotic drugs leading to hypokalemia and clinical cautions.\n\n概述\n低血钾可造成躯体多系统障碍，长期服用某些 抗精神病药可能会导致电解质代谢的异常，包括血清 钾的异常。我们报告一例49 岁女性精神分裂症患者， 在服用奎硫平和利培酮后出现低血钾，在换用其它抗 精神病药（氨磺必利）后，血钾恢复正常。我们还讨 论了抗精神病药导致低血钾的可能机制和临床注意事 项。\n\nKey words\nHypokalemiasomaticquetiapinerisperidoneantipsychotic drugsschizophrenia关键词\n低血钾躯体奎硫平利培酮抗精神病药精神分裂症\n==== Body\n1. Introduction\nThe normal value of blood potassium (K+) concentration is between 3.5 and 5.5 mmol/L with an average value of 4.2 mmol/L. Generally, hypokalemia is defined as the value of blood potassium concentration less than 3.5 mmol/L. Acute and severe hypokalemia can cause abnormalities in multiple systems. It is fatal in severe cases. The common symptoms of hypokalemia in the neuromuscular system are myasthenia, paroxysmal soft paralysis, and reduced muscle excitability. Hypokalemia could manifest as mental symptoms such as depression, drowsiness and loss or impairment in memory and orientation. In the cardiovascular system, hypokalemia can reduce myocardial stress. It could also induce arrhythmia and conduction blocks. It is fatal in the most serious cases. Severe hypokalemia in the digestive system can cause paralytic ileus. Long term use of antipsychotic drugs can lead to electrolyte imbalance including hypokelamia. The mechanism of this phenomenon is not clear. We report a 49-year-old female who developed hypokalemia after quetiapine and risperidone treatment.\n\n2. Case history\nThe patient was replaced in her job by a new colleague in 2011. At that time she was unwilling to do anything at work and thought her boss was bullying her. She felt aggrieved and depressed. On September 16th 2015, she said that her boss had assigned her to work in Canada. She spent most of the time during the day by herself. Three days later, she was found by police officers in Pudong District (a district of Shanghai). According to the patient, she thought someone in the air told her to do this. Then she retired and stayed at home where her mood was fairly stable. She cursed at the air sometimes. Sometimes she said her manager’s wife had been spying on her and trying to break up her family. On September 2016, she reported being afraid to eat at her own home. She thought that if she ate at home, her manager’s wife would throw dust into her parents’ bowls. Occasionally, she talked to herself saying that her manager would ask her to talk with him at midnight. When her mother suggested accompanying her to a doctor’s appointment, she said that her manager had cancelled the appointment. This patient was brought to our hospital’s emergency department by her family on August 15th 2017. A quick check for blood potassium showed 2.7 mmol/L, however this improved after potassium supplementation treatment. At the same time, she was given olanzapine 5 mg/d, but the outcome was poor. In addition, her family members felt that it was difficult to take care of her at home. Thus, she was sent to the hospital with a diagnosis of schizophrenia. During the 1 month before hospitalization, the patient had an irregular diet as she only ate once a day. She slept through the daytime but went out or did house chores at night. She had normal urine and stool activities. She did not have obvious weight change. She did not have self-injuring behavior or suicide attempts. Her routine blood, urine and hepatic function test were within normal ranges. Her blood potassium concentration was 3.11 mmol/L. Her chest radiograph and brain MRI were all normal. Electrocardiogram examination’s results showed sinus rhythm but changes in T-wave (V4-V6 were low, flat and inverted).\n\nThere was no special medical history except for an allergy to penicillin. She had an older brother. There was no reported family history of mental illness. Upon mental examination the patient had a normal level of consciousness. She was cleanly dressed. During the interview she was uncooperative, refusing to answer questions. The patient denied any auditory hallucinations. Her volition was not entirely impaired. She had normal memory, calculating abilities, discretion, knowledge and abstract thinking ability. Yet she lacked insight into her illness. The diagnosis given was schizophrenia.\n\nAfter being hospitalized, she was given olanzapine 20 mg/d for 14 days. 2 weeks later, her psychotic symptoms relieved. She could eat normally. However, she often got up at night, eating and drinking. She got hungry so easily that she had to eat multiple times during the night. Her blood potassium concentration was within the normal range. Therefore, she was switched to quetiapine 700 mg. 9 days later, her blood potassium concentration was 3.1 mmol/L. Mental status exam showed that the patient was conscious and had average interpersonal interactions. However, she denied having any previous auditory hallucinations or persecutory delusions. She still had fragmented suspicions with a stable mood and a lack of insight. Thus, she was switched to risperidone 5 mg/d. 14 days later, the patient felt feeble. The blood potassium level was 2.89 mmol/L. Since the patient was eating normally, this phenomenon was considered as the result of quetiapine and risperidone consumption. Therefore, she was switched to amisulpride 0.4 g/d with potassium supplementation 1.5 g/d. Blood potassium concentration was 3.85 mmol/L 7 days later. Furthermore, hallucinations, delusions and other psychotic symptoms disappeared.\n\n3. Discussion\nThe patient ate well after she was admitted into the hospital. She did not experience vomiting or diarrhea during treatment. In addition, she did not have any past medical history of cardiovascular or kidney disease. Therefore, the most probable cause for hypokalemia was quetiapine and risperidone. Previous literature indicates that antipsychotic drugs such as clozapine,[1] olanzapine,[2] risperidone[3] and quetiapine [3] can lead to hypokalemia. However, the mechanism of this phenomenon is still unclear. One possible explanation for this is that antipsychotic drugs induce hypercatecholemia, which could include high blood pressure, hypokalemia, and tachycardia.[4] Catecholamine induces the transfer of potassium ions from the outside to the inside of cells[6] by the increase of insulin level mediated by alpha 2 adrenergic receptors.[5] Another possible explanation is losing potassium ions in the kidney. Antipsychotic drugs may have aldosterone-like effects. Aldosterone is an adrenocortical hormone. It is generated by the adrenocortical globular zone. Aldosterone mainly acts on the distal tubules and collecting tubules of glomerulus. It could increase the activity of Na-K-ATP enzyme in the basement membrane. As the result, it could help to absorb the sodium ions and water from the urine back to the blood and discharge potassium ions in the urine.[1] Thus, high levels of aldosterone will lead to hypokalemia by causing the kidney to discharge more potassium ions.\n\nAfter she was switched to amisulpride, the patient’s blood potassium level returned to normal. Based on the current literature, there was no evidence indicating that amisulpride leads to hypokalemia. The mechanism underlying this is unclear. One possible explanation is that the affinity of amisulpride’s receptors is relatively simple. Amisulpride has selective affinity to dopamine D2/D3 receptors but lacks affinity to other neurotransmitter receptors and pharmacologic sites. Therefore, it has relatively fewer adverse side effects. [7]\n\nIn conclusion, the mechanism underlying the hypokalemia caused by the antipsychotic drugs quetiapine and risperidone is still unclear. One possible mechanism is the aldosterone effect and the catecholamine effect of antipsychotic drugs. Catecholamine transfers potassium from the outside to the inside of cells. It could also induce the loss of blood potassium in the kidneys. In clinical practice, blood potassium concentration should be monitored to prevent serious accidents. Future basic and clinical studies could focus on the potassium concentration in urine and the total potassium discharged within 24 hours under a controlled diet. In future research, we could effectively explore the biological mechanism of abnormal electrolytes caused by antipsychotic drugs. We could also explore the relationship between abnormal electrolytes and acute psychosis and treatment effects of antipsychotics.\n\nFunding statement\n\nThe present study was funded by the Chinese National Science Foundation (81201057), Shanghai Clinical Center for Psychiatric Disease, and the Shanghai Municipal\n\nCommission Award (20124109), Medical Guidance foundation of the Shanghai Science and Technology Committee (15411964400), and the International Cooperation Foundation of the Shanghai Mental Health Center (2015-YJGJ-02).\n\nConflict of interest statement\n\nThe authors declared no conflicts of interest related to this manuscript.\n\nInformed consent\n\nThe patient signed informed consent for the present report’s publication.\n\nAuthors’ contributions\n\nQiongwei Yang wrote up the draft. Xiaoyun Guo and Dengtang Liu made critical revisions. Xiaoyun Guo made the clinical diagnosis and carried out psychiatric evaluations. The manuscript was finalized after all writers reviewed it.\n\nQiongwei Yang graduated as a resident psychiatrist and a level three national psychological consultant. She studied in the department of medicine at Havana Medical University in Cuba as an international student sent by the National Education Department. She graduated with a major in clinical medicine from Ningxia Medical University in 2013. She has been working in the Minkang Hospital of the Ningxia Civil Affairs Department since June 2014 with a research interest in pharmacological treatments for schizophrenia and bipolar disorder. She is currently studying and taking advanced training at the Shanghai Mental Health Center.\n==== Refs\nReferences\n1. Hoorn EJ van der Poel MF \nHypokalemic hypertension related to clozapine: a case report . J Clin Psychopharmacol . 2014 ; 34 (3 ): 390 -392 . 10.1097/JCP.0000000000000044 24317452 \n2. Huang G Fu Q Xu J. \nPotential torsades de pointes triggered by hypokalemia related to olanzapine in a patient with implantable cardioverter-defibrillator . J Clin Psychopharmacol . 2014 ; 34 (5 ): 651 -652 . 10.1097/JCP.0000000000000189 25127223 \n3. Malik AR Wolf PK Ravasia S. \nHypokalemia from risperidone and quetiapine overdose . Can J Psychiatry. \n2005 ; 50 (1 ): 76 \n10.1177/070674370505000119 15754671 \n4. Krentz AJ Mikhail S Cantrell P Hill GM \nDrug Points: Pseudophaeochromocytoma syndrome associated with clozapine . BMJ. \n2001 ; 322 (7296 ): 1213 11358774 \n5. Brown MJ Brown DC Murphy MB \nHypokalemia from beta2-receptor stimulation by circulating epinephrine . N Engl J Med . 1983 ; 309 (23 ): 1414 -1419 . 10.1056/NEJM198312083092303 6314140 \n6. Schnack C Podolsky A Watzke H Schernthaner G Burghuber OC \nEffects of somatostatin and oral potassium administration on terbutaline-induced hypokalemia . Am Rev Respir Dis . 1989 ; 139 (1 ): 176 -180 . 10.1164/ajrccm/139.1.176 2563217 \n7. Kerwin R \nFrom pharmacological profiles to clinical outcomes . Int Clin Psychopharmacol. \n2000 ; 15 (Suppl 4 ): S1 -S4 . 10.1016/j.msec.2005.06.025\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1002-0829",
"issue": "30(3)",
"journal": "Shanghai archives of psychiatry",
"keywords": "Hypokalemia; antipsychotic drugs; quetiapine; risperidone; schizophrenia; somatic",
"medline_ta": "Shanghai Arch Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "9891453",
"other_id": null,
"pages": "204-206",
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"pmid": "30858673",
"pubdate": "2018-06-25",
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"title": "Hypokalemia Caused by Quetiapine and Risperidone Treatment in Schizophrenia: A Case Report.",
"title_normalized": "hypokalemia caused by quetiapine and risperidone treatment in schizophrenia a case report"
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{
"abstract": "BACKGROUND\nIn this retrospective study, we investigated the efficacy and safety of radioimmunotherapy with (90)Yttrium- ibritumomab tiuxetan ((90)Y-RIT) in 9 patients with recurrent follicular lymphoma (FL) who were treated in a consolidation setting after having achieved complete (CR) or partial remission (PR) with Fludarabine, Cyclophosphamide and Rituximab (FCR).\n\n\nMETHODS\nThe median age was 63 years (range 46-77). All patients were relapsed with histologically confirmed CD20-positive (grade 1 or 2) FL, at relapse they received FCR every 28 days: F (25 mg/m(2)x 3 days), C (1 gr/m(2) day 1) and R (375 mg/m(2) day 4) for 4 cycles. Those who achieved at least a PR with <25 % bone marrow involvement were treated with (90)Y-RIT 11.1 or 14.8 MBq/Kg, at 3 months after completing FCR. Patients underwent a further restaging at 12 weeks after (90)Y-RIT with a total body CT scan, FDG-PET/CT and bilateral bone marrow biopsy.\n\n\nRESULTS\nNine patients completed the treatment: FCR followed by (90)Y-RIT (6 patients at 14.8 MBq/Kg, 3 patients at 11.1 MBq/Kg). After FCR, 7 patients obtained CR and 2 PR; after (90)Y-RIT 2 patients in PR converted to CR 12 weeks later. With a median follow up of 95 months (range 20-114) since FCR and 88 months (range 13-104) since (90)Y-RIT 3 deaths were not related to lymphoma; all 3 deceased patients obtained CR before (90)Y-RIT and died still in CR. The median overall (OS) and progression free survival (PFS) have not been reached, in this analysis both OS or PFS are 67 % at 7.5 year. The most common grade 3 or 4 adverse events were hematologic.\n\n\nCONCLUSIONS\nThese results confirm the long term efficacy and safety of 4 cycles of FCR followed by (90)Y-RIT in relapsed grades 1 and 2 FL and suggest that this regimen could be a therapeutic option for this setting of patients, specially at age of 60-75 with no unexpected toxicities.",
"affiliations": "Department of Hematology Regina Elena National Cancer Institute, Via Elio Chianesi, 53 - 00144 Rome, Italy.;Department of Nuclear Medicine Regina Elena National Cancer Institute, Rome, Italy.;Unit of Hematology and Stem Cell Transplant Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy.;Biostatistics Regina Elena National Cancer Institute, Rome, Italy.;Department of Radiology Regina Elena National Cancer Institute, Rome, Italy.;Department of Nuclear Medicine Regina Elena National Cancer Institute, Rome, Italy.;Department of Hematology Regina Elena National Cancer Institute, Via Elio Chianesi, 53 - 00144 Rome, Italy.;Department of Pathology Regina Elena National Cancer Institute, Rome, Italy.",
"authors": "Pisani|Francesco|F|;Sciuto|Rosa|R|;Dessanti|Maria Laura|ML|;Giannarelli|Diana|D|;Kayal|Ramy|R|;Rea|Sandra|S|;Marchesi|Francesco|F|;Marino|Mirella|M|",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s40164-015-0012-3",
