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"abstract": "Donor lymphocyte infusion (DLI) is typically used in 3 clinical situations: therapeutically for proven relapse of malignancy, prophylactically in patients with high-risk of relapse, and in case of mixed chimerism. Mixed chimerism, which occur after transplantation can be a sign of possible rejection. In case of increased mixed chimerism, immunotherapy with donor lymphocyte infusions could reverse this process. After DLI, both acute and chronic graft-versus-host disease and marrow aplasia are well-known toxicities. In this paper, we present a case report of young patient with chronic granulomatous disease (CGD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), with successful immunotherapy following mixed chimerism, which was complicated by bone marrow aplasia that required a second stem cell infusion. DLI seems to be an effective and highly promising treatment method of transplant rejection in patients with CGD but can induce bone marrow aplasia and may require a second stem cell infusion.",
"affiliations": "Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Lublin, Poland.;Laboratory of Genetic Diagnostics, Medical University, Lublin, Poland.;Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland.;Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Lublin, Poland.;Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Lublin, Poland.",
"authors": "Cienkusz|Magdalena|M|;Lejman|Monika|M|;DĄbrowska-Leonik|Nel|N|;Choma|Marta|M|;Drabko|Katarzyna|K|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5114/ceji.2020.94786",
"fulltext": "\n==== Front\nCent Eur J Immunol\nCent Eur J Immunol\nCEJI\nCentral-European Journal of Immunology\n1426-3912 1644-4124 Termedia Publishing House \n\n40503\n10.5114/ceji.2020.94786\nCase Report\nBone marrow aplasia following donor lymphocyte infusion in 4-year-old patient with chronic granulomatous disease after allogeneic stem cell transplantation: case report\nCIENKUSZ MAGDALENA 1 LEJMAN MONIKA 2 DĄBROWSKA-LEONIK NEL 3 CHOMA MARTA 1 DRABKO KATARZYNA 1 1 Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Lublin, Poland\n2 Laboratory of Genetic Diagnostics, Medical University, Lublin, Poland\n3 Department of Immunology, Children’s Memorial Health Institute, Warsaw, Poland\nCorrespondence: Magdalena Cienkusz, MD PhD, Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Lublin, Poland, 6 Prof. Antoni Gębala St., 20-093 Lublin, Poland, e-mail: magdalena.cienkusz@wp.pl\n24 9 2020 \n2020 \n45 3 346 350\n16 7 2018 03 10 2018 Copyright © 2020 Termedia2020This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0). License (http://creativecommons.org/licenses/by-nc-sa/4.0/)Donor lymphocyte infusion (DLI) is typically used in 3 clinical situations: therapeutically for proven relapse of malignancy, prophylactically in patients with high-risk of relapse, and in case of mixed chimerism. Mixed chimerism, which occur after transplantation can be a sign of possible rejection. In case of increased mixed chimerism, immunotherapy with donor lymphocyte infusions could reverse this process. After DLI, both acute and chronic graft-versus-host disease and marrow aplasia are well-known toxicities. In this paper, we present a case report of young patient with chronic granulomatous disease (CGD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), with successful immunotherapy following mixed chimerism, which was complicated by bone marrow aplasia that required a second stem cell infusion. DLI seems to be an effective and highly promising treatment method of transplant rejection in patients with CGD but can induce bone marrow aplasia and may require a second stem cell infusion.\n\nchildrenhematopoietic stem cell transplantationchronic granulomatous diseasedonor lymphocyte infusionbone marrow aplasia\n==== Body\nIntroduction\nChronic granulomatous disease (CGD) is a rare inherited immune deficiency caused by mutations in the genes CYBB, NCF1, NCF2, NCF4, or CYBA, encoding one of the NADPH oxidase subunits (gp91phox, p47phox, p67phox, p40phox, p22phox) [1-3]. Typical manifestations are recurrent bacterial and fungal infections causing diarrhea, growth failure, lung disease, and granuloma formation in different organs. This defect occurs with estimated frequency of one in 250,000 individuals [4, 5]. CGD could be diagnosed with granulocyte function tests showing impaired phagocytic activity, such as dihydrorhodamine (DHR) flow cytometry burst assay or nitro blue tetrazolium reduction tests (NBT) [6]. Conventional treatment consists of anti-infectious prophylaxis with antibiotics and antimycotics, steroids, interferon γ (IFN-γ); however, the outcomes are still unsatisfactory. The annual mortality rate is 2-5%, and only 50% of patients with CGD reaches the age of 30 [1, 7, 8].\n\nAllogeneic hematopoietic stem cell transplantation (allo-HSCT) has been used in patients with chronic granulomatous disease since 1976 with various results [9-11]. Nowadays, HSCT from a matched donor is a safer procedure, if performed before chronic infections and severe organ damage [2, 8, 12]. The European Society for Blood and Marrow Transplantation (EBMT) suggests that patients with CGD require toxicity-reduced conditioning [13]. The risk of toxic complications of this regimen is lower than that associated with conventional procedures, but it may increase a risk of graft rejection. Mixed chimerism occurring after transplantation can be a sign of possible rejection. In case of increased mixed chimerism, immunotherapy with donor lymphocyte infusions (DLI) could reverse this process [14]. Donor T cells cause immunologic clearance of residual host lymphocytes and stem cells, allowing engraftment and growth of the donor stem cells [15, 16]. Donor lymphocyte infusion is typically used in 3 clinical situations: therapeutically for proven relapse of malignancy, prophylactically in patients with high-risk of relapse, and in case of mixed chimerism. The main complications after DLI are graft-versus</ i>-host disease (GVHD), with 4-61% of cases and bone marrow aplasia occurring in 30-40% of CML [17].\n\nWe present a case report of a young patient with CGD after allo-HSCT, with successful immunotherapy following mixed chimerism, which was complicated by bone marrow aplasia that required a second stem cell infusion. Written informed consent was obtained from the patient’s parents for publication of this case report.\n\nCase report\nA 3.5-year-old boy was diagnosed as CGD at the Department of Immunology of the Children’s Memorial Health Institute in Warsaw. In the medical history, the first symptoms of the disease were present six months earlier and included lymphadenopathy with multiple abscesses of lymph nodes, recurrent severe pulmonary infections, diarrhea, cutaneous granulomas, and hepatosplenomegaly. NADPH-oxidase activity in stimulated neutrophils was absent in DHR flow cytometry burst assay, NBT was 1%, and stimulated NBT > 150 was 0%, 50-150 was 0%, 20-50 was 0%, and 0 was 100%. Molecular analysis by next generation sequencing (NGS) detected CYBB mutation on the X chromosome. Due to serious infectious and significant malnutrition, which required parenteral nutrition, in this case, the decision to proceed with HSCT was made immediately after the diagnosis.\n\nCoexisting conditions included celiac disease, hypothyroidism, thrombophilia (factor V Leiden mutation), and non-specific inflammation of duodenum and colon. Total neutrophil and leukocyte counts, peripheral blood lymphocyte phenotyping by flow cytometer, serum immunoglobulin levels, and other biochemistry results were normal. The family history of primary immunodeficiency was irrelevant.\n\nPretransplant treatment included anti-infection prophylaxis with antibiotics and antimycotics, immunosuppression with steroids and azathioprine, and substitution of levothyroxine.\n\nA transplant from matched unrelated donor was performed at the age of 4 years. The reduced toxicity conditioning regimen consisted of treosulfan at the total dose of 42 γ per square meter, fludarabine at the total dose of 150 mg per square meter, and thiotepa at the total dose of 10 mg per kilogram. As GVHD prophylaxis, the patient received cyclosporine A, anti-T lymphocyte globulin (ATG), and mycophenolate mophetil. A total of 5 × 106 CD34+ bone marrow stem cells per kilogram were infused.\n\nEngraftment was achieved on day +19, and full donor-derived hemopoietic chimerism using quantitative fluorescent PCR assays (QF-PCR) and short tandem repeats (STR) was noted on day +12 for the first time. The early post- transplant period was complicated on day +2 by acute ileus with unknown etiology, which did not require surgical intervention. The patient presented acute GVHD of grade I, involving the skin and oral mucosa from day +26, which did not require treatment. Molecular analysis of peripheral blood revealed 100% of donor cells weekly to day +40. The patient was discharged in a particularly good condition on day +43 post-transplant. The presence of oxidase-positive neutrophils in DHR flow cytometry burst assay was 90.8% (0.91 index) on day +51.\n\nOn day +57, mixed chimerism occurred in peripheral blood with tendency to increase (Fig. 1), but general clinical condition of the patient was good and blood counts were normal. Based on those results, cyclosporine A was discontinued on day +68, but the recipient signal was systematically growing. As the next immunotherapeutic intervention, we decided to perform DLI. DLI started on day +98 and the patient was given 7 increasing doses every 4 weeks. During those procedures, chimerism was still mixed with decreasing donor signal, and DHR flow cytometry burst assay was positive in 19.5% (0.2 index) on day +176. Detailed information on infusions are presented in Table 1.\n\nFig. 1 Kinetics of cellular chimerism after the first allo-hematopoietic stem cell transplantation (allo-HSCT) and donor lymphocyte infusion (DLI)\n\nTable 1 Detailed information on the donor lymphocyte infusions (DLI)\n\nNo. of DLI\tNo. of CD3+ cells\tDay after the first allo-HSCT\tChimerism\n% donor cells\tALT\n(U/l)\tAST\n(U/l)\tUrea\n(mg/dl)\tCreatinine\n(mg/dl)\t\n1\t1 × 106/kg\t+98\t50\t25\t29\t16\t0.3\t\n2\t1 × 106/kg\t+106\t40\t31\t36\t14\t0.3\t\n3\t1 × 107/kg\t+113\t42\t40\t47\t20.1\t0.3\t\n4\t1 × 107/kg\t+126\t41\t20\t27\t19\t0.3\t\n5\t50 × 106/kg\t+140\t37\t17\t22\t24\t0.4\t\n6\t50 × 108/kg\t+154\t38\t16\t24\t26\t0.3\t\n7\t100 × 108/kg\t+168\t30\t18\t24\t21\t0.3\t\nallo-HSCT – hematopoietic stem cell transplantation, PLT – platelets\n\nThe features of pancytopenia occurred on day +186 and the patient was admitted to hospital. The boy required transfusions of red cell concentrate (RCC) and platelet concentrate (PC), but his general condition was good, with no signs of infection and no symptoms of GVHD. Chimerism was checked every week and a slow increase in the donor signal was noticed, until full chimerism was obtained on day +221; unfortunately, there was no hematological recovery by this point. Bone marrow biopsy confirmed aplasia with full donor chimerism in bone marrow. We started administration of G-CSF with no effect. A decision was made to proceed with a second stem cell infusion from the same donor without conditioning, and it was performed 8 months after the first HSCT. No post-transplant immunosuppression was used. G-CSF was given from day +4 after the second HSCT and on day +20, a recovery of neutrophils and reticulocytes was noticed (Table 2). The presence of oxidase-positive neutrophils by DHR flow cytometry burst assay tested on day +45 after the second HSCT showed 95.3% (1.06 index). The patient was followed by an outpatient schedule and required only routine anti-infection prophylaxis and immunoglobulin substitution.\n\nTable 2 Laboratory test and chimerism before and after the second allo-hematopoietic stem cell transplantation (allo-HSCT)\n\nDay after the first allo-HSCT\tDay after the second allo-HSCT\t% donor cells\tNo. of RBC\n(×106/ul)\tNo. of HG\n(g/dl)\tNo. of WBC\n(×103/ul)\tNo. of NEUTR\n(×103/ul)\tNo. of PLT\n(×103/ul)\tIgG\n(g/dl)\t\n+196\t\t78\t2.86\t6.7\t1.82\t0.08\t53\t7.15\t\n+208\t\t93\t3.17\t8.0\t1.11\t0.01\t4\t7.12\t\n+221\t\t100\t3.57\t9.2\t0.73\t0.01\t30\t-\t\n+230\t0\t100\t3.88\t10.1\t0.68\t0.01\t36\t5.73\t\n\t+6\t100\t2.29\t5.8\t0.58\t0.01\t7\t-\t\n\t+20\t100\t3.83\t10.6\t3.38\t1.83\t24\t-\t\n\t+51\t100\t3.53\t10.0\t2.70\t0.58\t64\t4.24\t\n\t+87\t100\t4.02\t11.6\t5.25\t1.77\t91\t4.20\t\n\t+115\t100\t4.04\t11.5\t6.10\t2.77\t102\t4.87\t\n\t+143\t100\t4.33\t11.8\t6.79\t3.00\t139\t6.04\t\n\t+285\t100\t6.41\t13.0\t8.42\t1.6\t129\t5.34\t\nRBC – red blood cells, HG – hemoglobin, WBC – white blood cells, NEUTR – neutrophils, PLT – platelets, IgG – immunoglobulin G\n\nAt 12 months after immunotherapy, chronic GVHD limited to the skin occurred and the patient was treated with steroids and cyclosporine A. At 9 months after the patient’s second allo-HSCT, his general condition was good, with stable engraftment, 100% of donor cells, and the presence of oxidase-positive neutrophils in DHR flow cytometry burst assay.