"fulltext": "\n==== Front\nExp Hematol OncolExp Hematol OncolExperimental Hematology & Oncology2162-3619BioMed Central London 1210.1186/s40164-015-0012-3ResearchLong term efficacy and safety of Fludarabine, Cyclophosphamide and Rituximab regimen followed by 90Y-ibritumomab tiuxetan consolidation for the treatment of relapsed grades 1 and 2 follicular lymphoma Pisani Francesco +39 0652665360fr.pisani@tiscali.it Sciuto Rosa sciuto@ifo.it Dessanti Maria Laura ldessanti@hotmail.com Giannarelli Diana giannarelli@ifo.it Kayal Ramy rkayal@libero.it Rea Sandra rea@ifo.it Marchesi Francesco fmarchesi@ifo.it Marino Mirella mirellamarino@inwind.it Department of Hematology Regina Elena National Cancer Institute, Via Elio Chianesi, 53 - 00144 Rome, Italy Department of Nuclear Medicine Regina Elena National Cancer Institute, Rome, Italy Unit of Hematology and Stem Cell Transplant Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy Biostatistics Regina Elena National Cancer Institute, Rome, Italy Department of Radiology Regina Elena National Cancer Institute, Rome, Italy Department of Pathology Regina Elena National Cancer Institute, Rome, Italy 24 6 2015 24 6 2015 2015 4 1720 3 2015 17 6 2015 © Pisani et al. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nIn this retrospective study, we investigated the efficacy and safety of radioimmunotherapy with 90Yttrium- ibritumomab tiuxetan (90Y-RIT) in 9 patients with recurrent follicular lymphoma (FL) who were treated in a consolidation setting after having achieved complete (CR) or partial remission (PR) with Fludarabine, Cyclophosphamide and Rituximab (FCR).\n\nMethods\nThe median age was 63 years (range 46–77). All patients were relapsed with histologically confirmed CD20-positive (grade 1 or 2) FL, at relapse they received FCR every 28 days: F (25 mg/m2x 3 days), C (1 gr/m2 day 1) and R (375 mg/m2 day 4) for 4 cycles. Those who achieved at least a PR with <25 % bone marrow involvement were treated with 90Y-RIT 11.1 or 14.8 MBq/Kg, at 3 months after completing FCR. Patients underwent a further restaging at 12 weeks after 90Y-RIT with a total body CT scan, FDG-PET/CT and bilateral bone marrow biopsy.\n\nResults\nNine patients completed the treatment: FCR followed by 90Y-RIT (6 patients at 14.8 MBq/Kg, 3 patients at 11.1 MBq/Kg). After FCR, 7 patients obtained CR and 2 PR; after 90Y-RIT 2 patients in PR converted to CR 12 weeks later. With a median follow up of 95 months (range 20–114) since FCR and 88 months (range 13–104) since 90Y-RIT 3 deaths were not related to lymphoma; all 3 deceased patients obtained CR before 90Y-RIT and died still in CR. The median overall (OS) and progression free survival (PFS) have not been reached, in this analysis both OS or PFS are 67 % at 7.5 year. The most common grade 3 or 4 adverse events were hematologic.\n\nConclusions\nThese results confirm the long term efficacy and safety of 4 cycles of FCR followed by 90Y-RIT in relapsed grades 1 and 2 FL and suggest that this regimen could be a therapeutic option for this setting of patients, specially at age of 60–75 with no unexpected toxicities.\n\nKeywords\nFollicular lymphoma90Y-ibritumomab tiuxetanRadioimmunotherapyissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nMost cases of follicular lymphoma are characterized by recurrence of disease. There is usually a pattern of repeated remissions and relapses until patients become refractory to treatment. The duration of remissions becomes shorter with repeated induction attempts. Transformation to more aggressive non-Hodgkin lymphoma (NHL) occurs in 15 % to 50 % of the patients at 5 years. Therefore, it is important to have many treatment options: combination chemotherapy, radiation, immunotherapy, radioimmunotherapy and myeloablative therapy with stem-cell rescue for some patients with good performance status and responsive disease to overcome the development of resistance. A number of cytotoxic agents in combination are active in this patient population. The fludarabine, cyclophosphamide and rituximab (FCR) regimen provided encouraging results as initial or salvage therapy in patients with CLL or indolent NHL [1, 2]. Radioimmunotherapy is also an excellent modality in the treatment of NHL; the target antigen, radionuclide emission properties and chemical stability of radioimmunoconjugates are important factors that contribute to the effectiveness of RIT. 90Y can deliver a high beta energy to tumor (2–3 MeV) and 90Yttrium- ibritumomab tiuxetan (90Y-RIT ) consists of the anti-CD20 monoclonal antibody ibritumomab (an IgG1k antibody which is the murine parent immunoglobulin to rituximab) covalently bound to the chelating agent tiuxetan and radiolabeled with 90Y.\n\nThe phase III FIT trial (First-line Indolent Trial), enrolled 414 patients with stage III or IV who had attained a CR or PR after induction chemotherapy. It showed that consolidation of first remission with 90Y-RIT was highly effective with no unexpected toxicities, producing a statistically significant longer time to progression in both PR and CR patients groups. In the last update of the trial the median PFS has not yet been reached (>7.9 years) for patients in the 90Y-RIT arm and 4.9 years in control arm [3–5]. Furthermore, several phase II trials show high rates of conversion from PR to CR and significant improvements in PFS [6–14] using consolidation therapy with 90Y-RIT obtained, after initial treatment. 90Y-RIT also has been reported to be effective in patients with relapsed or refractory FL [15–17]. Here, we report updated long–term efficacy and toxicity results of 90Y-RIT consolidation in 9 patients relapsed with grade 1 and 2 FL patients responding to FCR that were treated at our Institute [18].\n\nResults\nPatients characteristics\nIn this retrospective analysis 9 patients had received 4 cycles of FCR followed by 90Y-RIT (6 patients at 14.8 MBq/Kg, 3 patients at 11.1 MBq/Kg). Baseline characteristics are presented in Table 1. The median age was 63 years (range 46–77), all patients were relapsed patients: 2 patients received a prior therapy, 5 patients received 2 prior treatments and 2 patients received 3 regimens. Seven patients were previously treated with rituximab plus chemotherapy, 2 patients had no previous rituximab treatment history, 1 patient received also high-dose therapy followed by autologous stem cell transplantation (Table 2).Table 1 Patient characteristics\n\n\tPatients (n = 9)\t\nMale/Female\t3/6\t\nMedian Age (Range)\t63 (46–77) years\t\nDisease stage\tat diagnosis\tat start of FCR\t\nI\t1\t0\t\nII\t1\t5\t\nIII\t1\t3\t\nIV\t6\t1\t\nBone marrow involvement\t\t\n 0 %\t7\t\n 10 % to ≤25 %\t2\t\nExtranodal involvement\t1 (liver)\t\nFLIPI\t\t\nLow\t1\t\nLow-intermediate\t6\t\nIntermediate-high\t2\t\nBulky disease\t1\t\nB-symptoms\t0\t\nPrevious therapy including rituximab\t\t\n No\t2\t\n Yes\t7\t\nNumber of previous regimens\t\t\n 1\t2\t\n 2\t5\t\n > 2\t2\t\nTable 2 Clinical characteristics\n\nPatients n\n\tSex/Age (y)\tPrevious treatment\tResponse to FCR\tResponse to RIT\tFollow up (mo) since RIT\t\n1\tF/68\tCHOP/R,radiotherapy\tCR\tCR\t104 alive in CR\t\n2\tF/66\tRadiotherapy, CHOP/R\tCR\tCR\t88 alive in CR\t\n3\tF/57\tCHOP/R\tPR\tCR\t99 alive in CR\t\n4\tF/67\tCHOP/R, radiotherapy\tCR\tCR\t13 dead in CR\t\n5\tM/46\tCHOP/like, ASCT, IFN maintenance for 24 months\tPR\tCR\t83 alive in CR\t\n6\tF/61\tMACOPB/R\tCR\tCR\t92 alive in CR\t\n7\tM/69\tCHOP, FM/R, CyDex/R\tCR\tCR\t30 dead in CR (t-MDS)\t\n8\tM/57\tChlorambucil, MACOPB/R\tCR\tCR\t32 dead in CR\t\n9\tF/77\tChlorambucil, radiotherapy\tCR\tCR\t99 alive in CR\t\n\nCHOP cyclophosfamide, doxorubicin, vincristine, prednisone; R Rituximab; MACOPB Methotrexate, Doxorubicin, cyclophoshamide, vincristine, prednisone, bleomycin; ASCT autologous stem cell transplantation; IFN alpha interferon, FM fludarabine, mitoxantrone; Cy Dex cyclophosphamide, dexamethasone; t-MDS treatment-related myelodysplastic syndrome\n\n\n\nEfficacy and safety\nAfter 4 cycles of FCR 7 patients obtained CR and 2 PR, 2 patients in PR converted to CR after 90Y-RIT. In February 2015, with a median observation period of 95 months (range 20–114) since FCR and 88 months (range 13–104) since RIT, the median OS and the PFS have not been reached, 6/9 patients were alive in CR and current analysis has shown that either OS or PFS are 67 % at 7.5 year (Fig. 1). Grade 3 or 4 neutropenia occurred in 8/9 patients treated with FCR and in 9/9 patients assessable after 90Y-RIT. Subsequently to radioimmunotherapy the median neutrophil nadir was 0.8 × 109/ L (range 0.1-0.9 × 109/ L) at week 5, the median platelet count nadir was 49 × 109/ L (range 17–80 × 109/ L) at week 5. The median duration nadir for both neutrophils or platelets was 14 days. One patient developed herpes zoster infection after 8 months following valacyclovir discontinuation; another patient developed fungal infection. Both infections disappeared after specific treatment. One patient developed t-MDS (treatment-related myelodysplastic syndrome) at 26 months after 90Y-RIT. This patient before FCR and consolidation with 90Y-RIT had received 3 previous regimens: at diagnosis 6 courses of CHOP, at first relapse, 3 years later, 4 courses of FM/R (fludarabine, mitoxantrone plus rituximab) and after 1 year at the second relapse the patient received cyclophosphamide plus dexamethasone and rituximab, remaining in CR for 48 months. The patient died at 73 years of age of sepsis during support therapy for t-MDS. Other 2 patients died: 1 for acute renal failure and 1 for ictus cerebri.Fig. 1 Progression Free Survival from RIT\n\n\n\nDiscussion\nCytotoxic chemotherapies lose efficacy with subsequent rounds of therapy in the retreatment of follicular lymphoma, eventually leading to refractory disease, however the question remains whether the survival of patients with FL is improving with new treatment regimens.\n\nIn the current retrospective analysis, nine patients with relapsed grade 1 and 2 FL, responding to FCR regimen and consolidated with 90Y–RIT obtained a significant high rate of response with 100 % of CR and acceptable toxicity. The conversion from PR to CR was already shown in the published phase III study (FIT-study) in first-line FL [3, 4] and also in phase II studies [5–12] of consolidation with the radioimmunotherapy agent 131 I-tositumomab after first-line induction [19, 20] thus, confirming the ability of 90Y-RIT to improve responses also in patients who are pretreated with rituximab based combination therapy [3]; even if in our two patients there is no proof that this conversion was due to RIT and not to a late response to FCR. In the FIT study, close to 17 % of the patients in the control arm, converted from PR to CR during watchful waiting [3], but our 2 patients who had higher risk of resistance already being pretreated must be considered.\n\nIn our analysis, the OS at 2 years was 89 %, at 3 years 76 % and at 4 years 61 % and OS and PFS are 67 % at 7.5 years. In another study conducted on patients with recurrent FL, treated with FCR, 75 % OS rate at 4 years and 61 % PFS rate at 4 years were registered, but in that study only 7 % of patients had been treated previously with rituximab and furthermore no patients had received combination treatment with chemotherapy plus rituximab [21]. Furthermore our results are in line with those recently described in a Japanese study [22] on 94 patients with relapsed or refractory low grade B cell non-Hodgkin lymphoma, among them 61 patients with grade 1 and 2 FL, treated with 90Y-RIT alone as salvage therapy and showing a CR rate of 69 %. In the Japanese cohort, during a median follow up of 46.5 months, the PFS rates of the first 50 patients who had undergone ≤ 2 and ≥ 3 previous regimens, and for those who achieved CR compared with those who did not were 38 and 11 months, respectively; the number of previous regimens and CR were statistically significant (p = 0.0011 and p < 0.0001, respectively). In our study 7/9 patients underwent ≤ 2 previous regimens before FCR and all of patients reached CR after 90Y-RIT with a PFS of 67 % at 7.5 years. Regarding AEs no grade 3 or 4 anemia was noted and no erythropoietic growth factors were used; there was high incidence of grade 3 or 4 neutropenia and thrombocytopenia but no platelet transfusions were necessary and granulocyte colony-stimulating factors were utilized in the majority of patients during FCR treatment and in all of them after 90Y–RIT. Despite the high incidence of grade 3 or 4 neutropenia, there were no patients requiring hospitalization for infection. We registered a case of herpes zoster infection after 8 months following valacyclovir discontinuation that disappeared after retreatment, and a case of fungal infection by conidiobolus, developed 10 months after 90Y-RIT and disappeared with itraconazole treatment. Other previous studies have already shown the low percentage of patients requiring hospitalization for infections [3, 15] and a favorable safety profile [23, 24]. A case of t-MDS with complex karyotype was diagnosed 26 months after 90Y-RIT consolidation: this patient received 3 previous regimens before FCR plus 90Y-RIT and as already mentioned the patient died of sepsis. This patient had been previously treated with topoisomerase II inhibitors, alkylating agents and purine nucleoside analogs. Czuczman et al. reported incidence of t-MDS and t-AML (treatment-related acute myeloid leukemia) after 90Y–RIT of 0.3 % per year after the diagnosis of NHL and 0.7 % per year after treatment. Most patients with t-MDS or t-AML had multiple cytogenetic aberrations, commonly on chromosomes 5 and 7, suggesting an association with previous exposure to chemotherapy. In Czuczman study, these malignancies were diagnosed at a median of 5.6 years (range 1.4 to 13.9) after the diagnosis of NHL and 1.9 years (range 0.4 to 6.3) after radioimmunotherapy [25]. The conclusion of this study was that the annualized incidences of t-MDS and t-AML were consistent with that expected in patients with NHL who had extensive previous chemotherapy and did not seem to increase after 90Y-RIT. However, in the FIT study 8 patients who developed MDS/AML were treated with 90Y-RIT, suggesting a role played by 90Y-RIT in the risk of secondary MDS/AML, thus it is reasonable to consider monitoring these patients closely. Cytogenetic testing before treatment with RIT may identify existing chromosomal abnormalities in previously treated patients, particularly those who have been treated with alkylating agents and purine analogs and would be at higher risk of developing t-MDS or t-AML.\n\nIn our series, the other two deaths were not related to progressive disease and all three deceased patients obtained CR before 90Y-RIT and died still in CR; so far the six survivors have maintained a high quality of life without having to make many visits to the hospital due to toxicity. Additional follow up is required to determine potential long-term AEs with 90Y-RIT consolidation. In our patients, the response to 90Y-RIT was assessed by CT, bone marrow biopsies and also with FDG-PET. This imaging procedure is useful to evaluate disease extension before treatment and response to RIT in FL. A study has shown that the post-90Y–RIT PET result is an independent predictive factor of PFS [26].\n\nConclusions\nThis retrospective analysis of 9 relapsed grades 1 or 2 FL heavily pretreated patients with median age 63 years demonstrates that sequential treatment with FCR and 90Y-RIT did not give rise to cumulative toxicity; it was feasible, safe and yielded high OS and PFS in patients with recurrent FL. Hematologic toxicity occurring with FCR or with 90Y-RIT was clinically controllable and acceptable in a population composed mainly of patients with a history of prior treatment using rituximab plus chemotherapy. With caution due to the low number of patients, these results suggest that this regimen could be an option used for the treatment in this setting of patients, specially at age of 60–75. 90Y-RIT as consolidation appears to be best suited to patients with low burden of disease and may be more acceptable in those who are not candidates for high dose therapy/transplant approaches.\n\nDesign and methods\nThe patients who were included in the current retrospective analysis had CD20+ histologically confirmed relapsed grade 1 or 2 follicular lymphoma and had received at least 1 prior treatment. In this single institution study, between August 2005 and July 2010, 9 patients at relapse had received 4 cycles of FCR: fludarabine at a dose of 25 mg/m2 i.v. on days 1 to 3; cyclophosphamide at a dose of 1 gr/ m2 i.v. on day 1 and rituximab at a dose of 375 mg/ m2 was given on day 4 of each cycle every 28 days. Patients were restaged with CT scan, FDG PET/CT and bone marrow biopsies after the last course of FCR, who had achieved at least a partial remission with < 25 % bone marrow involvement received, 12 weeks since the last course of FCR, 2 infusions of rituximab 250 mg/ m2 one week apart, with the first infusion administered alone and the second infusion followed immediately by 90 Y–RIT (14.8 MBq/Kg – 11 MBq/Kg), if the platelet number was between 100 x 109/ L and 149 x 109/ L, not exceeding a total of 1.184 MBq it was administered as a slow i.v. push over 10 min (Fig. 2). The patients were age ≥ 18 years, with WHO performance status of 0 to 2 and the last chemotherapy with or without rituximab was administered at least 3 months before start of FCR; no patient under maintenance therapy with rituximab was considered. Before starting 90Y-RIT an absolute neutrophil count ≥ 1.5 × 109 L, hemoglobin levels ≥ 9 gr/dl and a platelet count ≥ 100 × 109 L were required. None of the patients had central nervous system (CNS) involvement and positive HIV. All patients provided an informed consent according to institutional guidelines.Fig. 2 Treatment schema\n\n\n\nNo real-time quantitative PCR (RQ-PCR) evaluation of peripheral or marrow blood samples for bcl-2 t(14;18) translocation was performed at baseline nor thereafter. Safety was assessed by adverse events (AEs), with toxicity grading based on the National Cancer Institute Common Toxicity Criteria (version 4.0), clinical laboratory evaluations, and physical examinations. Filgrastim was administered when the neutrophil count was less than 1×109/L and platelet support was planned for eventual episodes of bleeding and platelet count less than 15×109/L. In patients developing grade 4 neutropenia or thrombocytopenia, the duration of cytopenia was measured from the first day of laboratory evidence of grade 4 toxicity until the last day of grade 4 toxicity without further support. OS was calculated from the date of FCR treatment to the date of death from any cause; OS was analyzed by using the Kaplan-Meier method.\n\nAbbreviations\nFCRFludarabine cyclophosphamide rituximab\n\nFLFollicular lymphoma\n\nNHLNon-Hodgkin lymphoma\n\nRITRadioimmunotherapy\n\nMeVMegaelectronvolt\n\nMBqMegabecquerel\n\nOSOverall survival\n\nPFSProgression free survival\n\nt-MDSTreatment related myelodysplastic syndrome\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nFP was the principal investigator and contributed to the study design, the writing of the report. Provision of study materials or patients: RS, MLD, DG, RK, SR, FM, MM. All the authors cited have been involved in drafting the manuscript and revising it critically for important intellectual content. All authors read and approved the final manuscript.\n\nThe technical assistance of Mrs. Tania Merlino is greatly appreciated.\n==== Refs\nReferences\n1. 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"fulltext_license": "CC BY",