\n\nDiscussion\nAllo-HSCT is the only curative treatment for CGD, and experimental gene therapies in clinical trials are not available for every patient. The standard treatment consisting of lifelong anti-infectious prophylaxis, steroids, and interferon gamma may lead to an occurrence of major organ failure as a result of prolonged toxic therapies. Moreover, a transplant is recommended only in severe cases, after the failure of conventional methods and when the patient is chronically ill [18]. Therefore, the time to initiate a transplant procedure in patients with CGD is still under discussion. Goździk et al. postulated that the appropriate moment to perform HSCT in young patients with proven diagnosis of CGD is before the onset of life-threatening infections [1]. Similarly, Kansoy et al. and Leung et al. claimed that bone marrow transplantation should be performed in the first years of life before development of irreversible organ damage [2, 18]. Seger et al. reported outcomes of 27 patients with CGD transplanted from 1985 to 2000, based on the European Bone Marrow Transplant Registry for primary immunodeficiencies. In their paper, most transplant recipients were children (n = 25) and survival rate was high, especially in patients without an infection at the moment of transplantation. In that group of patients, deaths occurred in 4 cases, with pre-existing fungal infections refractory in all conventional treatments [8]. In our opinion, allo-HSCT should be considered at every stage of treatment of CGD patients, also immediately after diagnosis.\n\nToxicity-reduced conditioning, especially in patients with irreversible organ damage, can provide an engraftment with minimal complications. However, on the other hand, this procedure increases the risk of incomplete engraftment or graft rejection and GVHD. Such was the case of our patient, who had mixed chimerism after allo-HSCT with reduced conditioning, and symptoms of rejection could be reversed by donor lymphocyte infusions.\n\nAfter DLI, both acute and chronic graft-versus-host disease and marrow aplasia are well-known toxicities [17]. These complications were reported in about 30-45% of patients treated with DLI [17, 19]. Our patient did not show any side effects of infusion, and only limited skin GVHD occurred within one year after DLI. Four months after the first infusion, the patient achieved full donor-derived hemopoietic chimerism, unfortunately resulting in pancytopenia, which could be managed with the second transplant from the same donor without conditioning. The mechanism of bone marrow aplasia after DLI is not fully understood. Hematologic recovery depends on the presence of hematopoietic progenitors. Most likely, DLI damages residual host hematopoiesis before recovery of donor hematopoiesis. In case of marrow failure, second stem cell infusion could reverse pancytopenia, as in our patient [19].\n\nMixed chimerism does not necessarily lead to recurrence of disease symptoms. The donor cells can effectively mask the defect in superoxide-producing NADPH oxidase of the recipient’s neutrophils. Kansoy et al. presented a case report of an 8-month-old boy with CGD after allo-HSCT, whose chimerism in peripheral blood was 50% of donor cells at five years after the transplantation, and 85% of his neutrophils had normal oxidative burst activity. During the 60 months of follow-up, this young patient had no severe infectious disease, was generally in very good health condition, and growing properly [2]. In contrast, NADPH-oxidase activity in stimulated neutrophils was absent in our patient who had between 30-52% of donor cells in the serum. Therefore, the decision to use an immunotherapeutic intervention should be made not only on the analysis of chimerism, but also on the assessment of severity of symptoms of the underlying disease and unacceptable results of oxidative burst activity.\n\nIn the literature, reports on donor lymphocyte infusion at unstable mixed chimerism after allogeneic stem cells transplantation for non-malignant disorders mainly consider patients with thalassemia, sickle cell anemia, or hemoglobinopathies [20-22]. The effectiveness of DLI therapy was reported in a few cases of children with chronic granulomatous disease [1, 8, 11, 14, 23]. None of those reviews reported complications such as bone marrow aplasia, which was observed in our patient after DLI. Horwitz et al. reported 10 patients (5 children, 5 adults) with CGD, who underwent HSCT followed by DLI at 30 days or more after the transplantation. The median follow-up time was 17 months. During this period, infections like fungal pneumonia, herpes zoster keratitis, pneumococcal sepsis, or lymphoproliferative disorder due to EBV, occurred in 4 cases. None of those patients had pancytopenia [14]. Akioka et al. described an effective DLI at unstable mixed chimerism after HSCT in a 14-year-old male with CGD. The post-DLI period was complicated only by an acute hepatic GVHD [23]. Nagler et al. presented a case of a boy suffering from chronic granulomatous disease, who underwent HSCT, and the mixed chimerism was the reason for the use of DLI after which, no side effects were observed [11]. Similarly to our patient, Goździk et al. described a patient who underwent HSCT twice (patient no. 1). However, in contrast to our case, the reason why the second transplantation of bone marrow cells was performed was the rejection of transplant despite the use of DLI, not bone marrow aplasia or other hematological complications [1]. Therefore, in our opinion, this case is exceptional.\n\nConclusions\nDLI seems to be an effective and highly promising method of treatment of transplant rejection in patients with CGD but can induce bone marrow aplasia and may require a second stem cell infusion.\n\nThe authors declare no conflict of interest.\n==== Refs\n1 Goździk J , Pituch-Noworolska A , Skoczeń S , et al (2011 ): Allogeneic haematopoietic stem cell transplantation as therapy for chronic granulomatous disease-single centre experience\n. J Clin Immunol \n31 : 332 -337\n.21384251 \n2 Kansoy S , Kutukculer N , Aksoylar S , et al (2006 ): Successful bone marrow transplantation in an 8-month-old patient with chronic granulomatous disease\n. Turk J Pediatr \n48 : 253 -255\n.17172071 \n3 Leiding JW , Holland SM (2016 ): Chronic granulomatous disease\n. GeneReviews [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK99496/.\n4 Winelstein JA , Marino MC , Johnston RB , et al (2000 ): Chronic granulomatous disease. Report on a national registry of 368 patients\n. Medicine (Baltimore) \n79 : 155 -169\n.10844935 \n5 Van der Berg JM , van der Koppen E , Ahlin A , et al (2009 ): Chronic granulomatous disease: the European experience\n. PlosOne \n4 : e5234 .\n6 Siedlar M (2017 ): Chronic granulomatous disease In: Wybrane zagadnienia z pierwotnych niedoborów odporności oraz diagnostyki immunologicznej , Pietrzyk JJ , Kwinta P (eds). Wydawnictwo Uniwersytetu Jagiellońskiego , Kraków : 72 -74\n.\n7 Margolis DM , Melnick DA , Alling DW , et al (1990 ): Trimethoprim-sulfamethoxazole prophylaxis in the management of chronic granulomatous disease\n. J Infect Dis \n162 : 723 -726\n.2117627 \n8 Seger RA , Gungor T , Belohradsky BH , et al (2002 ): Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000\n. Blood \n100 : 4344 -4350\n.12393596 \n9 Foroozanfar N , Hobbs JR , Hugh-Jones K , et al (1977 ): Bone marrow transplantation from an unrelated donor for chronic granulomatous disease\n. Lancet \n1 : 210 -213\n.64747 \n10 Kamani N , August CS , Douglas SD , et al (1984 ): Bone marrow transplantation in chronic granulomatous disease\n. Pediatr \n105 : 42 -46\n.\n11 Nagler A , Ackerstein A , Kapelushinikj , et al (1999 ): Donor lymphocyte infusion post-non-myeloablative allogeneic peripheral blood stem cell transplantation for chronic granulomatous disease\n. Bone Marrow Transplant \n24 : 339 -342\n.10455377 \n12 Calvino MC , Maldonado MS , Otheo E , et al (1996 ): Bone marrow transplantation in chronic granulomatous disease\n. Eur J Pediatr \n156 : 877 -879\n.\n13 https://www.ebmt.org/sites/default/files/migration_legacy_files/document/Inborn%20Errors%20Working%20Party%20ESID%20EBMT%20HSCT%20Guidelines%202017.pdf \n14 Horwitz ME , Barrett J , Brown MR , et al (2001 ): Treatment of chronic granulomatous disease with nonmyeloblative conditioning and a T-cell-depleted hematopoietic allograft\n. N Engl J Med \n12 : 881 -888\n.\n15 Sykes M , Sheard MA , Sachs DH (1988 ): Graft-versus-host-related immunosuppression is induced in mixed chimeras by alloresponses against either host or donor lymphohematopoietic cells\n. J Exp Med \n168 : 2391 -2396\n.3264329 \n16 Pelot MR , Pearson DA , Swenson K , et al (1999 ): Lymphohematopoietic graft-vs.-host reactions can be induced without graft-vs.-host disease in murine mixed chimeras established with a cyclophosphamide-based nonmyeloablative conditioning regimen\n. Biol Blood Marrow Transplant \n5 : 133 -143\n.10392959 \n17 Castagna L , Sarina B , Bramanti S , et al (2016 ): Donor lymphocyte infusion after allogeneic stem cell transplantation\n. Transfus Apher Sci \n54 : 345 -355\n.27216544 \n18 Leung TF , Chik K , Li C , et al (1999 ): Bone marrow transplantation for chronic granulomatous disease: long-term follow-up and review of literature\n. Bone Marrow Transplant \n24 : 567 -570\n.10482944 \n19 Keil F , Haas OA , Fritsch G , et al (1997 ): Donor leukocyte infusion for leukemic relapse after allogeneic marrow transplantation: lack of residual donor hematopoiesis predicts aplasia\n. Blood \n89 : 3113 -3117\n.9129013 \n20 Karasu GT , Yesilipek MA , Karauzum SB et al (2012 ): The value of donor lymphocyte infusions in thalassemia patients at imminent risk of graft rejection following stem cell transplantation\n. Pediatr Blood Cancer \n58 : 453 -458\n.21990066 \n21 Lucarelli G , Galimberti M , Polchi P , et al (1990 ): Bone marrow transplantation in patients with thalassemia\n. N Engl J Med \n322 : 417 -421\n.2300104 \n22 Lucarelli G , Isgrò A , Sodani P , et al (2012 ): Hematopoietic Stem Cell Transplantation in Thalassemia and Sickle Cell Anemia\n. Cold Spring Harb Perspect Med \n2 : 1 -5\n.\n23 Akioka S , Itoh H , Ueda I , et al (1998 ): Donor lymphocyte infusion at unstable mixed chimerism in an allogeneic BMT recipient for chronic granulomataous disease\n. Bone Marrow Transplant \n22 : 609 -611\n.9758355\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1426-3912",
"issue": "45(3)",
"journal": "Central-European journal of immunology",
"keywords": "bone marrow aplasia; children; chronic granulomatous disease; donor lymphocyte infusion; hematopoietic stem cell transplantation",
"medline_ta": "Cent Eur J Immunol",
"mesh_terms": null,
"nlm_unique_id": "9702239",
"other_id": null,
"pages": "346-350",
"pmc": null,
"pmid": "33437188",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "9129013;10844935;10455377;12393596;10392959;9758355;64747;2300104;21990066;3264329;21384251;19381301;2117627;6376746;11259721;10482944;27216544;17172071;8891557",
"title": "Bone marrow aplasia following donor lymphocyte infusion in 4-year-old patient with chronic granulomatous disease after allogeneic stem cell transplantation: case report.",
"title_normalized": "bone marrow aplasia following donor lymphocyte infusion in 4 year old patient with chronic granulomatous disease after allogeneic stem cell transplantation case report"