"issn_linking": "2162-3619",
"issue": "4()",
"journal": "Experimental hematology & oncology",
"keywords": "90Y-ibritumomab tiuxetan; Follicular lymphoma; Radioimmunotherapy",
"medline_ta": "Exp Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "101590676",
"other_id": null,
"pages": "17",
"pmc": null,
"pmid": "26120498",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "18194857;12663713;19819921;22287683;25142378;24344981;16896003;19525191;18854568;21303501;18981007;17709799;17380530;17068667;23547079;20147744;15681517;24883180;16649223;16690521;18342572;23573825;21700527;17503433;16110029",
"title": "Long term efficacy and safety of Fludarabine, Cyclophosphamide and Rituximab regimen followed by (90)Y-ibritumomab tiuxetan consolidation for the treatment of relapsed grades 1 and 2 follicular lymphoma.",
"title_normalized": "long term efficacy and safety of fludarabine cyclophosphamide and rituximab regimen followed by 90 y ibritumomab tiuxetan consolidation for the treatment of relapsed grades 1 and 2 follicular lymphoma"
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"abstract": "We report clinicopathological features of a 23-year-old woman with Down syndrome (DS) presenting with subacute myelopathy treated with chemotherapy, including intravenous and intrathecal administration of methotrexate (MTX), and with allogenic bone-marrow transplantation for B lymphoblastic leukemia. Autopsy revealed severe demyelinating vacuolar myelopathy in the posterior and lateral columns of the spinal cord, associated with macrophage infiltration, marked axonal loss and some swollen axons. Pathological changes of posterior and lateral columns were observed from the medulla oblongata to lumbar cord. Proximal anterior and posterior roots were preserved. Cerebral white matter was relatively well preserved. There were no vascular lesions or meningeal dissemination of leukemia. Longitudinal extension of cord lesions was extensive, unlike typical cases of subacute combined degeneration (SACD), but distribution of lesions and histological findings were similar to that of SACD. DS patients show heightened sensitivity to MTX because of their genetic background. Risk factors for toxic myelopathy of DS are discussed, including delayed clearance of MTX despite normal renal function, alterations in MTX polyglutamation and enhanced folic acid depletion due to gene dosage effects of chromosome 21. Alteration of folate metabolism and/or vitamin B12 levels through intravenous or intrathecal administration of MTX might exist, although vitamin B12 and other essential nutrients were managed using intravenous hyperalimentation. To the best of our knowledge, this is the first report of an autopsy case that shows myelopathy mimicking SACD in a DS patient accompanied by B lymphoblastic leukemia. The case suggests a pathophysiological mechanism of MTX-related myelopathy in DS patients with B lymphoblastic leukemia mimicking SACD.",
"affiliations": "Department of Pathology, Division of Pediatric Oncology, National Center for Child Health and Development, Tokyo; Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki.",
"authors": "Satomi|Kaishi|K|;Yoshida|Mari|M|;Matsuoka|Kentaro|K|;Okita|Hajime|H|;Hosoya|Yosuke|Y|;Shioda|Yoko|Y|;Kumagai|Masa-Aki|MA|;Mori|Tetsuya|T|;Morishita|Yukio|Y|;Noguchi|Masayuki|M|;Nakazawa|Atsuko|A|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D008727:Methotrexate",
"country": "Australia",
"delete": false,
"doi": "10.1111/neup.12114",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0919-6544",
"issue": "34(4)",
"journal": "Neuropathology : official journal of the Japanese Society of Neuropathology",
"keywords": "Down syndrome; methotrexate; myelopathy; precursor B-cell lymphoblastic leukemia-lymphoma; subacute combined degeneration",
"medline_ta": "Neuropathology",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D004314:Down Syndrome; D005260:Female; D005493:Folic Acid Antagonists; D006801:Humans; D015448:Leukemia, B-Cell; D008727:Methotrexate; D013118:Spinal Cord Diseases; D052879:Subacute Combined Degeneration; D055815:Young Adult",
"nlm_unique_id": "9606526",
"other_id": null,
"pages": "414-9",
"pmc": null,
"pmid": "24661121",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Myelopathy mimicking subacute combined degeneration in a Down syndrome patient with methotrexate treatment for B lymphoblastic leukemia: report of an autopsy case.",
"title_normalized": "myelopathy mimicking subacute combined degeneration in a down syndrome patient with methotrexate treatment for b lymphoblastic leukemia report of an autopsy case"
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"activesubstancename": "METHOTREXATE"
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"abstract": "Endophthalmitis post glaucoma drainage implant (GDI) surgery is rare, often associated with tube or plate exposure. We report a case of endophthalmitis following glaucoma shunt intraluminal stent exposure in a patient who underwent Baerveldt glaucoma implant surgery. Endophthalmitis following manipulation of intraluminal stents is a rare complication of GDIs but potentially vision threatening condition that needs to be carefully screened for and treated immediately. How to cite this article: Kwon HJ, Kerr NM, Ruddle JB, Ang GS. Endophthalmitis associated with Glaucoma Shunt Intraluminal Stent Exposure. J Curr Glaucoma Pract 2016;10(1):36-37.",
"affiliations": "Resident and Clinical Observer, Department of Ophthalmology, The Royal Victorian Eye and Ear Hospital, Victoria, Australia.;Glaucoma Fellow, Department of Ophthalmology, The Royal Victorian Eye and Ear Hospital, Victoria, Australia.;Consultant, Department of Ophthalmology, The Royal Victorian Eye and Ear Hospital, Victoria, Australia.;Consultant, Department of Ophthalmology, The Royal Victorian Eye and Ear Hospital, Victoria, Australia.",
"authors": "Kwon|Hye Jin|HJ|;Kerr|Nathan M|NM|;Ruddle|Jonathan B|JB|;Ang|Ghee Soon|GS|",
"chemical_list": null,
"country": "India",
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"doi": "10.5005/jp-journals-10008-1199",
"fulltext": "\n==== Front\nJ Curr Glaucoma PractJ Curr Glaucoma PractJOCGPJournal of Current Glaucoma Practice0974-03330975-1947Jaypee Brothers Medical Publishers 10.5005/jp-journals-10008-1199Case ReportEndophthalmitis associated with Glaucoma Shunt Intraluminal Stent Exposure Kwon Hye Jin Resident and Clinical Observer, Department of Ophthalmology, The Royal Victorian Eye and Ear Hospital, Victoria, AustraliaKerr Nathan M Glaucoma Fellow, Department of Ophthalmology, The Royal Victorian Eye and Ear Hospital, Victoria, AustraliaRuddle Jonathan B Consultant, Department of Ophthalmology, The Royal Victorian Eye and Ear Hospital, Victoria, AustraliaAng Ghee Soon Consultant, Department of Ophthalmology, The Royal Victorian Eye and Ear Hospital, Victoria, AustraliaHye Jin Kwon, Resident and Clinical Observer, Austin Health, 145 Studley Rd, Heidelberg, VIC 3084 Australia, Phone: 61399298666, e-mail: hkwon724@gmail.comJan-Apr 2016 12 5 2016 10 1 36 37 12 12 2015 22 1 2016 Copyright © 2016; Jaypee Brothers Medical Publishers (P) Ltd.2016\nThis work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit\nhttp://creativecommons.org/licenses/by/3.0/ABSTRACT\nEndophthalmitis post glaucoma drainage implant (GDI) surgery is rare, often associated with tube or plate exposure.\n\nWe report a case of endophthalmitis following glaucoma shunt intraluminal stent exposure in a patient who underwent Baerveldt glaucoma implant surgery.\n\nEndophthalmitis following manipulation of intraluminal stents is a rare complication of GDIs but potentially vision threatening condition that needs to be carefully screened for and treated immediately.\n\nHow to cite this article: Kwon HJ, Kerr NM, Ruddle JB, Ang GS. Endophthalmitis associated with Glaucoma Shunt Intraluminal Stent Exposure. J Curr Glaucoma Pract 2016;10(1):36-37.\n\nKeywords\nCase studyEndophthalmitisGlaucoma shuntIntraluminal stent.\n==== Body\nBACKGROUND\nIntraluminal stents are an effective method of reducing hypotony following glaucoma shunt surgery.1 We report a case of endophthalmitis associated with intraluminal stent exposure that highlights the importance of early repair of stent exposure, preferably in the operating theater.\n\nCASE REPORT\nA 64 years old man presented to the emergency department with a 2-weeks history of a red and painful right eye. Five weeks prior to presentation, a Baerveldt 350 mm2 (Pharmacia and Upjohn, Kalamazoo, MI) tube with intraluminal stent (3-0 Supramid Extra TM) had been inserted superotemporally. After exiting the plate, the suture was buried in inferotemporal subconjunctival space. His glaucoma was due to a combination of neovascular and steroid-induced glaucoma for 7 months post intravitreal triamcinolone for bevacizumab-resistant diabetic macular edema. Prior to shunt surgery, the visual acuity was 6/15 in his right eye and the intraocular pressure (IOP) was 30 mm Hg on maximum medical therapy. He had a previous history of cataract surgery but no other glaucoma surgery. Surgery was uneventful and his IOP was initially well-controlled at 15 mm Hg without medical therapy.\n\nOn slit-lamp examination, trace cells were observed in the anterior chamber and the end of the intraluminal suture tip was noted to be exposed through a small conjunctival defect. The exposed suture was trimmed and the patient was prescribed topical chloramphenicol 0.5% four times a day and prednisolone acetate 1% 2-hourly.\n\nOn review 1 month later, the intraluminal suture tip was noted to be exposed again without any signs of intraocular inflammation. His right eye IOP was 22 mm Hg, persistently above target. The intraluminal suture was removed at the slit lamp with povidone iodine 5% antisepsis. Intraocular pressure was measured 30 minutes following removal and remained 22 mm Hg. He was again prescribed topical chloramphenicol 0.5% four times a day and prednisolone acetate 1% 2-hourly.\n\nOne week after stent removal, the patient presented to the emergency department with a 3-day history of a red and painful right eye with reduced vision. He was using topical prednisolone acetate 1% 2-hourly but was non-adherent with topical antibiotics. On examination, the visual acuity in his right eye was perception of light. Fibrin was present in the anterior chamber and there was a 1 mm hypopyon (Fig. 1). B-scan showed vitreous debris. The patient was diagnosed with endophthalmitis and was admitted for urgent intravitreal antibiotics and vitrectomy. Repeat intravitreal tap and injections were performed on days 2 and 6 following vitrectomy due to ongoing intraocular inflammation. Microscopy showed a moderate amount of polymorphs in the aqueous and vitreous but no organisms were identified on culture at any stage. After discussion with the vitreoretinal surgeon, a decision was made not to remove the Baerveldt tube given the poor visual prognosis and because the patient’s pain and inflammation were improving. Seven months following endophthalmitis his visual acuity was hand movements and the IOP was 3 mm Hg in his right eye.\n\nFig. 1: Hypopyon and track of pus from tube at presentation with endophthalmitis\n\nDISCUSSION\nEarly hypotony may complicate glaucoma shunt surgery. Hypotony can be limited by external ligation and partial occlusion of the tube with an intraluminal stent, such as 3-0 braided nylon (Supramid Extra TM) or 3-0 polypropylene (Prolene TM).2 Intraluminal stents are placed in the inferior subconjunctival space to allow easy access for later removal. The intraluminal suture can be removed through a conjunctival incision in clinic or theater when sufficient bleb resistance has formed and the IOP is above target.1\n\nInfective endophthalmitis has been described due to tube or plate exposure, plate revision, and conjunctival dehiscence following glaucoma shunt insertion.3 One study in 1990 by Ball and Scharfenberg described the development of non-infective hypopyon in 7 out of 27 eyes following removal of intraluminal stents (4-0 chromic suture, ethicone) after Molteno tube surgery. The authors postulated that this was due to a drop in IOP at the time of suture removal causing inflammatory cells located around the chromic suture to be drawn into the anterior chamber.4 Recent studies looking at complications of glaucoma shunts have not reported any endophthalmitis related to the intraluminal stent.15\n\nIn our case, previous exposure of the intraluminal suture may have led to colonization of the stent with microorganisms. Seeded inflammatory cells or bacteria may have subsequently tracked along the tube when the suture was removed. Despite the use of iodine antisepsis, suture manipulation in clinic may have contributed to the development of endophthalmitis. In addition, systemic and local immunosuppression from poorly controlled diabetes and intravitreal steroid injection respectively may have increased the risk of infection.6\n\nCONCLUSION\nThis case highlights the importance of immediate repair or removal of exposed intraluminal stents to prevent the development of endophthalmitis. Despite the burden of increased healthcare costs, stent removal in theater should be considered.3 Doing so enables a more controlled release of the suture in a sterile environment, thus preventing the reflux of cells into the anterior chamber and reducing the risk of intraocular infection.\n\nSource of support: Nil\n\nConflict of interest: None\n==== Refs\nREFERENCES\n1 Sharkawi E Oleszczuk JD Barton K Systematic occlusion of shunts: control of early postoperative IOP and hypotony-related complications following glaucoma shunt surgery. J Glaucoma 2016 1 25 1 54 61 25383464 \n2 Sherwood MB Smith MF Prevention of early hypotony associated with Molteno implants by a new occluding stent technique. Ophthalmol 1993 100 1 85 90 \n3 Francis BA Diloreto DA Chong LP et al. Late-onset bacterial endophthalmitis following glaucoma drainage implantation. Ophthal Surg Laser Imag 2003 34 2 128 130 \n4 Ball SF Loftfield K Scharfenberg J Molteno rip-cord suture hypopyon. Ophthal Surg 1990 6 407 411 \n5 Jacob J Stalmans I Zeyen T Ahmed and Baerveldt glaucoma drainage implants: long-term results and factors influencing outcome. Bull Soc Belge Ophthalmol 2009 313 19 29 \n6 Moshfeghi DM Kaiser PK Scott IU et al. Acute endo-phthalmitis following intravitreal triamcinolone acetonide injection. Am J Ophthalmol 2003 136 5 791 796 14597028\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0974-0333",