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"abstract": "BACKGROUND\nFor patients with metastatic pancreatic cancer, FOLFIRINOX (fluorouracil [5-FU], leucovorin [LV], irinotecan [IRI], and oxaliplatin) has shown improved survival rates compared with gemcitabine but with significant toxicity, particularly in patients with a high tumor burden. Because of reported response rates exceeding 30 %, the authors began to use a modified (m) FOLFIRINOX regimen for patients with advanced nonmetastatic disease aimed at downstaging for resection. This report describes their experience with mFOLFIRINOX and aggressive surgical resection.\n\n\nMETHODS\nBetween January 2011 and August of 2013, 43 patients with borderline resectable pancreatic cancer (BRPC, n = 18) or locally advanced pancreatic cancer (LAPC, n = 25) were treated with mFOLFIRINOX (no bolus 5-FU, no LV, and decreased IRI). Radiation was used based on response and intended surgery. Charts were retrospectively reviewed to assess response, toxicities, and extent of resection when possible.\n\n\nRESULTS\nThe most common grade 3/4 toxicity was diarrhea in six patients (14 %) with no grade 3/4 neutropenia or thrombocytopenia. Resection was attempted in 31 cases (72 %) and accomplished in 22 cases (51.1 %) including 11 of 25 LAPC cases (44 %). Vascular resection was required in 4 cases (18 %), with R0 resection in 86.4 % of the resections. Complications occurred in 6 cases (27 %), with no perioperative deaths. The median progression-free survival period was 18 months if the resection was achieved compared with 8 months if no resection was performed (p < 0.001).\n\n\nCONCLUSIONS\nNeoadjuvant mFOLFIRINOX is an effective, well-tolerated regimen for patients with advanced nonmetastatic pancreatic cancer. When mFOLFIRINOX is coupled with aggressive surgery, high resection rates are possible even when the initial imaging shows locally advanced disease. Although data are still maturing, resection appears to offer at least a progression-free survival advantage.",
"affiliations": "James Cancer Hospital, The Ohio State University, Columbus, OH, USA.",
"authors": "Blazer|Marlo|M|;Wu|Christina|C|;Goldberg|Richard M|RM|;Phillips|Gary|G|;Schmidt|Carl|C|;Muscarella|Peter|P|;Wuthrick|Evan|E|;Williams|Terrence M|TM|;Reardon|Joshua|J|;Ellison|E Christopher|EC|;Bloomston|Mark|M|;Bekaii-Saab|Tanios|T|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000077146:Irinotecan; C056507:gemcitabine; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.1245/s10434-014-4225-1",
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"issn_linking": "1068-9265",
"issue": "22(4)",
"journal": "Annals of surgical oncology",
"keywords": null,
"medline_ta": "Ann Surg Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D003841:Deoxycytidine; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "9420840",
"other_id": null,
"pages": "1153-9",
"pmc": null,
"pmid": "25358667",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article",
"references": "17363191;17379445;18309942;19396496;19581537;20422030;21561347;22237781;22642850;22968073;23657686;8406311;16254431;17227978;17414605",
"title": "Neoadjuvant modified (m) FOLFIRINOX for locally advanced unresectable (LAPC) and borderline resectable (BRPC) adenocarcinoma of the pancreas.",
"title_normalized": "neoadjuvant modified m folfirinox for locally advanced unresectable lapc and borderline resectable brpc adenocarcinoma of the pancreas"
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"abstract": "Amyloidosis is characterized by pathological deposition of abnormal protein aggregates in various tissues, AL protein being the commonest. Amyloidosis derived from leukocyte cell-derived chemotaxin 2 (LECT2) is a recently recognized form of amyloidosis in the United States with predominant involvement of kidney and liver. We present a case of ALECT2 renal amyloid in a transplant recipient who presented with gradual worsening of graft function and subnephrotic proteinuria. To our knowledge, this is first case of LECT2 amyloidosis from Northern India in a transplant recipient. There is no effective therapy for amyloidosis derived from leukocyte cell-derived chemotaxin 2.",
"affiliations": "Division of Nephrology, Grecian Hospital, Mohali, Punjab, India.;Division of Nephrology, Grecian Hospital, Mohali, Punjab, India.;Department of Histopathology, Core Diagnostics, Gurgaon, Haryana, India.;Department of Histopathology, Medicos Centre, Chandigarh, India.;Department of Transplant Surgery, Surya Kidney Hospital, Mohali, Punjab, India.",
"authors": "Singh|Kulwant|K|;Sethi|Jasmine|J|;Duggal|Rajan|R|;Joshi|Kusum|K|;Bains|Arjinder S|AS|",
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"country": "India",
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"doi": "10.4103/ijn.IJN_258_19",
"fulltext": "\n==== Front\nIndian J Nephrol\nIndian J Nephrol\nIJN\nIndian Journal of Nephrology\n0971-4065 1998-3662 Wolters Kluwer - Medknow India \n\nIJN-30-204\n10.4103/ijn.IJN_258_19\nCase Report\nRare, Yet Emerging Cause of Graft Dysfunction—ALECT 2 Amyloidosis\nSingh Kulwant Sethi Jasmine Duggal Rajan 1 Joshi Kusum 2 Bains Arjinder S. 3 Division of Nephrology, Grecian Hospital, Mohali, Punjab, India\n1 Department of Histopathology, Core Diagnostics, Gurgaon, Haryana, India\n2 Department of Histopathology, Medicos Centre, Chandigarh, India\n3 Department of Transplant Surgery, Surya Kidney Hospital, Mohali, Punjab, India\nAddress for correspondence: Dr. Kulwant Singh, Division of Nephrology, Grecian Hospital, Sector 69, Mohali - 160 062, Punjab, India. E-mail: kulmin2k2@gmail.com\nMay-Jun 2020 \n11 2 2020 \n30 3 204 206\n23 7 2019 04 9 2019 18 10 2019 Copyright: © 2020 Indian Journal of Nephrology2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Amyloidosis is characterized by pathological deposition of abnormal protein aggregates in various tissues, AL protein being the commonest. Amyloidosis derived from leukocyte cell-derived chemotaxin 2 (LECT2) is a recently recognized form of amyloidosis in the United States with predominant involvement of kidney and liver. We present a case of ALECT2 renal amyloid in a transplant recipient who presented with gradual worsening of graft function and subnephrotic proteinuria. To our knowledge, this is first case of LECT2 amyloidosis from Northern India in a transplant recipient. There is no effective therapy for amyloidosis derived from leukocyte cell-derived chemotaxin 2.\n\nALECT2 amyloidgraft dysfunctionrenal transplant\n==== Body\nIntroduction\nAmyloidosis is characterized by extracellular deposition of insoluble fibers that result from abnormal protein folding. AL amyloidosis is most frequent type of amyloidosis in United States, whereas in developing countries AA amyloidosis is more common.[1] In 2008, Benson et al. discovered a new form of amyloid derived from leukocyte cell-derived chemotaxin 2 (ALECT2) in a nephrectomy specimen done for renal cell carcinoma.[2] ALECT 2 amyloidosis is now as common as AA amyloidosis in United States accounting for 2.7–10% of patients with renal amyloidosis.[3] ALECT2 amyloidosis exhibits a strong ethnic bias, with 88–92% of reported patients being Hispanics mostly of Mexican descent.[4] We describe a case of renal ALECT2 amyloidosis in a renal transplant recipient who presented with gradual renal dysfunction and subnephrotic proteinuria. This case report highlights the fact that primary amyloidosis is one of the underdiagnosed causes of renal dysfunction.\n\nCase Presentation\nA forty-three-year-old renal allograft recipient of Indo Aryan lineage was referred for evaluation of gradual rise in serum creatinine. He was diagnosed with advanced renal dysfunction 18 years back when he presented with breathlessness and accelerated blood pressure. Evaluation revealed advanced azotemia, subnephrotic proteinuria, and bilateral shrunken kidneys. Renal biopsy was not done in view of shrunken kidneys. He underwent first renal transplant in 2001 with mother as donor, with no induction and maintenance with cyclosporine, azathioprine, and prednisolone. He had acute graft dysfunction after 6 months of transplant and developed graft loss due to refractory cell-mediated rejection. He underwent second transplant in 2003 with father as donor (2 years after the first transplant). No induction was given and he was maintained on tacrolimus, azathioprine, and prednisolone. His serum creatinine remained in the range of 1.2–1.4 mg/dl for next 12 years. In 2017, his creatinine rose to 4.6 mg/dl and biopsy revealed cell-mediated rejection with evidence of chronic calcineurin inhibitor toxicity. He was treated with 3 doses of pulse steroid (500 mg) and tacrolimus was switched to sirolimus. Serum creatinine decreased to 1.3 mg/dl but later had gradual rise of serum creatinine over 2 years from 1.3 to 2.3 mg/dl till last month with subnephrotic proteinuria of 500 mg/day. Kidney biopsy was done in January 2019 which showed diffuse infiltration of interstitium and vascular area with pale eosinophilic material strongly positive for Congo red stain suggestive of amyloid [Figures 1 and 2] and changes of chronic calcineurin inhibitor toxicity. Serum amyloid-associated protein (SAA) and immunofluorescence study was negative for immunoglobulins and complements. Immunohistochemistry with anti LECT2 antibodies showed diffuse positivity within amyloid deposits [Figure 3]. Electron microscopy was attempted on the paraffin block but due to extensive processing artifacts, it was not interpretable. Serum protein electrophoresis was negative for monoclonal proteins. Serologies including hepatitis panel, antinuclear and antineutrophilic cytoplasmic antibodies, and complements were within normal range. The first biopsy was reevaluated and showed very minimal PAS negative material in the interstitium, but due to insufficient tissue, Congo red could not be performed for confirmation. His father (donor) was also evaluated to rule out any donor source of the deposits, but he was clinically asymptomatic with normal renal function and no proteinuria. The patient had no hepatomegaly on ultrasound and his liver function tests were normal, thus ruling out liver involvement. He was managed conservatively with angiotensin converting enzyme inhibitor and immunosuppression continued. Serum creatinine on the last follow-up was stable at 2.5 mg/dl.\n\nFigure 1 Extensive deposits of weak PAS positive material along tubular basement membrane and interstitium characteristic of amyloid (magnification 40×)\n\nFigure 2 Congo Red Staining of the deposited material along tubular basement membrane and in the interstitium\n\nFigure 3 Strong staining for LECT2 by immunohistochemistry along tubular basement membrane and interstitial deposits\n\nDiscussion\nLECT2 Amyloidosis is the fourth most common type of amyloidosis with a prevalence of 3.5% in the largest amyloid cohort of 4139 cases described by Mayo Clinic.[5] The LECT2 gene has been mapped to chromosome 5q31. Patients with homozygous G allele with single amino acid switch at position 40 are predisposed to develop LECT2 amyloidosis.[6] Most patients are elderly and present with mild-to-moderate renal insufficiency and variable proteinuria. In contrast to AL and AA amyloidosis, LECT2 amyloidosis is a relatively benign disease associated with a slow GFR decline and minimal proteinuria.[34] Hepatic ALECT2 amyloidosis most commonly presents with elevation of alkaline phosphatase.[7] Histologically, it is typically deposited in interstitium and mesangial regions with strong congophilia.[38] This is in contrast to AL and AA amyloidosis in which glomerular and vessels are the major site of amyloid deposition. Contrary to Apo AI amyloidosis and Apo AIV amyloidosis, which mainly affect the medullary interstitium, ALECT2 amyloidosis shows a predominant involvement of cortical interstitium.[34] Immunofluorescence is usually negative. A minority (9%) of patients with ALECT2 amyloidosis show false-positive staining for serum amyloid A (SAA).[4] Amyloid typing by immunohistochemistry using commercially available antibodies against LECT2 is a highly sensitive diagnostic tool.[9] Typing the amyloid deposits by mass spectroscopy-based proteomics is, however, the best tool to diagnose LECT2 amyloidosis, which is available in limited centers only.[10] Patient survival is superior to that seen in renal AL and AA, presumably because of the absence of cardiac involvement. Currently no effective treatment is available for this disease.[6]\n\nConclusion\nTo conclude, we should suspect this entity when the deposition of amyloid material is more in interstitium and vessel walls in comparison to glomerular component with prominent congophilia.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Chugh KS Datta BN Singhal PC Jain SK Sakhuja V Dash SC Pattern of renal amyloidosis in Indian patients Postgrad Med J 1981 57 31 5 7279820 \n2 Benson MD James S Scott K Liepnieks JJ Kluve-Beckerman B Leukocyte chemotactic factor 2: A novel renal amyloid protein Kidney Int 2008 74 218 22 18449172 \n3 Larsen CP Kossmann RJ Beggs ML Soloman A Walker PD Clinical, morphologic, and genetic features of renal leukocyte chemotactic factor 2 amyloidosis Kidney Int 2014 86 378 82 24522497 \n4 Said SM Sethi S Valeri AM Chang A Nast CC Krahl L Characterization and outcomes of renal leukocyte chemotactic factor 2-associated amyloidosis Kidney Int 2014 86 370 7 24451324 \n5 Theis JD Dasari S Vrana JA Mereuta OM Grogg KL Gertz MA Proteome of amyloidosis: Mayo Clinic experience in 4139 cases Blood 2013 122 1900 23896410 \n6 Nasr SH Dogan A Larsen CP Leukocyte cell-derived chemotaxin 2-associated amyloidosis: A recently recognized disease with distinct clinicopathologic characteristics Clin J Am Soc Nephrol 2015 10 2084 93 25873265 \n7 Mereuta OM Theis JD Vrana JA Law ME Grogg KL Leukocyte cell-derived chemotaxin 2 (LECT2)-associated amyloidosis is a frequent cause of hepatic amyloidosis in the United States Blood 2014 123 1479 82 24415538 \n8 Larsen CP Walker PD Weiss DT Solomon A Prevalence and morphology of leukocyte chemotactic factor 2-associated amyloid in renal biopsies Kidney Int 2010 77 816 9 20182418 \n9 Larsen C Leukocyte chemotactic factor 2 amyloidosis can be reliably diagnosed by immunohistochemical staining Hum Pathol 2014 45 2179 \n10 Sethi S Vrana JA Theis JD Leung N Sethi A Nasr SH Laser microdissection and mass spectrometry-based proteomics aids the diagnosis and typing of renal amyloidosis Kidney Int 2012 82 226 34 22495291\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "30(3)",
"journal": "Indian journal of nephrology",
"keywords": "ALECT2 amyloid; graft dysfunction; renal transplant",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "204-206",
"pmc": null,
"pmid": "33013073",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "7279820;25873265;24415538;18449172;24451324;25123072;24522497;20182418;22495291",
"title": "Rare, Yet Emerging Cause of Graft Dysfunction-ALECT 2 Amyloidosis.",
"title_normalized": "rare yet emerging cause of graft dysfunction alect 2 amyloidosis"
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"abstract": "Toxicity from antimuscarinic agents precipitates a constellation of signs and symptoms; two of the most significant are agitation and delirium. Benzodiazepines are commonly used for treatment; physostigmine is also effective but is underutilized due to concerns for safety and short duration of action. The objective of this study was to compare lorazepam to physostigmine for the treatment of antimuscarinic delirium and agitation.\nThis was a blinded, randomized clinical trial in patients presenting for antimuscarinic toxidrome. Inclusion criteria were: ≥10-<18 years old, at least one central and two peripheral antimuscarinic symptoms, delirium and moderate agitation. Subjects were randomized to either (1) lorazepam bolus (0.05 mg/kg) followed by a 4-h normal saline infusion, or (2) physostigmine 0.02 mg/kg bolus followed by a 4-h physostigmine infusion (0.02 mg/kg/h). Primary outcomes were the control of delirium and agitation after bolus and during the infusion.\nTen (53%) subjects were enrolled in the lorazepam arm, 9 (47%) in the physostigmine arm. Diphenhydramine was the most common agent ingested (16, 84%). Fewer patients receiving physostigmine had delirium after the initial bolus (44% vs 100%, p = 0.01) and at the 4th hour of infusion (22% vs 100%, p < 0.001) compared to patients who received lorazepam. There was a significant decrease in agitation scores in the physostigmine arm compared to the lorazepam arm after the initial bolus (89% vs 30%, p = 0.02), but no difference at the 4th hour of infusion (p > 0.99). There were no seizures, bradycardia, bronchorrhea, bronchospasm, intubation, or cardiac dysrhythmias.\nPhysostigmine was superior to lorazepam in controlling antimuscarinic delirium and agitation after bolus dosing, and control of delirium after a 4-h infusion. There were no serious adverse events in either treatment arm. Physostigmine bolus and infusion should be considered in adolescent patients with significant delirium and agitation from antimuscarinic agents.",
"affiliations": "Section of Emergency Medicine, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO, USA.;Departments of Emergency Medicine and Medical Toxicology, St. Luke's University Health Network, Bethlehem, PA, USA.;En route Care Research Center, Lackland AFB, San Antonio, TX, USA.;MedTox Laboratories, Laboratory Corporation of America Holdings, Saint Paul, MN, USA.;Section of Emergency Medicine, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO, USA.;Section of Emergency Medicine, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO, USA.;Department of Emergency Medicine, University of Colorado Anschutz Medical Campus, University of Colorado Hospital, Aurora, CO, USA.",
"authors": "Wang|George Sam|GS|;Baker|Keith|K|;Ng|Patrick|P|;Janis|Gregory C|GC|;Leonard|Jan|J|;Mistry|Rakesh D|RD|;Heard|Kennon|K|",
"chemical_list": "D014151:Anti-Anxiety Agents; D018727:Muscarinic Antagonists; D004155:Diphenhydramine; D010830:Physostigmine; D008140:Lorazepam",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2020.1854281",
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"issue": "59(8)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "CNS and psychological; CNS/psychological; complications of poisoning; organ/tissue specific; other; pharmaceuticals",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000293:Adolescent; D017109:Akathisia, Drug-Induced; D014151:Anti-Anxiety Agents; D003693:Delirium; D004155:Diphenhydramine; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007902:Length of Stay; D008140:Lorazepam; D008297:Male; D018727:Muscarinic Antagonists; D010830:Physostigmine; D016896:Treatment Outcome",
"nlm_unique_id": "101241654",
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"pages": "698-704",
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"pmid": "33295809",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "A randomized trial comparing physostigmine vs lorazepam for treatment of antimuscarinic (anticholinergic) toxidrome.",
"title_normalized": "a randomized trial comparing physostigmine vs lorazepam for treatment of antimuscarinic anticholinergic toxidrome"
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"abstract": "Intravenous unfractionated heparin (UFH) remains one of the most commonly used anticoagulants in the hospital setting. The optimal protocol for initiation and maintenance of UFH has been difficult to determine. Over the past two decades, weight-based nomogram protocols have gained favor. Herein, we present a retrospective study of 377 patients at a single tertiary academic center treated with low intensity (LI) and standard intensity (SI) UFH protocols for therapeutic anticoagulation. UFH levels are measured by anti-Xa assay activity with therapeutic levels of 0.30 to 0.70 IU/mL for SI and 0.25 to 0.35 IU/mL for LI. Patients treated on the LI protocol were more likely to have had a previous history of bleeding and lower baseline hemoglobin. Incidence of new or worsening thrombus while on UFH was comparable between both protocols (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.29-2.98, p=0.899). Patients on LI protocol had higher incidence of bleeding while on UFH (OR 1.21, 95% CI 0.51-2.89, p=0.667). Our study thus suggests that the LI protocol may have comparable efficacy to the SI protocol in treating venous thromboembolism (VTE) and that target anti-Xa levels of 0.25 to 0.35 IU/mL may be more optimal in high-risk patients.",
"affiliations": "Hematology and Oncology, University of Maryland Medical Center, Baltimore, USA.;Hematology and Oncology, University of Florida Health, Gainesville, USA.;Gastroenterology, University of Florida Health, Gainesville, USA.;Neurology, University of Florida Health, Gainesville, USA.;Internal Medicine, University of Florida Health, Gainesville, USA.;Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA.;Hematology and Oncology, University of Florida Health, Gainesville, USA.;Internal Medicine, University of Florida Health, Gainesville, USA.;Internal Medicine, University of Florida Health, Gainesville, USA.;Internal Medicine, University of Florida Health, Gainesville, USA.;Hematology and Oncology, University of Florida Health, Gainesville, USA.;Hematology and Oncology, University of Florida Health, Gainesville, USA.",
"authors": "Lutfi|Forat|F|;Bishnoi|Rohit|R|;Patel|Vikas J|VJ|;Elfasi|Aisha|A|;Setteducato|Michael|M|;Zhang|Shuyao|S|;Shah|Chintan P|CP|;Kurian|Saji|S|;Kamath|Chethana|C|;Kim|Dae Jun|DJ|;Zumberg|Marc S|MS|;Murphy|Martina|M|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.8339\nInternal Medicine\nHematology\nBleeding and Thrombotic Risk in Low Dose Heparin Infusion as Compared to Standard Dose Heparin Infusion\nMuacevic Alexander Adler John R Lutfi Forat 1 Bishnoi Rohit 2 Patel Vikas J 3 Elfasi Aisha 4 Setteducato Michael 5 Zhang Shuyao 6 Shah Chintan P 2 Kurian Saji 5 Kamath Chethana 5 Kim Dae Jun 5 Zumberg Marc S 2 Murphy Martina 2 \n1 \nHematology and Oncology, University of Maryland Medical Center, Baltimore, USA \n\n2 \nHematology and Oncology, University of Florida Health, Gainesville, USA \n\n3 \nGastroenterology, University of Florida Health, Gainesville, USA \n\n4 \nNeurology, University of Florida Health, Gainesville, USA \n\n5 \nInternal Medicine, University of Florida Health, Gainesville, USA \n\n6 \nInternal Medicine, University of Texas Southwestern Medical Center, Dallas, USA \n\nForat Lutfi foratlutfi@gmail.com\n28 5 2020 \n5 2020 \n12 5 e83397 5 2020 28 5 2020 Copyright © 2020, Lutfi et al.2020Lutfi et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/32818-bleeding-and-thrombotic-risk-in-low-dose-heparin-infusion-as-compared-to-standard-dose-heparin-infusionIntravenous unfractionated heparin (UFH) remains one of the most commonly used anticoagulants in the hospital setting. The optimal protocol for initiation and maintenance of UFH has been difficult to determine. Over the past two decades, weight-based nomogram protocols have gained favor. Herein, we present a retrospective study of 377 patients at a single tertiary academic center treated with low intensity (LI) and standard intensity (SI) UFH protocols for therapeutic anticoagulation. UFH levels are measured by anti-Xa assay activity with therapeutic levels of 0.30 to 0.70 IU/mL for SI and 0.25 to 0.35 IU/mL for LI. \n\nPatients treated on the LI protocol were more likely to have had a previous history of bleeding and lower baseline hemoglobin. Incidence of new or worsening thrombus while on UFH was comparable between both protocols (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.29-2.98, p=0.899). Patients on LI protocol had higher incidence of bleeding while on UFH (OR 1.21, 95% CI 0.51-2.89, p=0.667). Our study thus suggests that the LI protocol may have comparable efficacy to the SI protocol in treating venous thromboembolism (VTE) and that target anti-Xa levels of 0.25 to 0.35 IU/mL may be more optimal in high-risk patients.\n\nanticoagulant therapyheparinthrombosishemorrhagevenous thromboembolismThe 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\nSince the discovery of heparin by Howell in 1916 and its initial use on human subjects in 1935, it has been one of the most commonly utilized inpatient medications in modern medicine [1,2]. However, despite its frequent inpatient use and importance in preventing and treating venous thromboembolism (VTE), therapeutic protocols for unfractionated heparin (UFH) have varied between institutions and organizations. Given the importance of the use of therapeutic heparin in treating VTE and minimizing the risk of hemorrhage posed by its use, determining the optimal protocol is of the utmost importance.\n\nDetermining the optimal protocol for UFH bolus and subsequent infusion has been controversial. In 1989, the American College of Chest Physicians (ACCP) Clinic Practice Guideline on VTE treatment recommended an initial bolus of 5,000-units followed by 1000-units/hour [3]. More recently, guidelines have incorporated weight-based recommendations [4-12]. The 2012 ACCP guidelines published as the 9th edition in Chest recommend an initial bolus of 80-units/kg followed by 18 units/kg/hr adjusted to therapeutic levels [13]. \n\nIn patients deemed high-risk for hemorrhage, a low intensity (LI) rather than standard intensity (SI) protocol is often employed. However, to date, there has been little study of differences in adverse events, namely hemorrhage, and efficacy between LI and SI protocols. Furthermore, identifying the effect of patient-specific factors (e.g. age, indication for UFH, anticoagulant and anti-platelet use, medical, and surgical history) on outcomes has the potential to assist in determining the most appropriate protocol.