"issue": "10(1)",
"journal": "Journal of current glaucoma practice",
"keywords": "Case study; Endophthalmitis; Glaucoma shunt; Intraluminal stent.",
"medline_ta": "J Curr Glaucoma Pract",
"mesh_terms": null,
"nlm_unique_id": "101492611",
"other_id": null,
"pages": "36-7",
"pmc": null,
"pmid": "27231417",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "8433833;14597028;25383464;24877478;20108569;2381675",
"title": "Endophthalmitis associated with Glaucoma Shunt Intraluminal Stent Exposure.",
"title_normalized": "endophthalmitis associated with glaucoma shunt intraluminal stent exposure"
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"abstract": "Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor that is used as one of the first-line antihypertensive medications. Necrotizing pancreatitis induced by the use of ACE inhibitors is an extremely rare occurrence. Although an uncommon risk factor, our aim is to further highlight that patients with chronic use of lisinopril can develop such complications and should be considered among the list of differential diagnoses for pancreatitis. A 53-year-old Caucasian male with a history of hypertension treated with lisinopril presented with a one-day history of nausea, vomiting, and severe epigastric pain. On physical examination, there was tenderness to palpation in the epigastric region and left lower quadrant without rebound tenderness or guarding. A complete blood count showed a slight increase in white blood cell count to 12,000 cells/mm3 and serum lipase level was elevated at 1028 U/L. A subsequent CT scan of the abdomen with contrast revealed findings supporting necrotizing pancreatitis. The patient was treated with conservative medical management with goal-directed intravenous fluid support, early enteral feeding, and pain control. His condition resolved, and he was found doing well on follow-up visits.",
"affiliations": "Internal Medicine, University of Illinois College of Medicine at Peoria - OSF Saint Francis Medical Center, Peoria, USA.;Internal Medicine, Icahn School of Medicine at Mount Sinai, Elmhurst Hospital Center, Elmhurst, USA.;Gastroenterology, University of Illinois College of Medicine at Peoria - OSF Saint Francis Medical Center, Peoria, USA.",
"authors": "Syed|Salman B|SB|;Reyes|Jonathan Vincent M|JVM|;Baig|Muhammad|M|",
"chemical_list": null,
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"doi": "10.7759/cureus.14642",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.14642\nInternal Medicine\nRadiology\nGastroenterology\nLisinopril-Induced Acute Necrotizing Pancreatitis\nMuacevic Alexander\nAdler John R\nSyed Salman B 1\nReyes Jonathan Vincent M 2\nBaig Muhammad 3\n1 Internal Medicine, University of Illinois College of Medicine at Peoria - OSF Saint Francis Medical Center, Peoria, USA\n2 Internal Medicine, Icahn School of Medicine at Mount Sinai, Elmhurst Hospital Center, Elmhurst, USA\n3 Gastroenterology, University of Illinois College of Medicine at Peoria - OSF Saint Francis Medical Center, Peoria, USA\nSalman B. Syed salman.syed@osfhealthcare.org\n23 4 2021\n4 2021\n13 4 e1464223 4 2021\nCopyright © 2021, Syed et al.\n2021\nSyed et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/53511-lisinopril-induced-acute-necrotizing-pancreatitis\nLisinopril is an angiotensin-converting enzyme (ACE) inhibitor that is used as one of the first-line antihypertensive medications. Necrotizing pancreatitis induced by the use of ACE inhibitors is an extremely rare occurrence. Although an uncommon risk factor, our aim is to further highlight that patients with chronic use of lisinopril can develop such complications and should be considered among the list of differential diagnoses for pancreatitis.\n\nA 53-year-old Caucasian male with a history of hypertension treated with lisinopril presented with a one-day history of nausea, vomiting, and severe epigastric pain. On physical examination, there was tenderness to palpation in the epigastric region and left lower quadrant without rebound tenderness or guarding. A complete blood count showed a slight increase in white blood cell count to 12,000 cells/mm3 and serum lipase level was elevated at 1028 U/L. A subsequent CT scan of the abdomen with contrast revealed findings supporting necrotizing pancreatitis. The patient was treated with conservative medical management with goal-directed intravenous fluid support, early enteral feeding, and pain control. His condition resolved, and he was found doing well on follow-up visits.\n\nlisinopril\nacute pancreatitis\nnecrotizing pancreatitis\npancreas\nace inhibitor induced pancreatitis\nangiotensin converting enzyme inhibitor\ndrug induced pancreatitis\nlisinopril induced pancreatitis\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nAbout less than 0.1-2.0% of total acute pancreatitis cases have been related to drug use [1]. Diagnosis of drug-related pancreatitis is difficult to establish. In addition, a causal relationship is difficult to determine as patients are not re-challenged with the drug due to ethical considerations and due to the risk of inducing a life-threatening situation [2]. However, recurrent acute pancreatitis secondary to the repeated use of lisinopril has been reported in the literature [3].\n\nTo the best of our knowledge, based on an extensive review of the literature using PubMed, Google Scholar, and Medline only one other case has been reported about necrotizing pancreatitis with the use of lisinopril [4]. The exact mechanisms for angiotensin-converting enzyme (ACE) inhibitor-induced pancreatitis are unknown; however, many theories have been proposed. It is known that ACE inhibitors increase serum bradykinin concentrations, the mechanism linked to ACE-induced angioedema. A local accumulation of bradykinin may lead to both angioedema and acute pancreatitis. Therefore, it is thought that they may also cause localized angioedema in the pancreas, resulting in pancreatic duct obstruction. Some studies suggest that they may cause an increase in pancreatic enzymes (amylase and lipase) production as well as the formation of antibodies directed against the pancreatic cells [2]. ACE inhibitors are antihypertensives that may also precipitate pancreatic ischemia [4].\n\nAs the rate of hospitalizations related to acute pancreatitis in the United States continues to rise, it is imperative for physicians to diagnose offending agents to reduce the overutilization of our healthcare system [5]. Gallstones and alcohol use are the two most common causes of acute pancreatitis. The other causes of pancreatitis are rare and sometimes mislabeled as idiopathic. An accurate diagnosis will prevent readmission, decrease mortality, and provide the medical community with answers to unsolved questions.\n\nCase presentation\n\nA 53-year-old male presented to the emergency room with a one-day history of nausea, vomiting, and epigastric pain. The patient’s pain was severe in intensity and located in the mid-epigastric region with no reported abdominal trauma. His pain was associated with constant nausea and two episodes of non-bilious and non-bloody emesis episodes. He denied any febrile episodes, gastrointestinal overt bleeding, and chronic weight loss. He did not have any history of cigarette smoking, alcohol abuse disorder, or illicit drug usage. His past medical history was significant for essential hypertension being treated with oral lisinopril 20 mg daily. On physical examination, he was hemodynamically stable with body temperature, blood pressure, and heart rate of 37.3 °C, 140/90 mmHg, and 84 beats/min, respectively. Abdominal examination revealed tenderness to palpation in the epigastric region without rebound tenderness or guarding. At this point, our differential diagnosis was broad which included viral gastroenteritis, peptic ulcer disease, acute pancreatitis, acute cholecystitis, and choledocholithiasis.\n\nThe following investigations were normal or negative: complete metabolic panel, urinalysis, lipid profile, electrocardiogram, and chest X-ray. A complete blood count showed a slight increase in white blood cell count to 12,000 cells/mm3 and serum lipase level was elevated at 1028 U/L. Calcium levels were 9.5 mg/dl (within the reference range), triglycerides were 54 mg/dl (reference for age <150 mg/dl), blood ethanol levels within normal limits, HIV test was nonreactive and IgG4 test was negative. Ultrasound of the abdomen showed no acute sonographic abnormality, no gallstones, and no ductal dilation. A CT scan of the abdomen showed pancreatic inflammation and pancreatic necrosis (Figure 1).\n\nFigure 1 Diffuse hypoattenuation of the pancreatic parenchyma with peripancreatic fat stranding. Non-enhancing homogeneous fluid adjacent to the tail of the pancreas and within the left pararenal space (red arrows).\n\nDiagnosis of acute necrotizing pancreatitis was established on the basis of physical examination, elevated serum lipase levels, and imaging findings, and conservative management was initiated with goal-directed intravenous fluid support (Lactated Ringer's at 250 ml/hr), early enteral feeding, and pain control. Diet was cautiously advanced over the course of hospitalization. As lisinopril was thought to be the possible cause of necrotizing pancreatitis, it was added to his list of allergic medications, and a different class of antihypertensive medication was commenced. \n\nOutcome and follow up\n\nThe patient showed gradual clinical improvement and was discharged home on day 7. He was noted to be asymptomatic on subsequent outpatient visits.\n\nDiscussion\n\nThis report highlights that acute necrotizing pancreatitis can occur within therapeutic dose ranges of Lisinopril. Lisinopril-induced necrotizing pancreatitis is very rare; in addition to this case, there is only one other case reported based on extensive literature review. Literature reveals a variable onset of ACE inhibitor-induced pancreatitis. In this patient, the onset of pancreatitis was chronic, occurring after nine months of drug administration. Alternative causes such as alcohol use, gallstones, hypertriglyceridemia, blunt or penetrating abdominal trauma, autoimmune disorders, hypercalcemia, infection, anatomic, and genetic causes were excluded secondary to the patient’s history and laboratory findings. Therefore, a diagnosis of drug-induced pancreatitis was established.\n\nThe exact mechanism of this drug-induced pancreatitis has not yet been established; however, theories exist within the literature in the form of case reports, animal studies, and other observational data. Some of these theories include bradykinin accumulation, direct toxic effect, and upregulation of matrix metalloproteinase 9 (MMP-9) [6,7]. ACE inhibitors decrease the degradation of bradykinin which is linked to the known rare complication of angioedema. Bradykinin, a potent vasodilator, has been observed to cause localized angioedema around the pancreatic duct and increase vascular permeability allowing enzymes and toxic substances to invade the pancreas causing inflammation [1,2,8]. The theory that upregulation of MMP-9 leads to ACE inhibitor-induced pancreatitis comes from an animal study by Chen et al. The hypothesis is that MMP-9 also increases vascular permeability and increases the expression of transforming growth factor-beta which is involved in the regulation of inflammation, especially in the gut [9].\n\nThe severity of drug-induced pancreatitis varies and can range from mild to life-threatening. The exact incidence is unclear and potentially much higher due in part to possible poor recognition, especially for mild cases. Management of drug-induced pancreatitis includes discontinuation of the drug in question and supportive care.\n\nConclusions\n\nAs the common causes for pancreatitis were excluded, we concluded that the cause of our patient’s acute pancreatitis was secondary to his lisinopril use. Ethically, this patient did not undergo a re-challenge and lisinopril was placed under the allergy list. Lisinopril, a commonly prescribed medication for hypertension, should not be overlooked when doing a medication reconciliation during hospital admission for acute pancreatitis. This case report will serve as evidence for this rare complication and add to the existing literature regarding ACE inhibitors and necrotizing pancreatitis. Physicians should always consider drug-induced pancreatitis as part of the differential diagnosis for acute pancreatitis.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Drug-induced acute pancreatitis: a review Ochsner J Jones MR Hall OM Kaye AM Kaye AD 45 51 15 2015 https://pubmed.ncbi.nlm.nih.gov/25829880/ 25829880\n2 Simultaneous acute pancreatitis and angioedema associated with angiotensin-converting enzyme inhibitor Saudi J Kidney Dis Transpl Gorsane I Ayed TB Aoudia R Kaaroud H Hamida FB Harzallah A Abdallah TB 1479 1484 30 2019 31929301\n3 Recurrent acute pancreatitis probably secondary to lisinopril South Med J Kanbay M Selcuk H Yilmaz U Boyacioglu S 1388 1389 99 2006 17233197\n4 A case of fatal necrotizing pancreatitis: complication of hydrochlorothiazide and lisinopril therapy Dig Dis Sci Bedrossian S Vahid B 558 560 52 2007 17219076\n5 Trends and outcomes of hospitalizations related to acute pancreatitis: epidemiology from 2001 to 2014 in the United States Pancreas Gapp J Hall AG Walters RW Jahann D Kassim T Reddymasu S 548 554 48 2019 30946239\n6 Drug-induced isolated visceral angioneurotic edema Intern Med Arakawa M Murata Y Rikimaru Y Sasaki Y 975 978 44 2005 16258215\n7 Angiotensin-converting enzyme inhibitor-induced pancreatitis Clin Cardiol Muchnick JS Mehta JL 50 51 22 1999 9929757\n8 A rare cause of pediatric acute pancreatitis: perindopril intoxication Turk J Emerg Med Misirlioglu M Yildizdas D Ekinci F Horoz OO Yontem A 199 201 20 2020 33089030\n9 Captopril, an angiotensin-converting enzyme inhibitor, attenuates the severity of acute pancreatitis in rats by reducing expression of matrix metalloproteinase 9 Tohoku J Exp Med Chen P Yuan Y Wang S Zhan L Xu J 99 107 209 2006 16707851\n\n",
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"issn_linking": "2168-8184",
"issue": "13(4)",
"journal": "Cureus",
"keywords": "ace inhibitor induced pancreatitis; acute pancreatitis; angiotensin converting enzyme inhibitor; drug induced pancreatitis; lisinopril; lisinopril induced pancreatitis; necrotizing pancreatitis; pancreas",
"medline_ta": "Cureus",
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"references": "25829880;31929301;16707851;33089030;9929757;17233197;17219076;30946239;16258215",
"title": "Lisinopril-Induced Acute Necrotizing Pancreatitis.",
"title_normalized": "lisinopril induced acute necrotizing pancreatitis"
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"abstract": "A 37-year-old woman who had 8 weeks post partum, breast feeding and on a low carbohydrate and high protein (ketogenic) diet, was admitted to the hospital with acute onset of nausea, vomiting and abdominal pain of 1-day duration. On admission, she was found to have high anion gap metabolic acidosis, elevated beta-hydroxybutyric acid level, normal glucose level and evidence of ketoacidosis. She was treated with lactated Ringer solution, along with dextrose 5% solution with the resolution of symptoms and metabolic derangement.",
"affiliations": "Internal Medicine, Kent Hospital, Northborough, Massachusetts, USA ali_alkhayat@brown.edu.;Internal Medicine, Kent Hospital, Warwick, Rhode Island, USA.;Division of Pulmonary, Critical Care and Sleep Medicine, Brown University Warren Alpert Medical School, Providence, Rhode Island, USA.;Division of Pulmonary and Critical Care Medicine, South Shore Hospital, Weymouth, Massachusetts, USA.",
"authors": "Alkhayat|Ali|A|;Arao|Kevin|K|;Minami|Taro|T|;Manzoor|Kamran|K|",
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"keywords": "diet; nutrition and metabolism",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D020155:3-Hydroxybutyric Acid; D015746:Abdominal Pain; D000136:Acid-Base Equilibrium; D000328:Adult; D001786:Blood Glucose; D001942:Breast Feeding; D003937:Diagnosis, Differential; D050528:Diet, Carbohydrate-Restricted; D055423:Diet, Ketogenic; D005260:Female; D005947:Glucose; D006801:Humans; D007662:Ketosis; D049590:Postpartum Period; D000077325:Ringer's Lactate; D016896:Treatment Outcome; D014839:Vomiting",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32606112",