\n\nMaterials and methods\nA total of 377 adult patients receiving therapeutic UFH from July 2011 to July 2017 at a single tertiary academic center were retrospectively studied. Patients receiving UFH on a separate acute coronary syndrome protocol and those receiving concomitant thrombolytic agents were excluded. Only those patients treated on LI or SI UFH protocols were included in analysis. Indications for LI or SI UFH use was VTE (deep venous thrombosis (DVT) or pulmonary embolism (PE)), atrial fibrillation, acute coronary syndrome, arterial thrombus, cerebral ischemic event, portal vein thrombosis, and for cardiac valves.\n\nAt our institution, UFH is administered by SI (therapeutic target anti-Xa activity level 0.30 to 0.70 IU/mL) and LI (therapeutic target anti-Xa activity level 0.25 to 0.35 IU/mL) protocols. The anti-Xa activity assay is used preferentially over activated partial thromboplastin time (aPTT) as a method of determining in vivo heparin activity [14-19]. Both protocols are initiated with a weight-based bolus, followed by an initial infusion rate of 12 or 18 units/kg/hr for LI and SI protocols, respectively. UFH is dosed based on actual body weight if the patient weight is less than 125kg. For patients weighting greater than 125 kg, adjusted body weight is used to determine dosing (Table 1).\n\nTable 1 Nursing protocol for therapeutic infusion of unfractionated heparin (UFH)\nNote: heparin unfractionated levels are obtained six hours from initiation of the infusion and then checked every six hours until therapeutic on two consecutive measurements. Thereafter, heparin unfractionated levels are obtained every morning.\n\n*Total body weight is used for dose calculation if ≤125 kg, if >125 kg, adjusted body weight is used to determine dosing.\n\nLow Intensity:\tStandard Intensity:\t\nOptional bolus: 60 units/kg\tSuggested bolus: 80 units/kg\t\nInitial infusion rate: 12 units/kg/hr\tInitial infusion rate: 18 units/kg/hr\t\nUFH <0.11: bolus of 60 units/kg units and increase rate by 3 units/kg/hr\tUFH <0.2: bolus of 80 units/kg and increase rate by 4 units/kg/hr\t\nUFH 0.11-0.24: bolus of 30 units/kg and increase rate by 2 units/kg/hr\tUFH 0.2-0.29: bolus of 40 units/kg and increase rate by 2 units/kg/hr\t\nUFH 0.11-0.24: bolus of 30 units/kg and increase rate by 2 units/kg/hr\tUFH 0.3-0.7: at goal, no changes\t\nUFH 0.25-0.35: at goal, no change\tUFH 0.71-0.8: decrease rate by 1 units/kg/hr\t\nUFH 0.36 to 0.55: decrease rate by 2 units/kg/hr\tUFH 0.81-0.9: stop for 30 min and decrease by 2 units/kg/hr\t\nUFH >0.56: stop infusion for 60 min and decrease rate by 3 units/kg/hr\tUFH >0.91: stop infusion for 60 min and decrease by 3 units/kg/hr\t\nIntravenous infusion of UFH is ordered using an Electronic Medical Record (EMR) order set involving all steps for the monitoring of heparin concentrations measured in units/mL using an anti -Xa assay. The decision on whether to use LI or SI protocols is based on the ordering physician’s discretion and their personal assessment of the patient’s bleeding and thrombotic risk and treatment indication.\n\nChart review was done manually using the EMR and data was recorded in REDCap to standardize data collection and decrease researcher variability. REDCap is a secure web application for building and managing online databases. The primary outcomes measured were incidence of new or worsening thrombus and/or bleeding while receiving intravenous UFH. Bleeding was categorized into major and minor, based on the International Society on Thrombosis and Haemostasis (ISTH) definitions [20]. Secondary outcomes measured include the incidence of transfusion requirement within one month and the incidence of death within three months of initiation of UFH. IRB approval was obtained prior to collection of data (University of Florida IRB201702116). Data analysis was conducted using the SAS 9.4 statistical software (SAS Institute Inc., Cary, North Carolina). Descriptive statistics were determined for each study variable. Univariate analysis was applied to identify the risk factors associated with the outcome variable. The Fisher exact test was used to compare the geographic categorical variables between the outcome groups and the independent t-test was used to compare the numerical variables between the outcome groups. If the underlying assumptions of the t-test were violated, the corresponding nonparametric test (Wilcoxon rank-sum test) was used to replace the t-test. The statistically significant (p< .05) variables in the univariate analysis phase were selected to build a multivariable logistic regression model. The stepwise selection procedure was used for the model selection.\n\nResults\nOf the 377 patients studied, 42.0% (158) and 58.0% (219) were on LI and SI protocols, respectively. The majority of patients (76.1%) received an initial bolus of 60 units/kg (LI) or 80 units/kg (SI) with a higher prevalence of bolus in the SI group (84.0% versus 65.2%.) Median time to therapeutic levels was 5.5 hours in the LI group and 3.3 hours in the SI group (Table 2).\n\nPatients were predominately Caucasian (74.0%) with median age of 63 (range of 19-93) years-old. Gender and body mass index (BMI) were similar in both groups. The main indications for therapeutic UFH were VTE (46.9%) and atrial fibrillation (18.6%). The indication for UFH was comparable between both groups with the exception of a higher percentage of those on SI protocol being treated for VTE (53.4% versus 38.0%) (Table 2).\n\nMany patients were on home anti-platelet (35.0%) and anticoagulant (33.2%) therapy prior to admission. The percentage of patients on aspirin, anti-platelet, and injectable anticoagulants was similar in both groups. A higher percentage of patients on LI protocol were on oral anticoagulants (36.1% versus 24.2%). LI protocol patients were more likely to have had a history of previous bleeding (24.1% versus 12.8%). HAS-BLED scores (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) were comparable with a median score of 2 and range of 0-6 in LI and 0-7 in SI groups, respectively. Documented history of peptic ulcer disease within three months of heparin initiation was comparable in both groups (Table 2).\n\nInitial hemoglobin and platelet count was lower in the LI group. Median international normalized ratio (INR) was the same in both groups with a slightly greater range in the SI group. Initial median and range PTT was similar in both groups. Patients with active malignancy were comparable in both groups (24.1% versus 21.0%). A significantly higher percentage of patients on LI protocol had a recent surgery (34.8% versus 11.9%). There was a higher percentage of active smokers in the SI group (20.5% versus 11.4%) (Table 2).\n\nTable 2 Baseline patient characteristics\nBMI: body mass index; UFH: unfractionated heparin; VTE: venous thromboembolism; NSAIDs: nonsteroidal anti-inflammatory drugs; PPT: partial thromboplastin time; INR: international normalized ratio; HAS-BLED scores: hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly.\n\nVariable:\tLow Intensity: (N=158)\tStandard Intensity: (N=219)\t\nAge median (range):\t63.5 (19.0-92.0) years-old\t63.0 (23.0-93.0) years-old\t\nGender :\t \t \t\n Male:\t83 (52.5%)\t119 (54.3%)\t\n Female:\t75 (47.5%)\t100 (45.7%)\t\nRace:\t \t \t\n Caucasian:\t123 (77.9%)\t156 (71.2%)\t\n African American:\t28 (17.7%)\t53 (24.2%)\t\n Other:\t7 (4.4%)\t10 (4.6%)\t\nBMI:\t28.0 (16.6-53.0) kg/m2\n\t28.0 (15.8-55.5) kg/m2\n\t\nInitial bolus of UFH:\t103 (65.2%)\t184 (84.0%)\t\nTime to reach therapeutic level median (range):\t5.5 (0.1-138.6) hours\t3.3 (0.3-20.8) hours\t\nIndication for UFH:\t \t \t\n VTE:\t60 (38.0%)\t117 (53.4%)\t\n Atrial fibrillation:\t30 (19.0%)\t40 (18.3%)\t\n Arterial thrombus:\t14 (8.9%)\t10 (4.6%)\t\n Heart valve:\t15 (9.5%)\t8 (3.7%)\t\n Ischemic stroke:\t16 (10.1%)\t11 (5.0%)\t\n Acute coronary syndrome:\t10 (6.3%)\t16 (7.3%)\t\n Intra-cardiac thrombus:\t8 (5.1%)\t8 (3.7%)\t\n Portal vein thrombus:\t5 (3.2%)\t9 (4.1%)\t\nHome medications:\t \t \t\n Aspirin:\t45 (28.5%)\t65 (29.7%)\t\n Anti-platelet agent:\t53 (33.5%)\t79 (36.1%)\t\n Oral anticoagulants:\t57 (36.1%)\t53 (24.2%)\t\n Injectable anticoagulants:\t7 (4.4%)\t8 (3.7%)\t\n NSAIDs:\t7 (4.4%)\t16 (7.3%)\t\nPrevious history of bleeding:\t38 (24.1%)\t28 (12.8%)\t\nHAS-BLED score median (range):\t2 (0-6)\t2 (0-7)\t\nPeptic Ulcer Disease:\t6 (3.8%)\t7 (3.2%)\t\nInitial Hemoglobin/Hematocrit (range):\t9.8g/dL/29.6% (5.9-17.3g/dL/17.4-50.8%)\t11.6g/dL/35.0% (4.9-17.0g/dL/15.3-49.4%)\t\nInitial platelet count (range):\t192.5g/cm3 (48.0-982.0g/cm3)\t202.0g/cm3 (46.0-971.0g/cm3)\t\nInitial PTT median (range):\t33.0 (21.0-240.0)\t32.0 (13.5-240.0)\t\nInitial INR median (range):\t1.2 (0.9-2.5)\t1.2 (0.9-5.4)\t\nActive malignancy:\t38 (24.1%)\t46 (21.0%)\t\nSurgery within 1-week of starting UFH:\t55 (34.8%)\t26 (11.9%)\t\nCurrent smoker:\t18 (11.4%)\t45 (20.5%)\t\nThe incidence of new or worsening thrombosis was comparable between both protocols (3.2% versus 3.7%). Incidence of bleeding was 44% higher in the LI group (11.4% versus 7.3%). On average, the last anti-Xa level prior to bleeding was therapeutic per both intensity protocols (0.30 versus 0.60). The LI group had 58% higher transfusion rates within one month (29.7% versus 16.4%) (Table 3).\n\nTable 3 Bleeding and thrombosis while on therapeutic heparin\nUFH: unfractionated heparin.\n\nVariable:\tLow Intensity N (%, 95% CI):\tStandard Intensity N (%, 95% CI):\t\nNew or worsening thrombus while on UFH:\t5 (3.2%, 1.0-7.2%)\t8 (3.7%, 1.6-7.1%)\t\nBleeding while on UFH:\t18 (11.4%, 6.9-17.4%)\t16 (7.3%, 4.2-11.6%)\t\nLast anti-Xa level prior to bleed (range):\t.30 (0.0-.60)\t.60 (0.0-1.1)\t\nTransfusion requirement within one-month:\t47 (29.7%)\t36 (16.4%)\t\nDeath in three-months:\t25 (15.8%)\t24 (11.0%)\t\nNew bleeding events were more likely to occur than recurrent bleeding. The incidence of major bleeding was more likely in LI compared with SI (5.0% versus 2.7%). The most frequent site of bleeding was gastrointestinal for both protocols (Table 4).\n\nTable 4 Bleeding while on unfractionated heparin (UFH)\n*Major bleeding defined as bleeding that is fatal, involves a critical organ (intraspinal, intracranial, retroperitoneal, or pericardial) or that causes a >2 g/dL decline in hemoglobin or requires transfusion of red blood cells.\n\nVariable:\tLow Intensity:\tStandard Intensity:\t\nChronicity:\t \t \t\n New:\t16 (10.1%)\t14 (6.4%)\t\n Recurrent:\t2 (1.2%)\t2 (0.9%)\t\n*Grade:\t \t \t\n Major:\t8 (5.0%)\t6 (2.7%)\t\n Minor:\t10 (6.3%)\t10 (4.6%)\t\nBleed location:\t \t \t\n Gastrointestinal:\t5 (3.2%)\t3 (1.4%)\t\n Genitourinary:\t2 (1.2%)\t2 (0.9%)\t\n Surgical Site:\t5 (3.2%)\t2 (0.9%)\t\n Retroperitoneal:\t1 (0.6%)\t2 (0.9%)\t\n Epistaxis:\t2(1.2%)\t0 (0%)\t\n Soft tissue/musculoskeletal:\t1 (0.6%)\t2 (0.9%)\t\n Other:\t2 (1.2%)\t5 (2.3%)\t\nThe odds of experiencing new or worsening thrombus while on UFH was comparable (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.29-2.98, p=0.899) in both groups. In multivariate analysis, the odds of bleeding while on LI was 1.21 times (95% CI 0.51-2.89) more likely than SI (p=0.667). Mortality at three-months from initiation of UFH was also comparable (OR 0.95, 95% CI 9.50-1.80, p=0.872) (Table 5).\n\nTable 5 Multivariate analysis of clinical outcomes, low intensity (LI) vs standard intensity (SI)\nUFH: unfractionated heparin.\n\nVariable:\tOdds Ratio (95% CI):\tp-value:\t\nNew or worsening thrombus while on UFH:\t0.93 (0.29-2.98)\t0.899\t\nBleeding while on UFH:\t1.21 (0.51-2.89)\t0.667\t\nDeath in three-months:\t0.95 (0.50-1.80)\t0.872\t\nDiscussion\nThe use of UFH remains an important modality in treatment and prophylaxis of VTE. Throughout the years, determining the optimal treatment protocol, therapeutic levels, and assays of measurement has been difficult to ascertain. To date, there does not exist a single, monolithic protocol, universally implemented at all institutions. However, guidelines with both weight-based and non-weight-based nomograms have been proposed [4-12]. The more recent 2012 ACCP guidelines follow a weight-based nomogram and are classified as a Grade 2C recommendation [13]. They do not, however, have a recommended therapeutic level range or recommended assay of measurement in adult patients. In neonates and children, there is a Grade 2C recommendation of an anti-Xa activity level of 0.35-0.70 units/mL [21]. Furthermore, a scoring system to risk-stratify patients for bleeding on UFH, similar to the HAS-BLED score for atrial fibrillation, does not exist.\n\nAt the University of Florida (Gainesville, FL), a tertiary academic center, intravenous UFH is administered by SI and LI protocols with target anti-Xa activity levels of 0.30 to 0.70 IU/mL and 0.25 to 0.35 IU/mL, respectively. These protocols include a suggested bolus, standard initial infusion rates, and titration parameters until a therapeutic range is reached as noted in Table 1. The development of this protocol occurred in close collaboration with Hematology faculty and staff pharmacy based on previously published weight-based UFH nomograms and clinical practice recommendations [19,22-27].\n\nGiven limited available data on the efficacy and risks of the implemented protocol at our institution and others, investigators designed a review of 377 patients treated with intravenous UFH. The primary endpoints studied were new or worsening thrombosis and bleeding. The incidence of new or worsening thrombus was low and similar in both groups and not statistically significant (3.2% versus 3.7%, OR 0.93, p=0.899). The incidence of bleeding was higher in the LI group (11.4% versus 7.3%) with those on LI being 1.21 times more likely to experience bleed than the SI group, although not statistically significant (p=0.667). The LI group was more likely to have had a previous history of bleed and had lower average baseline hemoglobin/hematocrit (9.8 g/dL/29.6% versus 11.6 g/dL/35.0%). The LI group was more likely to require transfusion within one month (29.7% versus 16.4%). The increased incidence of bleeding and transfusion requirements in the LI group was likely due to the higher-risk population selected for a low intensity protocol.\n\nGiven that the decision to use a protocol was based solely on clinician judgement, there was a desire to see if an existing scoring system could be utilized to better serve clinicians in deciding the most appropriate protocol. The existing HAS-BLED scoring system was thus used. The HAS-BLED system was developed to assess the one-year risk of major bleeding events in patients on anticoagulation for atrial fibrillation [28]. Interestingly, the HAS-BLED median score and range were nearly identical in both LI and SI groups despite notable differences in bleeding history and incidence. This suggests that the HAS-BLED scoring system is not applicable in determining the risk of bleeding in patients on UFH. The necessity of developing an applicable scoring system for patients on UFH for VTE remains.\n\nWe acknowledge multiple limitations in this project, including its retrospective nature without randomization. However, many baseline patient characteristics (e.g. age, gender, BMI, indication for anticoagulation) were comparable between both groups. The LI population was higher risk for bleeding based on previous history and comorbidities and thus explains the physician’s choice of LI protocol and the higher noted incidence of bleeding while on UFH. This higher risk of bleeding in patients receiving the LI protocol also likely explains the increased incidence of bleeding when compared to the SI protocol.\n\nConclusions\nIn conclusion, a LI protocol may have comparable efficacy to a SI protocol based on the similar incidence of new or worsening thrombus. This is of notable importance in patients at high risk for bleeding. In the future, a prospective randomized trial of both protocols matched for comorbidities, risk factors, and indications is needed to further elaborate on the findings of this study with the ultimate goal of developing a risk stratification scoring system and weight-based dosing nomogram for use by clinicians. \n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study. University of Florida IRB issued approval 201702116. IRB approval, project number 201702116 for retrospective chart review.\n\nAnimal Ethics\nAnimal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.\n==== Refs\nReferences\n1 Drug Discovery: Practices, Processes, and Perspectives Li JJ Corey EJ New Jersey John Wiley & Sons 2013 https://www.wiley.com/en-us/Drug+Discovery%3A+Practices%2C+Processes%2C+and+Perspectives-p-9780470942352 \n2 WHO Model Lists of Essential Medicines 5 2020 2019 https://www.who.int/medicines/publications/essentialmedicines/en/ \n3 Antithrombotic therapy for venous thromboembolic disease Chest Hyers TM Hull RD Weg JG 37 51 95 1989 https://journal.chestnet.org/article/S0012-3692(16)61926-8/fulltext \n4 The weight-based heparin dosing nomogram compared with a “standard care” nomogram: a randomized controlled trial Ann Intern Med Raschke RA Reilly BM Guidry JR Fontana JR Srinivas S 874 881 119 1993 https://annals.org/aim/article-abstract/706814/weight-based-heparin-dosing-nomogram-compared-standard-care-nomogram-randomized 8214998 \n5 Comparison of a weight-based heparin nomogram with traditional heparin dosing to achieve therapeutic anticoagulation Pharmacotherapy Shalansky KF FitzGerald JM Sunderji R Traboulay SJ O’Malley B McCarron BI Naiman S 1076 1084 16 1996 8947981 \n6 Reevaluation of a weight-based heparin dosing nomogram: is institution-specific modification necessary? Ann Pharmacother Schlicht JR Sunyecz L Weber RJ Tabas GH Smith RE 1454 1459 31 1997 9416380 \n7 Weight-based heparin dosing: clinical response and resource utilization Clin Ther Lackie CL Luzier AB Donovan JA Feras HI Forrest A 699 710 20 1998 9737830 \n8 Antithrombotic therapy for venous thromboembolic disease Chest Büller HR Agnelli G Hull RD Hyers TM Prins MH Raskob GE 401 428 126 2004 \n9 Antithrombotic therapy for venous thromboembolic disease Chest Kearon C Kahn SR Agnelli G Goldhaber S Raskob GE Comerota AJ 454 545 133 2008 \n10 Prevention of venous thromboembolism Chest Geerts WH Pineo GF Heit JA Bergquist D Lassen MR Colwell CW Ray JG 338 400 126 2004 \n11 Partnering with nurses to manage heparin therapy with a weight-based protocol Am J Health Syst Pharm Price CK Colodny L 110 116 57 2000 10688237 \n12 An institution-specific heparin titration nomogram: development, validation, and assessment of compliance Pharmacotherapy Sherman DS Clarke SH Lefkowitz JB Valuck RJ Lindenfeld JA Stringer KA 1167 1174 21 2001 11601661 \n13 Introduction to the ninth edition: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines Chest Guyatt GH Akl EA Crowther M Schünemann HJ Gutterman DD Lewis SZ 48 52 141 2012 \n14 Challenges in variation and responsiveness of unfractionated heparin Pharmacotherapy Francis JL Groce JB III 108 119 24 2004 \n15 Laboratory monitoring of heparin therapy: partial thromboplastin time or anti-Xa assay? Lab Med Lehman CM Frank EL 47 51 40 2009 \n16 Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls Expert Opin Drug Saf Warkentin TE 25 43 13 2014 23971903 \n17 A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin Arch Intern Med Levine MN Hirsh J Gent M 49 56 154 1994 8267489 \n18 Monitoring unfractionated heparin therapy with antifactor Xa activity results in fewer monitoring tests and dosage changes than monitoring with the activated partial thromboplastin time Pharmacotherapy Rosborough TK 760 766 19 1999 10391423 \n19 Activated partial thromboplastin time versus antifactor Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion Ann Pharmacother Guervil DJ Rosenberg AF Winterstein AG Harris NS Johns TE Zumberg MS 861 868 45 2011 21712506 \n20 Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH J Thromb Haemost Kaatz S Ahmad D Spyropoulos AC Schulman S 2119 2126 13 2015 26764429 \n21 Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest Guyatt GH Akl EA Crowther M Gutterman DD Schuünemann HJ 7 47 141 2012 22215823 \n22 Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis N Engl J Med Hull RD Raskob GE Hirsh J Jay RM Leclerc JR Geerts WH 1109 1114 315 1986 https://www.nejm.org/doi/full/10.1056/NEJM198610303151801 3531862 \n23 The use of anti-xa assay to monitor intravenous unfractionated heparin therapy J Pharm Pract Rosenberg AF Zumberg M Taylor L Leclaire A Harris N 210 216 23 2010 21507816 \n24 Establishing a therapeutic range for heparin therapy Ann Intern Med Brill-Edwards P Ginsberg JS Johnston M Hirsh J 104 109 119 1993 8512158 \n25 Weight-based heparin protocol using antifactor Xa monitoring Am J Heal Pharm Smith ML Wheeler KE 371 374 67 2010 \n26 A review of unfractionated heparin and its monitoring US Pharm Tahir R 0 36 32 2007 https://www.uspharmacist.com/article/a-review-of-unfractionated-heparin-and-its-monitoring \n27 A standard heparin nomogram for the management of heparin therapy Arch Intern Med Cruickshank MK Levine MN Hirsh J Roberts R Siguenza M 333 337 151 1991 1789820 \n28 A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation Chest Pisters R Lane DA Nieuwlaat R de Vos CB Crijns HJGM Lip GYH 1093 1100 138 2010 20299623\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(5)",
"journal": "Cureus",
"keywords": "anticoagulant therapy; hemorrhage; heparin; thrombosis; venous thromboembolism",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e8339",
"pmc": null,
"pmid": "32617214",
"pubdate": "2020-05-28",
"publication_types": "D016428:Journal Article",
"references": "8947981;9416380;8512158;21712506;20299623;15334856;8267489;18574272;9737830;22315257;1789820;8214998;10391423;20172987;15383478;3531862;21507816;15383479;11601661;10688237;22315255;23971903;26764429;2644102",
"title": "Bleeding and Thrombotic Risk in Low Dose Heparin Infusion as Compared to Standard Dose Heparin Infusion.",
"title_normalized": "bleeding and thrombotic risk in low dose heparin infusion as compared to standard dose heparin infusion"
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"companynumb": "US-PFIZER INC-2019104195",
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"activesubstancename": "HEPARIN SODIUM"
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"abstract": "Bilateral anterior shoulder dislocation is a rare clinical entity with few case reports and limited series published in the literature. Bilateral shoulder dislocations are rare and of them, most are posterior. We present a highly unusual case of bilateral, atraumatic, anterior shoulder dislocation with concomitant comminuted greater tuberosity fracture on the right side, secondary to seizure, in a patient without known epilepsy, induced by oral chloroquine medication. We demonstrate the treatment approach that led to a satisfactory clinical outcome, evidenced by radiological union, clinical assessment and Patient Reported Outcome Measure data, following non-operative management of both shoulders. The unusual mechanism for anterior shoulder dislocation, the asymmetric dislocation pattern and peculiar precipitant for the causative seizure all provide interesting learning points from this case.",
"affiliations": "Department of Trauma and Orthopaedics, Barnet and Chase Farm Hospital, London, UK.;Department of Trauma and Orthopaedics, Barnet and Chase Farm Hospital, London, UK.;Department of Trauma and Orthopaedics, Barnet and Chase Farm Hospital, London, UK.;Department of Trauma and Orthopaedics, Barnet and Chase Farm Hospital, London, UK.",
"authors": "Martin|Alexander Nicholas|AN|;Tsekes|Dimitris|D|;White|William James|WJ|;Rossouw|Dan|D|",
"chemical_list": "D002738:Chloroquine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D001915:Braces; D002738:Chloroquine; D018460:Fractures, Comminuted; D006801:Humans; D008297:Male; D012640:Seizures; D012783:Shoulder Dislocation; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27005796",
"pubdate": "2016-03-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24082765;9715604;12195251;16125271;9265081;1486619;17606108;10981583;8527012;24684914;17503059;24895390;12051004;10759574;25425611;11179947;23026366;25685749;19025598",
"title": "Chloroquine-induced bilateral anterior shoulder dislocation: a unique aetiology for a rare clinical problem.",
"title_normalized": "chloroquine induced bilateral anterior shoulder dislocation a unique aetiology for a rare clinical problem"
} | [
{
"companynumb": "GB-IPCA LABORATORIES LIMITED-IPC201603-000360",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
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"actiondrug": "1",
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"activesubstancename": "CHLOROQUINE PHOSPHATE"
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... |
{
"abstract": "BACKGROUND\nImmediate hypersensitivity reaction to ursodiol is rare and there is no previously published protocol on ursodiol desensitization.\n\n\nMETHODS\nA 59-year-old woman with primary biliary cholangitis (PBC) developed an immediate hypersensitivity reaction to ursodiol-the first-line treatment for PBC. When she switched to a second-line treatment, her PBC continued to progress. As such, she completed a novel 12-step desensitization protocol to oral ursodiol. She experienced recurrent pruritus after each dose following desensitization, which subsided after a month of being on daily ursodiol.\n\n\nCONCLUSIONS\nImmediate hypersensitivity reaction to ursodiol is uncommon. Our case demonstrated that this novel desensitization protocol to ursodiol could be safely implemented when alternative options are not available or have proven inferior in efficacy.",