"pubdate": "2020-06-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ketoacidosis associated with ketogenic diet in a non-diabetic lactating woman.",
"title_normalized": "ketoacidosis associated with ketogenic diet in a non diabetic lactating woman"
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"abstract": "New potent direct-acting antiviral (DAA) regimens against hepatitis C virus have been approved in recent years. However, information about the rate of adverse events (AEs) across different DAA regimens is limited. We aimed to evaluate differences in AEs and treatment efficacy in patients with chronic hepatitis C (CHC), genotype (GT) 1 or 3, randomized to two different treatment arms, correspondingly.\n\n\n\nWe randomly assigned 96 patients in a 1 : 1 ratio, to treatment for 12 weeks with either paritaprevir/ombitasvir/ritonavir/dasabuvir/ribavirin (RBV) or ledipasvir/sofosbuvir (SOF)/RBV if infected with GT1 (72 patients) or to daclatasvir/SOF/RBV for 12 weeks or SOF/RBV for 24 weeks, if infected with GT3 (24 patients). Data on AEs were collected throughout the entire study period.\n\n\n\nA total of 70 (97%) patients with CHC with GT1 and 20 (83%) patients with GT3 achieved cure. The GT3 treatment arm was prematurely terminated, owing to change in national treatment guidelines. Thus, only AEs for GT1 patients are described. AEs occurred in 70 (97%) GT1 patients, and most common AEs were anemia (n=56/78%), fatigue (n=53/74%), and headache (n=33/46%). No difference was observed in relation to treatment group (P=1.0), anemia (P=1.0), or liver cirrhosis (P=0.53). In seven (11%) patients, AEs assessed by the investigator to be possibly related to the DAA regimen were still present 12 weeks after treatment.\n\n\n\nWe found no difference in AEs possibly related to the DAA regimen in patients with CHC, but surprisingly, AEs possibly related to the DAA regimen persisted in a significant number of patients after treatment. This finding can be of importance for clinicians in relation to patient information concerning AEs possibly related to DAA treatment.",
"affiliations": "Departments of Infectious Diseases.;Departments of Infectious Diseases.;Department of Infectious Diseases, Odense University Hospital.;Department of Infectious Diseases, Aarhus University Hospital, Skejby.;Department of Medicine, Lillebaelt Hospital, Kolding, Denmark.;Hepatology, Copenhagen University Hospital, Rigshospitalet.;Departments of Infectious Diseases.;Department of Infectious Diseases, Odense University Hospital.;Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre.;Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen.;Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre.;Departments of Infectious Diseases.;Departments of Infectious Diseases.",
"authors": "Sølund|Christina|C|;Andersen|Ellen S|ES|;Mössner|Belinda|B|;Laursen|Alex L|AL|;Røge|Birgit T|BT|;Kjær|Mette S|MS|;Gerstoft|Jan|J|;Christensen|Peer B|PB|;Pedersen|Martin S|MS|;Schønning|Kristian|K|;Fahnøe|Ulrik|U|;Bukh|Jens|J|;Weis|Nina|N|",
"chemical_list": "D000813:Anilides; D000998:Antiviral Agents; D001562:Benzimidazoles; D002219:Carbamates; D003521:Cyclopropanes; D005449:Fluorenes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586541:ledipasvir; C586094:ombitasvir; D012254:Ribavirin; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir; D000069474:Sofosbuvir",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000001192",
"fulltext": null,
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"issn_linking": "0954-691X",
"issue": "30(10)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D015081:2-Naphthylamine; D000328:Adult; D000740:Anemia; D000813:Anilides; D000998:Antiviral Agents; D001562:Benzimidazoles; D002219:Carbamates; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005221:Fatigue; D005260:Female; D005449:Fluorenes; D005838:Genotype; D006261:Headache; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D008297:Male; D008875:Middle Aged; D011392:Proline; D012254:Ribavirin; D019438:Ritonavir; D000069474:Sofosbuvir; D013449:Sulfonamides; D016896:Treatment Outcome; D014498:Uracil; D014633:Valine; D019562:Viral Load",
"nlm_unique_id": "9000874",
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"pages": "1177-1186",
"pmc": null,
"pmid": "29994874",
"pubdate": "2018-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Outcome and adverse events in patients with chronic hepatitis C treated with direct-acting antivirals: a clinical randomized study.",
"title_normalized": "outcome and adverse events in patients with chronic hepatitis c treated with direct acting antivirals a clinical randomized study"
} | [
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"companynumb": "DK-KADMON PHARMACEUTICALS, LLC-KAD201810-000658",
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"abstract": "Rasburicase is a recombinant urate-oxidase enzyme and is a very important medication for tumor lysis syndrome. Methemoglobinemia and hemolysis are known side effects of rasburicase that result from oxidative stress caused by hydrogen peroxide, a byproduct generated during the breakdown of uric acid to allantoin. Patients with G6PD deficiency have a decreased tolerance to oxidative stress and are therefore at a greater risk of hemolysis and methemoglobinemia with rasburicase. Our patient is a 56-year-old Caucasian male with a recent diagnosis of grade 2-3a non-Hodgkin's lymphoma who presented to our emergency department with shortness of breath and dark discoloration of urine. Patient was discharged 36 hours ago from our hospital after he was given a first course of R-CHOP regimen and a dose of rasburicase. On further evaluation, patient was found to have severe anemia with hemolytic picture, hyperkalemia and acute kidney injury. He also had a discrepancy of the transcutaneous saturation (75%) and the saturation in an arterial blood gas value (99%). His methemoglobin level was found to be 11.9%. We were aware that methylene blue is a contraindication in patients with G6PD deficiency but considering patient being Caucasian and low risk for it and his deteriorating respiratory condition, it was decided to offer the treatment and patient received 1 dose of methylene blue which failed to improve his methemoglobinemia. He was also given vitamin C and 8 units of packed red blood cell throughout his stay in the hospital. Patient's hospital course was complicated by ARDS needed to be on mechanical ventilation support for 4 days and acute renal failure secondary to pigment nephropathy and acute tubular necrosis which required a hemodialysis support. Even if rasburicase induced methemoglobinemia and hemolysis are not very common complications, clinicians who prescribe and follow patients should detect this serious complication early and manage it accordingly. Our case can be used as a reminder that patients should be followed closely and given the right instructions on discharge to treat these complications which are associated with severe consequences. It is also vital to assume a diagnosis of G6PD deficiency until proven otherwise in a patient who presents with rasburicase induced hemolysis and avoid administration of methylene blue even if the patient is from a low risk ethnicity for G6PD as in our patient.",
"affiliations": "Internal Medicine Resident, Marshall University School of Medicine, Huntington, WV, USA.;Internal Medicine Resident, Marshall University School of Medicine, Huntington, WV, USA.;Internal Medicine Resident, Marshall University School of Medicine, Huntington, WV, USA.;Pulmonary and Critical Care Medicine, Marshall University School of Medicine, Huntington, WV, USA.",
"authors": "Raru|Yonas|Y|;Abouzid|Mahmoud|M|;Parsons|Julia|J|;Zeid|Fuad|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2018.12.011",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(18)30369-110.1016/j.rmcr.2018.12.011Case ReportRasburicase induced severe hemolysis and methemoglobinemia in a Caucasian patient complicated by acute renal failure and ARDS Raru Yonas raru@marshall.edua∗Abouzid Mahmoud aParsons Julia aZeid Fuad ba Internal Medicine Resident, Marshall University School of Medicine, Huntington, WV, USAb Pulmonary and Critical Care Medicine, Marshall University School of Medicine, Huntington, WV, USA∗ Corresponding author. raru@marshall.edu23 12 2018 2019 23 12 2018 26 142 145 25 11 2018 18 12 2018 18 12 2018 © 2018 The Authors. Published by Elsevier Ltd.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Rasburicase is a recombinant urate-oxidase enzyme and is a very important medication for tumor lysis syndrome. Methemoglobinemia and hemolysis are known side effects of rasburicase that result from oxidative stress caused by hydrogen peroxide, a byproduct generated during the breakdown of uric acid to allantoin. Patients with G6PD deficiency have a decreased tolerance to oxidative stress and are therefore at a greater risk of hemolysis and methemoglobinemia with rasburicase. Our patient is a 56-year-old Caucasian male with a recent diagnosis of grade 2-3a non-Hodgkin's lymphoma who presented to our emergency department with shortness of breath and dark discoloration of urine. Patient was discharged 36 hours ago from our hospital after he was given a first course of R-CHOP regimen and a dose of rasburicase. On further evaluation, patient was found to have severe anemia with hemolytic picture, hyperkalemia and acute kidney injury. He also had a discrepancy of the transcutaneous saturation (75%) and the saturation in an arterial blood gas value (99%). His methemoglobin level was found to be 11.9%. We were aware that methylene blue is a contraindication in patients with G6PD deficiency but considering patient being Caucasian and low risk for it and his deteriorating respiratory condition, it was decided to offer the treatment and patient received 1 dose of methylene blue which failed to improve his methemoglobinemia. He was also given vitamin C and 8 units of packed red blood cell throughout his stay in the hospital. Patient's hospital course was complicated by ARDS needed to be on mechanical ventilation support for 4 days and acute renal failure secondary to pigment nephropathy and acute tubular necrosis which required a hemodialysis support. Even if rasburicase induced methemoglobinemia and hemolysis are not very common complications, clinicians who prescribe and follow patients should detect this serious complication early and manage it accordingly. Our case can be used as a reminder that patients should be followed closely and given the right instructions on discharge to treat these complications which are associated with severe consequences. It is also vital to assume a diagnosis of G6PD deficiency until proven otherwise in a patient who presents with rasburicase induced hemolysis and avoid administration of methylene blue even if the patient is from a low risk ethnicity for G6PD as in our patient.\n==== Body\n1 Introduction\nTumor lysis syndrome (TLS) is an oncologic emergency caused by massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into systemic circulation. Catabolism of these nucleic acids into uric acid leads to hyperuricemia [1,2,11]. TLS most commonly occurs after the initiation of cytotoxic therapy in patients with high-grade lymphomas and acute lymphoblastic leukemia. However, TLS can occur spontaneously and with other tumor types with high proliferative rates, large tumor burden, or high sensitivity to cytotoxic therapy [11]. Rasburicase is a recombinant urate-oxidase enzyme which converts uric acid into allantoin, an inactive, soluble metabolite of uric acid [4]. Previous studies revealed that rasburicase reduces serum urate levels faster and with less acute kidney injury compared to allopurinol, so it is commonly used in patients with clinical TLS or in patients who are at high risk for TLS as is the case with high-grade lymphomas and acute lymphoblastic leukemia [1,5,6]. Methemoglobinemia and hemolysis are known side effects of rasburicase that result from oxidative stress caused by hydrogen peroxide, a byproduct generated during the breakdown of uric acid to allantoin. Patients with G6PD deficiency have a decreased tolerance to oxidative stress and are therefore at a greater risk of hemolysis and methemoglobinemia with rasburicase [6,8]. We present a Caucasian patient of north European descent with rasburicase induced severe hemolytic anemia and methemoglobinemia with a newly diagnosed glucose 6 phosphate dehydrogenase deficiency ().\n\n2 Case report\nA 56-year-old Caucasian male of north American descent with recent diagnosis of grade 3a follicular lymphoma, tobacco and marijuana use disorder presented to the emergency department with shortness of breath and hematuria. He was diagnosed with grade 3 follicular lymphoma two weeks prior to this admission when he presented to our hospital with abdominal pain and back pain associated with six-week duration of abdominal distention, decreased appetite and 14-kilogram weight loss. He underwent CT scan of abdomen at that time showing bulky retroperitoneal and mesenteric lymphadenopathy consistent with lymphoma and large volume ascites (Fig. 1). CT chest was also performed showing normal lung parenchyma with no involvement. The patient underwent CT guided core biopsy showing WHO grade 3a follicular lymphoma. Oncology was consulted, and he underwent a bone marrow biopsy showing normocellular bone marrow with no involvement by lymphoma. Peripheral blood revealed slight normocytic anemia but was otherwise normal. At the time of the first admission, hemoglobin was 13 g/dl, white blood cell count was 10300 per cubic millimeter, uric acid 5.7mg/dl, LDH 662 u/l, bilirubin 1.1mg/dl ad alkaline phosphatase was 201U/L. Electrolytes were within the normal range. Due to the high-grade nature of the lymphoma, the patient was admitted to the hospital to start chemotherapy. After appropriate counseling, he received Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. Twenty-four hours after receiving the first dose of chemotherapy, he had a significant increase in uric acid and phosphorus levels raising the concern for possible tumor lysis syndrome. He was given one dose of Rasburicase and his uric acid and phosphorus normalized. He was asymptomatic and was discharged home.Fig. 1 Laboratory values at admission and 36 hours before (Last discharge from hospital).\n\n\n\nAround 12 hours after the administration of Rasburicase, he began to experience shortness of breath, dizziness, and noticed that his urine became dark. He fell at home and injured his right arm but sustained no head trauma. He then noticed bloody urine, increased weakness and shortness of breath and he came to the emergency room (ER) for evaluation.\n\nOn arrival, patient denied any chest pain, cough, fever, chills, nausea or vomiting. He was alert and oriented, tachycardic and in mild respiratory distress. Oxygen saturation was around 75%. He had mild abdominal distension. There was decreased air entry in the right lower posterior chest.\n\nHis laboratory findings are as follows:\tNormal\tAt admission\t36 hours before\t\nWBC (K/cubic mm)\t4–11\t45.4\t15.1\t\nHemoglobin (g/dl)\t13–15\t7.9\t13.4\t\nPotassium (meq/l)\t3.5–5\t7.1\t4.8\t\nCreatinine (mg/dl)\t0.6–1.1\t1.11\t0.8\t\nPhosphorous (mg/dl)\t2.5–4.5\t3.9\t3.2\t\nLDH (u/l)\t87–241\t3800\t740\t\nBilirubin (mg/dl)\t0.2–1\t7\t1\t\nHaptoglobin\t30–200\t26\t–\t\n\n\nAt initial evaluation, he was in mild distress, but his transcutaneous saturation was around 75%. He was placed on bi-valve positive air way pressure from the emergency room. CT of the chest with pulmonary embolism protocol was negative and there was no abnormal pulmonary infiltrate. Arterial blood gas was ordered, and it showed a PH of 7.51, PCO2 of 35 and PO2 of 565 and oxygen saturation of 100%. The discrepancy of the transcutaneous saturation and the arterial blood gas value lead us for a possible diagnosis of methemoglobinemia secondary to Rasburicase and methemoglobin and carboxyhemoglobin levels were ordered. Laboratory values with time after admission is shown in Table 1.Table 1 Laboratory values with time after admission.