"affiliations": "Department of Medicine, University of Toronto, Toronto, ON, Canada. erika.lee@mail.utoronto.ca.;Department of Medicine, University of Toronto, Toronto, ON, Canada.",
"authors": "Lee|Erika Yue|EY|http://orcid.org/0000-0003-1108-2067;Song|Christine|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13223-021-00578-7",
"fulltext": "\n==== Front\nAllergy Asthma Clin Immunol\nAllergy Asthma Clin Immunol\nAllergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology\n1710-1484\n1710-1492\nBioMed Central London\n\n578\n10.1186/s13223-021-00578-7\nCase Report\nImmediate hypersensitivity reaction followed by successful oral desensitization to ursodiol\nhttp://orcid.org/0000-0003-1108-2067\nLee Erika Yue erika.lee@mail.utoronto.ca\n\n12\nSong Christine 12\n1 grid.17063.33 0000 0001 2157 2938 Department of Medicine, University of Toronto, Toronto, ON Canada\n2 grid.415502.7 Division of Clinical Allergy and Immunology, Department of Medicine, St. Michael’s Hospital, 30 Bond Street, Toronto, ON M5B 1W8 Canada\n22 7 2021\n22 7 2021\n2021\n17 7523 4 2021\n12 7 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\nImmediate hypersensitivity reaction to ursodiol is rare and there is no previously published protocol on ursodiol desensitization.\n\nCase presentation\n\nA 59-year-old woman with primary biliary cholangitis (PBC) developed an immediate hypersensitivity reaction to ursodiol—the first-line treatment for PBC. When she switched to a second-line treatment, her PBC continued to progress. As such, she completed a novel 12-step desensitization protocol to oral ursodiol. She experienced recurrent pruritus after each dose following desensitization, which subsided after a month of being on daily ursodiol.\n\nConclusion\n\nImmediate hypersensitivity reaction to ursodiol is uncommon. Our case demonstrated that this novel desensitization protocol to ursodiol could be safely implemented when alternative options are not available or have proven inferior in efficacy.\n\nKeywords\n\nImmediate drug hypersensitivity\nUrsodiol\nUrsodeoxycholic acid\nDesensitization\nPrimary biliary cholangitis\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nPrimary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver characterized by T-cell mediated attack of intralobular bile ducts [1, 2]. The eventual loss of these bile ducts results in cholestasis, which clinically manifests as fatigue, pruritus and jaundice [2]. Without treatment, PBC eventually leads to cirrhosis and liver failure.\n\nUrsodiol or ursodeoxycholic acid (UDCA) is the mainstay treatment for PBC. It is currently one of the only two approved therapies for PBC; the other therapy is obeticholic acid, which is considered second-line [3]. Ursodiol delays the progression to end-stage liver disease, prolongs survival and is generally well tolerated [3]. Patients who fail to respond to or do not tolerate the first-line ursodiol can have or switch to obeticholic acid [3]. Infrequent adverse effects of ursodiol include diarrhea, weight gain and paradoxically pruritus [4], but hypersensitivity to ursodiol has rarely been reported. Herein we describe a patient with PBC who developed an immediate allergic reaction to ursodiol and successfully completed an oral desensitization to ursodiol.\n\nCase presentation\n\nA 59-year-old woman who did not have any allergic or atopic history was diagnosed with PBC. She was started on ursodiol 500 mg twice daily at the time of her diagnosis. On Day 4 of therapy, she developed full-body hives, chest tightness and dyspnea within one hour of her dose. These symptoms self-resolved within an hour. Subsequently she lowered the dose of ursodiol to 250 mg twice daily at the recommendation of her hepatologist. On Day 2 of re-exposure, she developed similar but more severe symptoms within an hour of her dose. These symptoms resolved without treatment within an hour. Consequently, ursodiol was discontinued by her hepatologist and the patient was referred to the allergy clinic for ursodiol allergy.\n\nAt our clinic, we confirmed the history of her systemic reactions to ursodiol. Allergy testing was not done, as there is no validated skin testing or available serum IgE measurement for ursodiol. Patient declined drug provocation test due to fear of reaction. As such, the diagnosis of an IgE-mediated reaction to ursodiol was made based on detailed clinical history. Given the ongoing need for ursodiol, we recommended the patient to undergo desensitization. She declined the procedure due to personal reasons, so was switched to the second-line obeticholic acid for her PBC. In the following year, her PBC continued to progress and she was receptive to desensitization. Her hepatologist re-referred her to our clinic for consideration of desensitization to ursodiol.\n\nA new ursodiol desensitization protocol was developed (Table 1). A 12-step protocol was chosen based on the published standardized protocols for various drugs [5]. A 45-min interval was used between each step to ensure an adequate gastrointestinal absorption of the medication. The solution was made by our inpatient hospital pharmacy. Patient successfully completed the protocol in the intensive care unit and has remained on ursodiol 500 mg twice daily. Following desensitization, patient initially experienced recurrent pruritus each time after taking ursodiol. A careful evaluation in the clinic did not raise any concerns for an allergic reaction. After a discussion with the patient, she agreed to continue taking ursodiol and pruritus was somewhat reduced with a non-sedating antihistamine. At 1 month follow-up after the desensitization and being on daily ursodiol, patient reported a complete resolution of her pruritus and was able to tolerate ursodiol without any issues. Although she has been discharged from our clinic since, her hepatologist reported that her PBC has remained stable in the following two years while on daily ursodiol.Table 1 Ursodiol desensitization using a 12-step, 2-dilution protocol\n\nStep\tConcentration (mg/mL)\tTime (hr:min)\tRoute of administration\tVolume given per step (mL)\tDose given per step (mg)\tCumulative dose (mg)\t\n1\t5\t00:00\tOral\t0.05\t0.25\t0.25\t\n2\t5\t00:45\tOral\t0.1\t0.5\t0.75\t\n3\t5\t01:30\tOral\t0.2\t1\t1.75\t\n4\t5\t02:15\tOral\t0.4\t2\t2.75\t\n5\t5\t03:00\tOral\t0.8\t4\t6.75\t\n6\t5\t03:45\tOral\t1.25\t6.25\t13\t\n7\t5\t04:30\tOral\t2.5\t12.5\t25.5\t\n8\t20\t05:15\tOral\t1.25\t25\t30.5\t\n9\t20\t06:00\tOral\t2.5\t50\t80.5\t\n10\t20\t06:45\tOral\t3.75\t75\t155.5\t\n11\t20\t07:30\tOral\t7.5\t150\t305.5\t\n12\t20\t08:15\tOral\t10\t200\t505.5\t\nTarget dose of 500 mg\n\nDiscussion and conclusions\n\nUrsodiol is a hydrophilic bile acid that can increase the metabolic conversion of cholesterol to bile acids, thus reducing the fractional reabsorption of cholesterol by intestines [6]. Its mechanisms of action in PBC are not clearly defined, but the proposed mechanisms include increasing the hydrophilicity in the circulating bile acid pool, stimulating hepatocellular and ductal secretions, protecting against bile acid- and cytokine-induced injury, and exerting immunodulating and anti-inflammatory effects [6, 7]. Although ursodiol has been the standard of care for patients with PBC for years, up to 40% of patients fail to respond to it with inadequate biochemical improvement and thus are still at risk of progression to end-stage liver disease [8]. Although we do not know how our patient would have responded to ursodiol following desensitization from the liver standpoint, the worsening of her PBC while being on obeticholic acid prior to desensitization warranted her to change to ursodiol.\n\nUrsodiol is generally well tolerated and shown to improve pruritus in patients with PBC [6]. Paradoxically, exacerbation of pruritus after ursodiol administration has also been reported [4]. Our patient who developed pruritus after desensitization likely experienced a medication side effect as opposed to an allergic reaction in the absence of objective findings. Further, ursodiol hypersensitivity reaction is rare. Immediate hypersensitivity reaction to ursodiol was reported once in a patient who developed angioedema and cardiac arrhythmia [9]. Delayed hypersensitivity reaction to ursodiol was also reported once, manifesting as skin rash with biopsy-proven lichenoid reaction [10]. However, ursodiol desensitization has not been reported. Our case illustrates the safety and efficacy of a novel desensitization protocol to ursodiol. It also highlights the importance of pursuing desensitization in patients with immediate hypersensitivity to first-line therapy.\n\nTo our knowledge, this is the first reported case of an immediate allergic reaction followed by successful oral desensitization to ursodiol. We propose that this 12-step desensitization protocol to ursodiol can be safely implemented when alternative options are not available or have proven inferior in efficacy.\n\nAbbreviations\n\nPBC Primary biliary cholangitis\n\nUDCA Ursodeoxycholic acid\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nEL involved in drafting and submitting the manuscript. CS involved in drafting the manuscript. Both the authors read and approved the final manuscript.\n\nFunding\n\nNone.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nPatient consent was obtained.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Kaplan MM Primary biliary cirrhosis N Engl J Med 1996 335 1570 80 10.1056/NEJM199611213352107 8900092\n2. Lindor K Ursodeoxycholic acid for the treatment of primary biliary cirrhosis N Engl J Med 2007 357 1524 9 10.1056/NEJMct074694 17928600\n3. Corpechot C Abenavoli L Rabahi N Chretien Y Andreani T Johanet C Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis Hepatology 2008 48 871 7 10.1002/hep.22428 18752324\n4. Hempfling W Dilger K Beuers U Systematic review: ursodeoxycholic acid-adverse effects and drug interactions Aliment Pharmacol Ther 2003 18 963 72 10.1046/j.1365-2036.2003.01792.x 14616161\n5. Castells M Solensky R Post TW Rapid drug desensitization for immediate hypersensitivity reactions UpToDate 2020 Waltham UpToDate\n6. Gulamhusein AF Hirschfield GM Primary biliary cholangitis: pathogenesis and therapeutic opportunities Nat Rev Gastroenterol Hepatol 2020 17 93 110 10.1038/s41575-019-0226-7 31819247\n7. Poupon R Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action Clin Res Hepatol Gastroenterol 2012 36 Suppl 1 S3 12 10.1016/S2210-7401(12)70015-3 23141891\n8. Lammers WJ van Buuren HR Hirschfield GM Janssen HL Ivernizzi P Mason AL Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study Gastroenterology 2014 147 1338 49 10.1053/j.gastro.2014.08.029 25160979\n9. Phemister J Pourmorteza M Brahmbhatt P Reddy C Young M Hypersensitivity reaction to ursodiol resulting in cardiac arrhythmia Am J Gastroenterol 2015 110 S391 10.14309/00000434-201510001-00908\n10. Horiuchi Y Lichenoid eruptions due to ursodeoxycholic acid administration Gastroenterology 2001 121 501 502 10.1053/gast.2001.26929 11494975\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1710-1484",
"issue": "17(1)",
"journal": "Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology",
"keywords": "Desensitization; Immediate drug hypersensitivity; Primary biliary cholangitis; Ursodeoxycholic acid; Ursodiol",
"medline_ta": "Allergy Asthma Clin Immunol",
"mesh_terms": null,
"nlm_unique_id": "101244313",
"other_id": null,
"pages": "75",
"pmc": null,
"pmid": "34294117",
"pubdate": "2021-07-22",
"publication_types": "D016428:Journal Article",
"references": "31819247;11494975;18752324;14616161;25160979;17928600;8900092;23141891",
"title": "Immediate hypersensitivity reaction followed by successful oral desensitization to ursodiol.",
"title_normalized": "immediate hypersensitivity reaction followed by successful oral desensitization to ursodiol"
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"companynumb": "CA-GLENMARK PHARMACEUTICALS-2021GMK067437",
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"activesubstancename": "URSODIOL"
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{