\n\nTable 1\tNormal\tBefore Rasburicase\tAdmission\t12 hours\t24 hours\t36 hours\t48 hours\t60 hours\t\nWBC, K/cubic mm\t4–11\t15.1\t45.4\t46.6\t37.5\t36.2\t33.6\t25.8\t\nHgb, g/dl\t13–15\t13.4\t7.9\t6.1\t7.1\t7.5\t7.6\t7.3\t\nPotassium, meq/l\t3.5–5\t4.4\t7.1\t5.4\t5.2\t4.2\t3.7\t3.5\t\nCreatinine, mg/dl\t0.6–1.1\t0.74\t1.1\t1.32\t1.60\t1.72\t2.26\t3.82\t\nPhosphorous, mg/dl\t2.5–4.5\t3.6\t3.2\t3.9\t5.2\t5.5\t4.9\t4\t\nLDH, u/l\t87–241\t743\t3800\t5103\t5650\t5150\t2340\t1066\t\nBilirubin, mg/dl\t0.2–1\t1.2\t7\t6.3\t4\t2.7\t1.3\t1.1\t\nUric acid, mg/dl\t3.5–7.2\t7.1\t1.2\t3\t3\t3.1\t3.1\t4.1\t\nHaptoglobin, mg/dl\t30–200\t–\t26\t26\t27\t26\t100\t165\t\nMethemoglobin, %\t0–1.5%\t–\t11.1\t11.9\t6.9\t3.1\t1.9\t1.8\t\nCarbon monoxide, %\t0–3%\t–\t7.5\t6.9\t5.8\t4.6\t4.1\t3.9\t\n\n\nThe methemoglobin level was found to be 11.9% and his carboxyhemoglobin level was 7.5%. Rasburicase induced methemoglobinemia with severe hemolytic anemia, hyperkalemia and acute kidney injury was diagnosed. Since Rasburicase mostly causes hemolysis in patients with glucose 6 phosphate dehydrogenase deficiency (G6PD), quantitative test for it was sent even if our patient is a Caucasian male of north European descent with less probability of abnormal test. Hemoglobin was followed regularly and patient was placed on supportive management including steroids. But his respiratory condition worsened, and it was decided to start the patient with methylene blue. We were aware that methylene blue is contraindicated in patients with G6PD deficiency but considering low risk race for G6PD deficiency and his deteriorating respiratory condition, it was decided to offer the treatment for the patient.\n\nPatient was counselled about the situation and he decided he wanted the treatment and he was given one dose of 1mg/kg of methylene blue and he was also started with vitamin C and continued with IV fluid. Methemoglobin level was remeasured 2 hours after administration of the methylene blue, but patient didn't show any clinical or biochemical improvement. He was continued with supportive care and blood transfusion. His methemoglobin level gradually came down to 1.9% and carboxyhemoglobin level to 4%. The G6PD level came back slightly lower than normal which makes it an abnormal test since the expected result in acute hemolysis is normal to higher than normal values. Patient subsequently developed acute respiratory distress syndrome because of repeated blood transfusions due to severe anemia secondary to rasburicase induced hemolysis and IV fluid administration and he was intubated, and mechanical ventilation support was given. He needed to stay on mechanical ventilation for 4 days and was extubated. The extent of the hemolysis due to rasburicase was so severe that patient needed around 8 units of blood and he developed acute renal failure due to pigment nephropathy and acute tubular necrosis for which he was placed on hemodialysis throughout his stay in the hospital.\n\n3 Discussion\nRasburicase is a recombinant urate-oxidase enzyme, which converts uric acid to allantoin which is an inactive and soluble metabolite of uric acid. It does not inhibit the formation of uric acid [1]. Rasburicase has black box warnings as it may cause serious and fatal hypersensitivity reactions including anaphylaxis, hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, and methemoglobinemia [5]. Clinicians who prescribe or follow patients who are given rasburicase should be able to recognize and promptly manage hemolysis and methemoglobinemia associated with rasburicase as it is a serious complication with a severe consequence. Our patient had a discrepancy in the transcutaneous saturation and the saturation in the arterial blood gas value which tipped us for a possibility of methemoglobinemia secondary to Rasburicase.\n\nHe also had a drop of around 5.5mg/dl of hemoglobin in 36 hours which also gave us another clue that the patient has a complication from the rasburicase. Screening patients at high risk of glucose-6-phosphate dehydrogenase (G6PD) deficiency, individuals of African and Mediterranean descent, is recommended prior to initiation of rasburicase even if it is not done frequently in practice [2,3,7,9,10]. We were aware that methylene blue is contraindicated in patients with G6PD deficiency but considering patient being Caucasian of European descent and low risk for it and his deteriorating respiratory condition, it was decided to offer the treatment for him. On the other hand, it is also suggested that a high index of suspicion of G6PD deficiency is also crucial in a patient who develops methemoglobinemia or hemolytic anemia following rasburicase therapy, irrespective of ethnic origin [1,2,10,12,13].\n\nG6PD deficiency is associated with NADPH deficiency, and methylene blue is dependent on NADPH to reduce methemoglobin to hemoglobin. This renders methylene blue ineffective in G6PD-deficient patients, and it may aggravate methemoglobinemia at high doses by oxidizing hemoglobin [4,12,14]. Methemoglobin is generated when hemoglobin iron is oxidized from the ferrous (Fe2þ) to the ferric (Fe3þ) state. Administered methylene blue is converted to leukomethylene blue by the NADPH-dependent methemoglobin reductase system, which then transfers an electron to ferric iron reducing it to ferrous iron [3]. In retrospect, it would have been wiser not to give our patient the methylene blue considering his presentation with severe hemolysis and the low G6PD level that was demonstrated in the laboratory result which came back after 3 days even if patient was actively in hemolysis when the blood sample was taken. Most previously reported cases of rasburicase induced hemolysis and methemoglobinemia with G6PD deficiency were males just like our patient which could be explained by the X-linked mode of inheritance. But the condition was also reported in females [9]. We also used ascorbic acid on our patient. Ascorbic acid has an antioxidant effect not dependent on NADPH and is a safe and effective treatment for methemoglobinemia especially for patients with G6PD deficiency [1,4,6]. Rasburicase induced methemoglobinemia could develop as early as 2 hours after drug administration but our patient started to have symptoms 12 hours after rasburicase was given. This has a very important implication when patients are treated with rasburicase in an outpatient setting [2,3]. It is suggested to observe patients for at least 6 hours and then give proper instructions for the next 24 hours. Our patient was advised about the risks of rasburicase and was observed for about 6 hours but stayed at home 24 hours more after he started to have the symptoms which further complicated his condition.\n\nPrevious literature has shown that there is no apparent relationship between the dose of rasburicase administered and the peak methemoglobin level or the lowest hemoglobin level [3,8]. Most of the cases in literature responded for treatment within 3–7 days and our patient has responded for the treatment in that time range but he has more complications including ARDS and requirement for mechanical ventilation support, multiple transfusions and acute renal failure needing hemodialysis. Even if rasburicase induced methemoglobinemia and hemolysis are not very common complications, clinicians who prescribe and follow patients should detect this serious complication early and manage it accordingly. Our case can be used as a reminder that patients should be followed and given the right instructions on discharge to treat this complication which is associated with severe consequences.\n\n4 Conclusion\nRasburicase is a recombinant urate-oxidase enzyme and is a very important medication for tumor lysis syndrome. It has black box warnings as it may cause serious and fatal hypersensitivity reactions including anaphylaxis, hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, and methemoglobinemia. Even if rasburicase induced methemoglobinemia and hemolysis are not very common complications, clinicians who prescribe and follow patients should detect this serious complication early and manage it accordingly. Our case can be used as a reminder that patients should be followed closely and given the right instructions on discharge to treat these complications which are associated with severe consequences. It is also vital to assume a diagnosis of G6PD deficiency until proven otherwise in a patient who presents with rasburicase induced hemolysis and avoid administration of methylene blue even if the patient is from a low risk ethnicity like Caucasian as in our patient.\n\nConflict of interest\nThe authors have no conflict of interest.\n==== Refs\nReferences\n1 Cheah C.Y. Lew T.,E. Seymour J.,F. Burbury K. Rasburicase causing severe oxidative hemolysis and methemoglobinemia in a patient with previously unrecognized glucose-6-phosphate dehydrogenase deficiency Acta Haematol. 130 2013 254 259 23860572 \n2 Oluwasanjo A. Rasburicase-induced methaemoglobinaemia and G6PD deficiency in an unusual suspect Br. J. Haematol. 170 5 Sep 2015 595 26033222 \n3 Sonbol M.B. Yadav H. Vaidya R. Rana V. Witzig T.E. Methemoglobinemia and hemolysis in a patient with G6PD deficiency treated with rasburicase Am. J. Hematol. 88 2013 152 154 22573495 \n4 Sherwood G.B. Rasburicase-induced methemoglobinemia: case report, literature review, and proposed treatment algorithm Clin. Case Rep. 4 4 Apr 2016 315 319 27099716 \n5 Elitek (rasburicase) US Food and Drug Administration 2013 \n6 Browning L.A. Kruse J.A. Hemolysis and methemoglobinemia secondary to rasburicase administration Ann. Pharmacother. 39 2005 1932 1935 16204390 \n7 Bhat P. Sisler I. Collier A.B. Exchange transfusion as treatment for rasburicase induced methemoglobinemia in a glucose‐6‐phosphate dehydrogenase deficient patient Pediatr. Blood Cancer 51 2008 568 18561168 \n8 Bucklin M.H. Groth C.M. Mortality following rasburicase‐induced methemoglobinemia Ann. Pharmacother. 47 2013 1353 1358 24259700 \n9 Roberts D.A. Freed J.A. Rasburicase‐induced methemoglobinemia in two African‐American female patients: an under‐recognized and continued problem Eur. J. Haematol. 94 2014 83 85 24750455 \n10 Ibrahim U. Saqib A. Mohammad F. Atallah J.P. Odaimi M. Rasburicase-induced methemoglobinemia: the eyes do not see what the mind does not know J. Oncol. Pharm. Pract. 24 4 2018 Jun 309 313 28345492 \n11 Howard S.C. Jones D.P. Pui C.-H. The tumor lysis syndrome N. Engl. J. Med. 364 19 2011 1844 1854 21561350 \n12 Rehman A. Shehadeh M. Khirfan D. Jones A. Severe acute hemolytic anemia associated with severe methemoglobinemia in a G6PD-deficient man BMJ Case Rep. 2018 \n13 Younis M. Derbas L. Eikermann S.M. Not the typical pneumonia: an unusual case of rasburicase-induced methomoglobinemia Cureus 10 8 August 01, 2018 e3084 \n14 Ferguson D. Rasburicase-induced hemolytic anemia in previously undiagnosed G6PD deficiency Blood 132 6 9 Aug 2018 673 30093385\n\n",
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"title": "Rasburicase induced severe hemolysis and methemoglobinemia in a Caucasian patient complicated by acute renal failure and ARDS.",
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"abstract": "Acute esophagitis and esophageal strictures typically occur after local radiation therapy to the thoracic field. Toxicity is usually limited to the field of radiation and potentially augmented by concomitant use of chemotherapy, however esophageal stricturing due to chemotherapy alone is exceedingly rare. Gastrointestinal toxicity has been previously reported in the setting of 5-fluorouracil (5-FU)-based chemotherapy with abnormal thymidylate synthase or dihydropyrimidine dehydrogenase activities. We present a unique case of isolated chemotherapy-induced esophageal stricture in the setting of stage IIIa rectal adenocarcinoma which presented shortly after initiation of treatment with 5-FU-based chemotherapy in a patient with normal thymidylate synthase and dihydropyrimidine dehydrogenase assays. These findings prompt further investigation of pathways and potential risk factors leading to esophageal toxicity in patients treated with 5-FU-based chemotherapy.",
"affiliations": "Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, Mo., USA.;Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Mo., USA.;Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, Mo., USA.;Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, Mo., USA.;Division of Hematology and Oncology, Saint Louis University School of Medicine, St. Louis, Mo., USA.;Department of Radiology, Saint Louis University School of Medicine, St. Louis, Mo., USA.;Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, Mo., USA.",
"authors": "Chahla|Elie|E|;Cheesman|Antonio|A|;Hammami|Muhammad|M|;Taylor|Jason R|JR|;Poddar|Nishant|N|;Garrett|Robert W|RW|;Alkaade|Samer|S|",
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"fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000376608crg-0009-0044Published online: February, 2015A Unique Case of a Patient with Rectal Cancer Who Developed Benign Esophageal Stenosis after Localized Rectal Radiation and Systemic Chemotherapy Chahla Elie a*Cheesman Antonio bHammami Muhammad aTaylor Jason R. aPoddar Nishant cGarrett Robert W. dAlkaade Samer aaDivision of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, Mo., USAbDepartment of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Mo., USAcDivision of Hematology and Oncology, Saint Louis University School of Medicine, St. Louis, Mo., USAdDepartment of Radiology, Saint Louis University School of Medicine, St. Louis, Mo., USA*Elie Chahla, MD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO 63110 (USA), E-Mail elie.chahla@gmail.comJan-Apr 2015 10 2 2015 10 2 2015 9 1 44 48 Copyright © 2015 by S. Karger AG, Basel2015This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Acute esophagitis and esophageal strictures typically occur after local radiation therapy to the thoracic field. Toxicity is usually limited to the field of radiation and potentially augmented by concomitant use of chemotherapy, however esophageal stricturing due to chemotherapy alone is exceedingly rare. Gastrointestinal toxicity has been previously reported in the setting of 5-fluorouracil (5-FU)-based chemotherapy with abnormal thymidylate synthase or dihydropyrimidine dehydrogenase activities. We present a unique case of isolated chemotherapy-induced esophageal stricture in the setting of stage IIIa rectal adenocarcinoma which presented shortly after initiation of treatment with 5-FU-based chemotherapy in a patient with normal thymidylate synthase and dihydropyrimidine dehydrogenase assays. These findings prompt further investigation of pathways and potential risk factors leading to esophageal toxicity in patients treated with 5-FU-based chemotherapy.\n\nKey Words\nRectal cancerBenign esophageal stenosisLocalized rectal radiationSystemic chemotherapy\n==== Body\nIntroduction\nAcute esophagitis and esophageal strictures are relatively common adverse effects related to radiation therapy in the setting of head, neck and thoracic malignancies with an incidence rate ranging from 22 to 37% [1]. Toxicity is usually dose-dependent [2, 3, 4], occurs within 2–3 weeks after the initiation of radiation therapy and is primarily related to disruption of the basal epithelial layer of the esophagus [5]. Subsequent inflammation and scar formation within the esophageal muscularis result in stricture formation, typically seen 3–6 months after completion of radiotherapy [6, 7]. Esophageal strictures secondary to radiation therapy are usually located within the field of radiotherapy and potentially augmented by concomitant use of chemotherapy. However, esophageal strictures due to isolated chemotherapy use are extremely rare [8]. To our knowledge, only one case of isolated chemotherapy-induced esophageal stricture has been reported in the adult population, involving a patient with acute myelogenous leukemia [9]. No cases have been identified while undergoing adjuvant chemotherapy for solid tumors. We present the case of a patient receiving adjuvant chemotherapy for rectal cancer who subsequently developed a benign but severe recurrent esophageal stricture.\n\nCase Report\nA 55-year-old female was diagnosed with stage IIIa (cT2N0M0, uT2N1M0) rectal adenocarcinoma. She was treated with neoadjuvant chemotherapy with capecitabine (1,250 mg/m2 twice daily, days 1–14 of cycle) and localized radiation therapy (50.4 Gy in 28 fractions) to the rectum for 2 months. She subsequently underwent laparoscopic-assisted rectal resection, with pathology revealing moderately differentiated adenocarcinoma with negative margins, colonic J-pouch with diverting ileostomy, and adjuvant chemotherapy with modified FOLFOX-6 (oxaliplatin 85 mg/m2, 5-fluorouracil [5-FU] bolus 400 mg/m2, leucovorin 400 mg/m2 and 5-FU infusion 1,200 mg/m2/day for 2 days) for 2 cycles.\n\nThree weeks after initiation of adjuvant chemotherapy, the patient was hospitalized for management of new-onset dysphagia and odynophagia. Her symptoms persisted despite discontinuation of chemotherapy and empirical treatment with antifungal therapy for suspected Candida esophagitis. An esophagogram and a computed tomography (CT) of the chest revealed irregular long narrowing in the mid and distal esophagus (fig. 1, fig. 2). Upper endoscopic evaluation revealed an 11-cm-long esophageal stenosis with mucosal erythema and friability starting 25 cm from the incisors (fig. 1). Repeat biopsies and imaging studies failed to reveal an infectious or neoplastic etiology. The patient had no history of dysphagia prior to adjuvant chemotherapy and during the period when she received neoadjuvant concurrent chemotherapy and radiation, and her esophagus had been normal-appearing on two previous CT scans performed 2 months before adjuvant chemotherapy administration. The patient's symptoms improved after endoscopic dilation therapy, but she required repeated endoscopic therapy on a monthly basis including intralesional steroid injections. A fully covered esophageal stent was placed twice with short-term improvement in symptoms. Unfortunately, the patient also had secondary development of new esophageal strictures at the proximal and distal ends of the stent. The esophageal stents were ultimately removed and the patient's symptoms were controlled with repeat endoscopic dilation of the benign stricture every 4–6 weeks. She had no evidence of esophageal malignancy on repetitive endoscopy with multiple biopsies or cross-sectional imaging for 18 months since diagnosis, further confirming the benign process.\n\nDiscussion\nEsophageal strictures are a known complication of radiation therapy especially during treatment of head, neck and thoracic malignancies. Injury to the esophagus results in severe fibrosis, mucosal atrophy, ischemic ulcerations and esophageal strictures [10, 11]. Isolated chemotherapy-induced esophageal strictures are a very rare entity and have only been described in the pediatric literature, specifically in the management of acute leukemias. Yata et al. [9] reported the only other existing case in adults, pertaining a 41-year-old woman who developed a 6-cm-long lower esophageal stricture 12 days after re-induction therapy for acute myelogenous leukemia.\n\nOur patient received 28 sessions of low-dose localized radiation therapy to the rectum with concurrent neoadjuvant capecitabine chemotherapy without any gastrointestinal complications. Esophageal toxicity and stricturing did not occur until systemic adjuvant chemotherapy with modified FOLFOX-6 (oxaliplatin, 5-FU bolus and leucovorin) was provided. It is highly unlikely that localized radiation therapy to the rectum would be responsible for the esophageal findings described.\n\nSevere gastrointestinal toxicities of 5-FU-based chemotherapy can be more pronounced in patients with evidence of polymorphisms in the thymidylate synthase (TS) or dihydropyrimidine dehydrogenase (DPD) genes [12]. Low levels of TS expression are associated with toxicity to 5-FU. When DPD enzyme activity is low, the gastrointestinal mucosal involvement can be severe and, in rare cases, fatal. Surprisingly, our patient's DPD and TS enzymatic activity levels were both within normal limits.\n\nEsophageal strictures secondary to isolated use of systemic chemotherapy are an exceedingly rare complication. We suspect that this unexpected but dramatic adverse event is caused by mucosal damage limited to the esophagus due to the chemotherapeutic agents, since our patient did not receive localized radiation to the esophageal field.\n\nIn conclusion, we report a very unusual and rare case of acute gastrointestinal toxicity limited to the esophagus after initiation of systemic oxaliplatin and 5-FU-based chemotherapy in a patient with normal TS and DPD assays. The possibility of other genetic mutations leading to this complication should be further investigated in future studies.\n\nFig. 1 a Spot image taken during fluoroscopic esophagogram. A long stricture segment (11 cm) is noted in the mid to distal esophagus with associated mucosal irregularity (arrows). S = Stomach. b Endoscopic visualization in the middle third of the esophagus demonstrating very friable, erythematous and hyperemic mucosa with a stricture noted 25 cm from the incisors (between the two arrows).\n\nFig. 2 Contrast-enhanced CT of the chest. a Sagittal reformatted image demonstrating mild distention of the upper thoracic esophagus (asterisk) and long stricture segment of the mid and distal esophagus (arrows). b Axial CT through the upper thoracic esophagus demonstrating normal wall thickness with mild distention (arrow). c Axial CT through the strictured segment showing significant esophageal wall thickening and luminal narrowing (arrow).\n==== Refs\nReferences\n1 Lawson JD Otto K Grist W Johnstone PA Frequency of esophageal stenosis after simultaneous modulated accelerated radiation therapy and chemotherapy for head and neck cancer Am J Otolaryngol 2008 29 13 19 18061826 \n2 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 \n3 Morichau-Beauchant M Touchard G Battandier D Maire P Fontanel JP Daban A Babin P Matuchansky C Chronic radiation-induced esophagitis after treatment of oropharyngolaryngeal cancer: a little-known anatomo-clinical entity (in French) Gastroenterol Clin Biol 1983 7 843 850 6653970 \n4 Seaman WB Ackerman LV The effect of radiation on the esophagus; a clinical and histologic study of the effects produced by the betatron Radiology 1957 68 534 541 13432180 \n5 Phillips TL Ross G Time-dose relationships in the mouse esophagus Radiology 1974 113 435 440 4417427 \n6 O'Rourke IC Tiver K Bull C Gebski V Langlands AO Swallowing performance after radiation therapy for carcinoma of the esophagus Cancer 1988 61 2022 2026 2452006 \n7 Coia LR Myerson RJ Tepper JE Late effects of radiation therapy on the gastrointestinal tract Int J Radiat Oncol Biol Phys 1995 31 1213 1236 7713784 \n8 Guadagnolo BA Haddad RI Posner MR Weeks L Wirth LJ Norris CM Sullivan CA Goguen L Busse PM Tishler R Organ preservation and treatment toxicity with induction chemotherapy followed by radiation therapy or chemoradiation for advanced laryngeal cancer Am J Clin Oncol 2005 28 371 378 16062079 \n9 Yata K Yamada O Iwato K Kyo T Otsuki T Nakanishi H Suetsugu Y Mikami M Wada H Yawata Y Sugihara T Acute myelogenous leukemia associated with severe esophageal stricture after chemotherapy (in Japanese) Rinsho Ketsueki 2002 43 41 43 11868364 \n10 Kelly K Storey L O'Sullivan M Butler K McDermott M Corbally M McMahon C Smith OP O'Marcaigh A Esophageal strictures during treatment for acute lymphoblastic leukemia J Pediatr Hematol Oncol 2010 32 124 127 20168244 \n11 Mahboubi S Silber JH Radiation-induced esophageal strictures in children with cancer Eur Radiol 1997 7 119 122 9000412 \n12 Cho HJ Park YS Kang WK Kim JW Lee SY Thymidylate synthase (TYMS) and dihydropyrimidine dehydrogenase (DPYD) polymorphisms in the Korean population for prediction of 5-fluorouracil-associated toxicity Ther Drug Monit 2007 29 190 196 17417073\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "9(1)",
"journal": "Case reports in gastroenterology",
"keywords": "Benign esophageal stenosis; Localized rectal radiation; Rectal cancer; Systemic chemotherapy",
"medline_ta": "Case Rep Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101474819",
"other_id": null,
"pages": "44-8",
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"pmid": "25802497",
"pubdate": "2015",
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"references": "7713784;20168244;6653970;2452006;16062079;13432180;2032882;9000412;17417073;4417427;18061826;11868364",
"title": "A unique case of a patient with rectal cancer who developed benign esophageal stenosis after localized rectal radiation and systemic chemotherapy.",
"title_normalized": "a unique case of a patient with rectal cancer who developed benign esophageal stenosis after localized rectal radiation and systemic chemotherapy"
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"abstract": "We present a fatal drug poisoning case involving venlafaxine (VEN). The deceased took his medication regularly (including 150 mg VEN twice daily), and nothing in the case or autopsy findings pointed towards suicide. The toxicological assessment concluded that the cause of death was most likely due to a poisoning with a combination of VEN, oxycodone and ethanol, and the manner of death was considered to be an accident. The blood concentration of VEN was high (4.5mg/kg), and the ratio of the VEN metabolite O-desmethylvenlafaxine (ODV) to VEN was exceptionally low (0.006). Mechanistic pharmacokinetic simulations suggested that the low metabolite ratio was the result of combined poor metabolizer (PM) status of cytochrome P450 (CYP) 2C19 and CYP2D6. This hypothesis was confirmed by genetic analysis. Simulations revealed that it was likely that the combined missing CYP2D6 and CYP2C19 activity would cause higher concentrations of VEN, but the simulations also suggested that there could be additional reasons to explain the high VEN concentration found in this case. Thus, it seems likely that the potentially toxic VEN concentration was caused by reduced metabolic capacity. The simulations combined with genotyping were considered very useful in this fatal drug poisoning case.",
"affiliations": "Aarhus University, Department of Forensic Medicine, Section for Forensic Pathology and Clinical Forensic Medicine & Section for Toxicology and Drug Analysis, Brendstrupgaardsvej 100, 8200 Aarhus N, Denmark. jjor@forensic.au.dk",
"authors": "Jornil|J|J|;Nielsen|T S|TS|;Rosendal|I|I|;Ahlner|J|J|;Zackrisson|A L|AL|;Boel|L W T|LW|;Brock|B|B|",
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"country": "Ireland",
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"issue": "226(1-3)",
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"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D018687:Antidepressive Agents, Second-Generation; D001189:Aryl Hydrocarbon Hydroxylases; D002492:Central Nervous System Depressants; D003511:Cyclohexanols; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D000069468:Desvenlafaxine Succinate; D000431:Ethanol; D053593:Forensic Toxicology; D017353:Gene Deletion; D020440:Gene Duplication; D005838:Genotype; D006801:Humans; D008297:Male; D010098:Oxycodone; D020641:Polymorphism, Single Nucleotide; D000069470:Venlafaxine Hydrochloride",
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"references": null,
"title": "A poor metabolizer of both CYP2C19 and CYP2D6 identified by mechanistic pharmacokinetic simulation in a fatal drug poisoning case involving venlafaxine.",
"title_normalized": "a poor metabolizer of both cyp2c19 and cyp2d6 identified by mechanistic pharmacokinetic simulation in a fatal drug poisoning case involving venlafaxine"
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"abstract": "BACKGROUND\nThe use of programmed death-ligand 1 (PD-L1) checkpoint inhibitor therapy is expanding, although its adverse effects are not completely known. We report on a rare case of acute cytokine release syndrome related to pembrolizumab use in a patient with lung cancer.\n\n\nMETHODS\nA 79-year-old man with metastatic, PD-L1-positive, non-small-cell lung cancer developed a febrile condition associated with a systemic inflammatory response syndrome and suffered haemodynamic compromise four hours after the first intravenous administration of pembrolizumab. A thorough medical workup found no alternative cause and a grade 2 cytokine release syndrome (CRS) was diagnosed.Management and outcome: Aggressive fluid resuscitation and supportive therapy led to restitutio ad integrum.\n\n\nCONCLUSIONS\nAcute CRS after the administration of a PD-L1 inhibitor is infrequent but could be a fatal condition. Supportive treatment and, if necessary, corticosteroids should be considered.",
"affiliations": "Service of Internal Medicine, Department of Medicine, Réseau Hospitalier Neuchâtelois - La Chaux-de-Fonds, La Chaux-de-Fonds, Switzerland.;Service of Internal Medicine, Department of Medicine, Réseau Hospitalier Neuchâtelois - La Chaux-de-Fonds, La Chaux-de-Fonds, Switzerland.;Service of Internal Medicine, Department of Medicine, Réseau Hospitalier Neuchâtelois - La Chaux-de-Fonds, La Chaux-de-Fonds, Switzerland.;Department of Oncology, Réseau Hospitalier Neuchâtelois - La Chaux-de-Fonds, La Chaux-de-Fonds, Switzerland.;Service of Internal Medicine, Department of Medicine, Réseau Hospitalier Neuchâtelois - Pourtalès, Neuchâtel, Switzerland.",
"authors": "Normand|Clément V|CV|https://orcid.org/0000-0003-4507-4161;Zender|Hervé O|HO|;Staehli|Dominique M|DM|;Chouiter-Djebaili|Amina Faiza|AF|;John|Gregor|G|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; C582435:pembrolizumab",
"country": "England",
"delete": false,
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"issue": "27(6)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Pembrolizumab; acute side effect; cytokine release syndrome; immunotherapy; non-small-cell lung cancer",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; D002289:Carcinoma, Non-Small-Cell Lung; D000080424:Cytokine Release Syndrome; D006801:Humans; D008175:Lung Neoplasms; D008297:Male",
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"title": "Acute cytokine release syndrome after a first dose of pembrolizumab as second-line treatment for metastatic, programmed death-ligand 1-positive, non-small-cell lung cancer.",
"title_normalized": "acute cytokine release syndrome after a first dose of pembrolizumab as second line treatment for metastatic programmed death ligand 1 positive non small cell lung cancer"
} | [
{
"companynumb": "CH-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-316646",
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"abstract": "Toxic ingestions constitute a major health problem for infants and young children, with an estimated 500,000 poisonings in 1980, 90% of them in children less than five years old. Mortality and associated expense are considerable. Sympathetic amines, while less commonly involved in pediatric poisonings, deserve special attention because of their potent cardiovascular side effects, eg, tachycardia and hypertension. Tetrahydrozoline, the active ingredient in several nasal and ophthalmologic over-the-counter medications, has previously been implicated in childhood ingestions. We report a case of tetrahydrozoline ingestion in which, paradoxically, lethargy, bradycardia, and hypotension were noted.",
"affiliations": "College of Pharmacy, University of Minnesota, Minneapolis.",
"authors": "Jensen|P|P|;Edgren|B|B|;Hall|L|L|;Ring|J C|JC|",
"chemical_list": "D007093:Imidazoles; D013566:Sympathomimetics; C005810:tetrahydrozoline",
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"mesh_terms": "D001919:Bradycardia; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D006801:Humans; D007022:Hypotension; D007093:Imidazoles; D007223:Infant; D012894:Sleep Stages; D013566:Sympathomimetics",
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"title": "Hemodynamic effects following ingestion of an imidazoline-containing product.",
"title_normalized": "hemodynamic effects following ingestion of an imidazoline containing product"
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"activesubstancename": "TETRAHYDROZOLINE HYDROCHLORIDE"
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"abstract": "Cystic fibrosis (CF) with severe lung disease is a well-recognized indication for lung transplantation. Colonization with various organisms in CF patients may impact post-transplant morbidity and mortality. Burkholderia cepacia complex (BCC) is made up of distinct genomovars with significant morbidity and mortality associated with B. cenocepacia (genomovar III) following lung transplant. The outcomes of patients infected with genomovar B. dolosa (genomovar VI) have yet to be described in the literature. We performed a retrospective chart review of all cystic fibrosis patients colonized with B. dolosa from our center who underwent lung transplantation (n = 11) at various medical centers across the US between 2000 and 2014. Survival rates were 73%, 53%, and 30% for 1, 3, and 5 years, respectively. Median survival was 44 months (95% CI = 11.1-76.8). CF patients with B. dolosa that have undergone lung transplantation have decreased one-year survival when compared to all patients transplanted with cystic fibrosis. Conditional 5-year survival for B. dolosa-infected patients was 43% in patients that survived the first year post-transplant, suggesting that this first year is crucial in managing the infection. Importantly, the survival of the B. dolosa patients was higher than compared to previously reported survival rates of B. cenocepacia patients post-transplant.",
"affiliations": "Division of Respiratory Diseases, Boston Children's Hospital, Boston, MA, USA.;Division of Respiratory Diseases, Boston Children's Hospital, Boston, MA, USA.;Pulmonary Medicine, Cleveland Clinic, Cleveland, OH, USA.;Pulmonary Division, Brigham and Women's Hospital, Boston, MA, USA.;Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.;Department of Medicine, Duke University, Raleigh, NC, USA.;Department of Medicine, Duke University, Raleigh, NC, USA.;Division of Respiratory Diseases, Boston Children's Hospital, Boston, MA, USA.",
"authors": "Wang|Ruobing|R|0000-0003-0277-8329;Welsh|Sebastian K|SK|;Budev|Marie|M|;Goldberg|Hilary|H|;Noone|Peadar G|PG|;Gray|Alice|A|;Zaas|David|D|;Boyer|Debra|D|",
"chemical_list": null,
"country": "Denmark",
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"doi": "10.1111/ctr.13236",
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"issn_linking": "0902-0063",
"issue": "32(5)",
"journal": "Clinical transplantation",
"keywords": "\nBurkholderia dolosa\n; Burkholderia cepacia complex; Burkholderia infections; cystic fibrosis; lung transplantation",
"medline_ta": "Clin Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D019121:Burkholderia Infections; D042602:Burkholderia cepacia complex; D002648:Child; D003550:Cystic Fibrosis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D016040:Lung Transplantation; D008297:Male; D009657:North Carolina; D011183:Postoperative Complications; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D055815:Young Adult",
"nlm_unique_id": "8710240",
"other_id": null,
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"pmc": null,
"pmid": "29528522",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Survival after lung transplantation of cystic fibrosis patients infected with Burkholderia dolosa (genomovar VI).",
"title_normalized": "survival after lung transplantation of cystic fibrosis patients infected with burkholderia dolosa genomovar vi"
} | [
{
"companynumb": "PHHY2018US016077",
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{
"actiondrug": "6",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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{
"abstract": "We report a case of HER2-positive metastatic breast cancer achieved a complete response(CR)to paclitaxel(PTX) and trastuzumab(HER) in combination with pertuzumab(PER) in 5th therapy. A 69-year-old woman was diagnosed left breast cancer and underwent mastectomy and sentinel lymph node biopsy in January 2011. Pathological examination revealed an invasive ductal carcinoma that was ER 0%, PgR 0%, HER2(3+), Ki-67 67% and node negative. Two years after the operation, she found multiple lung metastases in both lungs. She was administered drug treatment as HER2-positive metastatic breast cancer, but multiple lung metastases got worse after 4th treatment. Weekly PTX, trastuzumab and pertuzumab were administered as 5th therapy. After 2 months, lung metastases diminished significantly. After 44 courses of drug treatment, positron emission tomography computed tomography(PET-CT)scan revealed CR. She wanted to cease treatment, so she continues to get CT scan every half a year and the CR has been maintained.",
"affiliations": "Dept. of Breast and Endocrine Surgery, Japanese Red Cross Okayama Hospital.",
"authors": "Mimata|Asuka|A|;Yoshitomi|Seiji|S|;Morikawa|Nozomi|N|;Hara|Kyoko|K|;Tsuji|Hisashi|H|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018719:Receptor, ErbB-2; C485206:pertuzumab; D000068878:Trastuzumab; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
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"issue": "48(2)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008408:Mastectomy; D017239:Paclitaxel; D000072078:Positron Emission Tomography Computed Tomography; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "263-265",
"pmc": null,
"pmid": "33597376",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of HER2-Positive Metastatic Breast Cancer Achieved a Complete Response to Paclitaxel and Trastuzumab in Combination with Pertuzumab in Fifth Therapy.",
"title_normalized": "a case of her2 positive metastatic breast cancer achieved a complete response to paclitaxel and trastuzumab in combination with pertuzumab in fifth therapy"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1902236",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VINORELBINE TARTRATE"
},
"drugadditional": null... |
{
"abstract": "Uncontrolled use of medicines bring with it serious health problems. Long-term and uncontrolled use of steroids, without the supervision of a healthcare professional, may cause unexpected infections due to immunosuppression. The authors present a patient with maxillary osteomyelitis caused by Kocuria species in a 41-year-old male who has been receiving methylprednisolone without control for 1.5 years.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Ataturk University, Erzurum, Turkey.",
"authors": "Kilinç|Adnan|A|;Tepecik|Tahsin|T|;Baş|Mehmet Zahit|MZ|;Sancar|Bahadir|B|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1097/SCS.0000000000004090",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1049-2275",
"issue": "29(2)",
"journal": "The Journal of craniofacial surgery",
"keywords": null,
"medline_ta": "J Craniofac Surg",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008437:Maxilla; D008775:Methylprednisolone; D008835:Micrococcaceae; D010019:Osteomyelitis; D012651:Self Medication; D013997:Time Factors",
"nlm_unique_id": "9010410",
"other_id": null,
"pages": "e118-e120",
"pmc": null,
"pmid": "29084112",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Maxillary Osteomyelitis Caused by Kocuria Species in a Patient Who Is on Long-Term Uncontrolled Use of Methylprednisolone.",
"title_normalized": "maxillary osteomyelitis caused by kocuria species in a patient who is on long term uncontrolled use of methylprednisolone"
} | [
{
"companynumb": "TR-JUBILANT CADISTA PHARMACEUTICALS-2018JUB00342",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
... |
{
"abstract": "Cytomegalovirus (CMV) reactivation remains one of the most common and life-threatening infectious complications following allogeneic hematopoietic stem cell transplantation, despite novel diagnostic technologies, several novel prophylactic agents, and further improvements in preemptive therapy and treatment of established CMV disease. Treatment decisions for CMV reactivation are becoming increasingly difficult and must take into account whether the patient has received antiviral prophylaxis, the patient's individual risk profile for CMV disease, CMV-specific T-cell reconstitution, CMV viral load, and the potential drug resistance detected at the time of initiation of antiviral therapy. Thus, we increasingly use personalized treatment strategies for the recipient of an allograft with CMV reactivation based on prior use of anti-CMV prophylaxis, viral load, the assessment of CMV-specific T-cell immunity, and the molecular assessment of resistance to antiviral drugs.",
"affiliations": "Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden.;Vaccine and Infectious Disease Division and.",
"authors": "Einsele|Hermann|H|;Ljungman|Per|P|;Boeckh|Michael|M|",
"chemical_list": "D000998:Antiviral Agents",
"country": "United States",
"delete": false,
"doi": "10.1182/blood.2019000956",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "135(19)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D005260:Female; D006402:Hematologic Diseases; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D019562:Viral Load; D014775:Virus Activation",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "1619-1629",
"pmc": null,
"pmid": "32202631",
"pubdate": "2020-05-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "30677427;10745262;28224776;12393659;17724444;9456256;15084929;11830461;29207952;30295846;30993417;2536135;28173959;28500691;11286223;19450758;26884374;10918402;28641094;26250410;30154125;1848680;25560711;1658652;11709367;30137245;29558479;22683614;11929799;30292744;18285548;20961907;9310503;31054984;28783452;9193754;29331844;20625005;19299333;7670117;1682592;22440913;9233710;26853648;21414843;10733491;29546589;25295744;27307504;29777573;9291333;11092465;28090089;8916975;1652311;16359371;27760756;31179485;23024295;12843000;1323614;12796800;24152053;8380243;31058862;24964991;24146744;24041869;20699126;19147520;14644993;11807708;31153807;7907729;8996768;21443904;25452035;31532960;30329038;24329788;28505028;31068147;27419179;31132546;25099585;26432076;22237175;7920315;21880629;20508161;29284181;20353832;28967706;15489872;23983215;20197104;27043969;11397964;24066743;27594527;29936407;19369230;3006831;21937692;29211658;24189264;26947200;16352807;28797778",
"title": "How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation.",
"title_normalized": "how i treat cmv reactivation after allogeneic hematopoietic stem cell transplantation"
} | [
{
"companynumb": "DE-MYLANLABS-2021M1041238",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "VALGANCICLOVIR"
},
"drugadditional": null,
... |
{
"abstract": "Stress-induced cardiomyopathy is an acute disease characterized by a large left ventricular apical dyskinesia (\"apical ballooning\"), triggered by intense emotional or physical stress, acute illnesses or, rarely, by alcohol or opiates withdrawal. Connection to stress and apical asynergy suggest a catecholamine-mediated pathogenesis. We recently observed a typical apical stress-induced cardiomyopathy, arising two weeks after a long-lasting antidepressant treatment withdrawal and recurring, a week later, with evidence of inferior wall akinesia. The reported case has several unusual features: 1) both episodes were not preceded by relevant triggering event (except antidepressant discontinuation); 2) early heterozonal relapse was observed; 3) the latency between antidepressant discontinuation and stress-induced cardiomyopathy onset is unusually long. The lack of relevant triggering stress and the evidence of multifocal asynergies could support the hypothesis of a non-catecholaminergic pathogenesis. Moreover, the long latency after antidepressant withdrawal may suggest that prolonged antidepressant treatments may have delayed pathological consequences, possibly related to their known neuroplastic effects.",
"affiliations": "CNR Institute of Clinical Physiology, Pisa, Italy; EXTREME CENTRE, Scuola Superiore Sant'Anna, Pisa, Italy. Electronic address: c.marabotti@alice.it.;UO Cardiovascolare - UTIC, Ospedale della Bassa val di Cecina, Cecina, Italy.;CNR Institute of Clinical Physiology, Pisa, Italy.;CNR Institute of Clinical Physiology, Pisa, Italy.",
"authors": "Marabotti|Claudio|C|;Venturini|Elio|E|;Marabotti|Alberto|A|;Pingitore|Alessandro|A|",
"chemical_list": "D000928:Antidepressive Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-9563",
"issue": "43(3)",
"journal": "Heart & lung : the journal of critical care",
"keywords": "Antidepressant drugs; Apical ballooning; Stress-induced cardiomyopathy; Tako-tsubo syndrome; Withdrawal syndrome",
"medline_ta": "Heart Lung",
"mesh_terms": "D000368:Aged; D000928:Antidepressive Agents; D004562:Electrocardiography; D005260:Female; D006801:Humans; D013375:Substance Withdrawal Syndrome; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "0330057",
"other_id": null,
"pages": "225-30",
"pmc": null,
"pmid": "24794783",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delayed multifocal recurrent stress-induced cardiomyopathy after antidepressants withdrawal.",
"title_normalized": "delayed multifocal recurrent stress induced cardiomyopathy after antidepressants withdrawal"
} | [
{
"companynumb": "IT-TEVA-527508ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Oral manifestations of side effects of medications, such as methotrexate (MTX) for management of rheumatoid arthritis (RA) and mycophenolate mofetil (MMF) for solid organ transplant (SOT), are very rare. The known side effects include entities called other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) due to immunosuppression caused by these medications. While there has been an increased incidence of oral cavity LPD reported in the literature associated with MTX, oral presentations that involve MMF are rare. This case report will detail a 74-year-old man with scleroderma treated with MMF who developed Epstein-Barr virus + polymorphic B-cell lymphoproliferative disorder in the right maxillary gingiva presenting as osteonecrosis of the jaw (ONJ). His oral presentation was successfully treated with a combination of surgery and MMF dosage reduction with an oral presentation free of disease at 6 months follow-up. This is the first known case report of an oral manifestation of MMF-related OIIA-LPD.",
"affiliations": "Resident, Division of Oral and Maxillofacial Surgery, Allegheny General Hospital, Pittsburgh PA.;Attending Physician, Division of Hematology and Cellular Therapy, Allegheny Health Network Cancer Institute, Allegheny General Hospital, Pittsburgh PA.;Resident, Division of Oral and Maxillofacial Surgery, Allegheny General Hospital, Pittsburgh PA.;Attending Physician, Division of Hematology and Cellular Therapy, Allegheny Health Network Cancer Institute, Allegheny General Hospital, Pittsburgh PA.;Division Chief, Residency Program Director, Director of Research, and Associate Professor, Division of Oral and Maxillofacial Surgery, Allegheny General Hospital, Pittsburgh PA. Electronic address: DrJosephCillo@gmail.com.",
"authors": "Taliaferro|Andrew|A|;Samhouri|Yazan|Y|;Rice|Jeremy|J|;Khan|Cyrus M|CM|;Cillo|Joseph E|JE|",
"chemical_list": "D009173:Mycophenolic Acid; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.joms.2020.08.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-2391",
"issue": "79(2)",
"journal": "Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons",
"keywords": null,
"medline_ta": "J Oral Maxillofac Surg",
"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D006801:Humans; D007049:Iatrogenic Disease; D008232:Lymphoproliferative Disorders; D008297:Male; D008727:Methotrexate; D009173:Mycophenolic Acid",
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "398-403",
"pmc": null,
"pmid": "32916134",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016454:Review",
"references": null,
"title": "Rare Oral Presentation of a Mycophenolate Mofetil-Related Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorder (MMF-OIA-LPD) Lesion: A Case Report and Literature Review.",
"title_normalized": "rare oral presentation of a mycophenolate mofetil related other iatrogenic immunodeficiency associated lymphoproliferative disorder mmf oia lpd lesion a case report and literature review"
} | [
{
"companynumb": "US-VISTAPHARM, INC.-VER202009-001633",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadd... |
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