"abstract": "The optimal therapeutic approach for young diffuse large B-cell lymphoma (DLBCL) patients with high-intermediate and high-risk age-adjusted international prognostic index (aaIPI) remains unknown. Hereby we report a 10-year single-centre study of 63 consecutively treated patients. To optimize outcome, two approaches were carried out: Cohort 1 patients received four cycles R-CHOP-21 (rituximab, cyclophosphamide, daunorubicin, vincristine, prednisolone over 21 days) followed by first-line high-dose chemotherapy with autologous stem-cell support (HDCT-ASCT), resulting in 2-year progression-free (PFS) and overall survival (OS) of 60·6% and 67·9%. 39·4% of those patients were not transplanted upfront, mainly due to early progressive disease (24·2%). Cohort 2 patients received an early intensified protocol of six cycles of CHOP-14 (cyclophosphamide, daunorubicin, vincristine, prednisolone over 14 days) with dose-dense rituximab and high-dose methotrexate resulting in promising overall response- (93·3%) and complete remission (90%) rates and sustained survival (2-year PFS and OS: 93·3%). In an intention-to-treat analysis, 2-year PFS (60·6% vs. 93·3%, hazard ratio [HR] 7·2, P = 0·009) and OS (69·7% vs. 93·3%, HR 4·95, P = 0·038) differed significantly, in favour of the early intensified protocol (Cohort 2). In a multivariate Cox-regression model, PFS (HR 8·12, 95% confidence interval [CI] 1·83-35·9, P = 0·006) and OS (HR 5·86, 95% CI 1·28-26·8, P = 0·02) remained superior for Cohort 2 when adjusted for aaIPI3 as the most important prognostic factor. Survival of young poor-prognosis DLBCL patients appears superior after early therapy intensification.",
"affiliations": "Department Haematology, Oncology & Stem Cell Transplantation, Faculty of Medicine and Medical Centre - University of Freiburg, Freiburg, Germany.;Department Haematology, Oncology & Stem Cell Transplantation, Faculty of Medicine and Medical Centre - University of Freiburg, Freiburg, Germany.;Department Haematology, Oncology & Stem Cell Transplantation, Faculty of Medicine and Medical Centre - University of Freiburg, Freiburg, Germany.;Community-based private haematology-oncology practice, Singen, Germany.;Department Haematology, Oncology & Stem Cell Transplantation, Faculty of Medicine and Medical Centre - University of Freiburg, Freiburg, Germany.;Department Haematology, Oncology & Stem Cell Transplantation, Faculty of Medicine and Medical Centre - University of Freiburg, Freiburg, Germany.;Clinical Trials Unit, Faculty of Medicine and Medical Centre - University of Freiburg, Freiburg, Germany.;Department Haematology, Oncology & Stem Cell Transplantation, Faculty of Medicine and Medical Centre - University of Freiburg, Freiburg, Germany.;Department Haematology, Oncology & Stem Cell Transplantation, Faculty of Medicine and Medical Centre - University of Freiburg, Freiburg, Germany.;Department Haematology, Oncology & Stem Cell Transplantation, Faculty of Medicine and Medical Centre - University of Freiburg, Freiburg, Germany.",
"authors": "Strüßmann|Tim|T|0000-0002-4975-1599;Fritsch|Kristina|K|;Baumgarten|Axel|A|;Fietz|Thomas|T|;Engelhardt|Monika|M|;Mertelsmann|Roland|R|;Ihorst|Gabriele|G|;Duyster|Justus|J|;Finke|Jürgen|J|;Marks|Reinhard|R|",
"chemical_list": "D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.14802",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "178(6)",
"journal": "British journal of haematology",
"keywords": "aaIPI; diffuse large B-cell lymphoma; dose-dense rituximab; high dose methotrexate; intensive chemotherapy",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D015331:Cohort Studies; D003520:Cyclophosphamide; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D011241:Prednisone; D011379:Prognosis; D000069283:Rituximab; D033581:Stem Cell Transplantation; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "927-935",
"pmc": null,
"pmid": "28643323",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Favourable outcomes of poor prognosis diffuse large B-cell lymphoma patients treated with dose-dense Rituximab, high-dose Methotrexate and six cycles of CHOP-14 compared to first-line autologous transplantation.",
"title_normalized": "favourable outcomes of poor prognosis diffuse large b cell lymphoma patients treated with dose dense rituximab high dose methotrexate and six cycles of chop 14 compared to first line autologous transplantation"
} | [
{
"companynumb": "DE-ROCHE-1960568",
"fulfillexpeditecriteria": "1",
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"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
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"abstract": "On-demand oral tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) has been approved for pre-exposure prophylaxis (PrEP) in MSM in France following the results of clinical studies, but data are limited on real-world experience.\n\n\n\nA single-center, open-label, prospective cohort study that recruited people at high risk of HIV infection in Paris.\n\n\n\nParticipants were enrolled in a single hospital-based outpatient clinic and were proposed to start PrEP with daily or on demand TDF/FTC. At baseline and every 3 months thereafter, patients were tested for HIV and creatinine plasma levels, and data on sexual behavior, other sexually transmitted infections (STIs), and tolerability were collected.\n\n\n\nFrom 10 November 2015 to 30 April 2017, 1069 patients were screened and 1049 (98.1%) started PrEP. Median age was 36 years, 99.4% were MSM with a median number of partners of 10, and 793 (75.6%) opted for on demand PrEP. Over 486 person-years of follow-up, four HIV-infections were diagnosed in poorly or nonadherent patients (incidence 0.82/100 person-years). Rate of condomless sex at last intercourse increased from 53.3% at baseline to 79% at month 12 (P < 10), but increase in bacterial STI rates was modest (14.6% at baseline vs. 19.2% at month 12; P < 10). Most adverse events were gastrointestinal and did not lead to PrEP discontinuation.\n\n\n\nMost PrEP users were high-risk MSM and opted for on-demand PrEP. PrEP use was associated with a low HIV incidence and a high rate of condomless sex with a modest increase in bacterial STIs.",
"affiliations": "Department of Infectious Diseases, Saint-Louis Hospital, AP-HP.;Department of Infectious Diseases, Saint-Louis Hospital, AP-HP.;Department of Infectious Diseases, Saint-Louis Hospital, AP-HP.;Department of Infectious Diseases, Saint-Louis Hospital, AP-HP.;COREVIH Ile de France Est, Saint-Louis Hospital.;INSERM SC10 US19, Villejuif.;Department of Infectious Diseases, Saint-Louis Hospital, AP-HP.;Department of Infectious Diseases, Saint-Louis Hospital, AP-HP.;Department of Infectious Diseases, Saint-Louis Hospital, AP-HP.;Association AIDES, Pantin.;COREVIH Ile de France Est, Saint-Louis Hospital.;Department of Infectious Diseases, Saint-Louis Hospital, AP-HP.;Department of Infectious Diseases, Saint-Louis Hospital, AP-HP.",
"authors": "Noret|Marion|M|;Balavoine|Stéphanie|S|;Pintado|Claire|C|;Siguier|Martin|M|;Brun|Alexandre|A|;Bauer|Rebecca|R|;Loze|Bénédicte|B|;Leplatois|Anne|A|;Aslan|Alexandre|A|;Moudachirou|Khafil|K|;Delaugerre|Constance|C|;Rozenbaum|Willy|W|;Molina|Jean-Michel|JM|",
"chemical_list": "D019380:Anti-HIV Agents; D000068698:Tenofovir; D000068679:Emtricitabine",
"country": "England",
"delete": false,
"doi": "10.1097/QAD.0000000000001939",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-9370",
"issue": "32(15)",
"journal": "AIDS (London, England)",
"keywords": null,
"medline_ta": "AIDS",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D019380:Anti-HIV Agents; D018890:Chemoprevention; D064420:Drug-Related Side Effects and Adverse Reactions; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections; D006761:Hospitals; D006801:Humans; D015994:Incidence; D008297:Male; D010045:Outpatients; D010297:Paris; D065129:Pre-Exposure Prophylaxis; D011446:Prospective Studies; D012725:Sexual Behavior; D000068698:Tenofovir",
"nlm_unique_id": "8710219",
"other_id": null,
"pages": "2161-2169",
"pmc": null,
"pmid": "30212403",
"pubdate": "2018-09-24",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Daily or on-demand oral tenofovir disoproxil fumarate/emtricitabine for HIV pre-exposure prophylaxis: experience from a hospital-based clinic in France.",
"title_normalized": "daily or on demand oral tenofovir disoproxil fumarate emtricitabine for hiv pre exposure prophylaxis experience from a hospital based clinic in france"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1046668",
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"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "EMTRICITABINE\\TENOFOVIR DISOPROXIL FUMARATE"
},
... |
{
"abstract": "Hyperemesis gravidarum is not uncommon. Its pathogenies is multifactorial but not fully understood. We present a case of a middle class, Caucasian pregnant woman aged 24 years with coexisting type 1 diabetes, who had severe hyperemesis gravidarum from the sixth week of pregnancy and was resistant to all standard and off-the-label treatments raising questions about the pathogenesis of hyperemesis gravidarum. She was managed with a multidisciplinary approach and was supported with total parenteral nutrition till she had an emergency caesarean section in the 29th week of pregnancy. Her vomiting stopped as soon as a small for gestational age but otherwise healthy male baby was delivered.",
"affiliations": "Department of Diabetes and Endocrine, Doncaster Royal Infirmary, Doncaster, UK.;Department of Gastroenterology, Doncaster Royal Infirmary, Doncaster, UK.;Obstetrics and Gynaecology, Doncaster Royal Infirmary, Doncaster, UK.",
"authors": "Arshad|Muhammad Fahad|MF|http://orcid.org/0000-0001-9932-0941;Javed|Nasir|N|;Bekhit|Mohammad|M|",
"chemical_list": "D000932:Antiemetics; D008803:Mianserin; D000078785:Mirtazapine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-222403",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "diabetes; pregnancy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000932:Antiemetics; D002585:Cesarean Section; D003922:Diabetes Mellitus, Type 1; D005260:Female; D005865:Gestational Age; D006801:Humans; D006939:Hyperemesis Gravidarum; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D008297:Male; D008803:Mianserin; D000078785:Mirtazapine; D056687:Off-Label Use; D010289:Parenteral Nutrition, Total; D011247:Pregnancy; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29275391",
"pubdate": "2017-12-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8373648;19900137;16957638;23863575;28641304;1904453;27251205;16007504;8729550;24659261",
"title": "Intractable hyperemesis gravidarum in a patient with type 1 diabetes.",
"title_normalized": "intractable hyperemesis gravidarum in a patient with type 1 diabetes"
} | [
{
"companynumb": "GB-PFIZER INC-2018372346",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLIZINE"
},
"drugadditional": "3",
... |
{
"abstract": "The case study is a 33-year-old white female with persistently elevated serum human chorionic gonadotropin (hCG) levels following methotrexate treatment and emergency surgery for ectopic pregnancy. At the time of the first methotrexate dose, the serum hCG concentration was 27,995 IU/L. The laboratory was consulted 3.5 months after the surgery, because serum hCG levels had stopped declining and had leveled off to around 80 to 90 IU/L but with negative urine pregnancy tests. Laboratory studies ruled out heterophile antibody interference and hook effect by multiple methods including analysis by different serum hCG assays, treatment with heterophile antibody blocking agents, and dilution studies. Three additional doses of methotrexate over six months were required for serum hCG concentrations to decline to undetectable levels. This case illustrates challenges that may arise with serum hCG measurements in management of ectopic pregnancies. Close collaboration between the laboratory and clinical service is key for optimal patient care.",
"affiliations": "Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.;Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.;Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa mkrasows@healthcare.uiowa.edu.",
"authors": "Kurt-Mangold|Michelle|M|;Van Voorhis|Bradley J|BJ|;Krasowski|Matthew D|MD|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D006063:Chorionic Gonadotropin; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1309/LMTDRFGJVJIM3VNM",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-5027",
"issue": "46(3)",
"journal": "Laboratory medicine",
"keywords": "cornual pregnancy; ectopic pregnancy; heterophile antibodies; human chorionic gonadotropin; immunoassay; methotrexate",
"medline_ta": "Lab Med",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000328:Adult; D006063:Chorionic Gonadotropin; D005260:Female; D006801:Humans; D008727:Methotrexate; D011247:Pregnancy; D011271:Pregnancy, Ectopic; D013997:Time Factors",
"nlm_unique_id": "0250641",
"other_id": null,
"pages": "254-8",
"pmc": null,
"pmid": "26199268",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Persistent Human Chorionic Gonadotropin After Methotrexate Treatment and an Emergency Surgical Procedure for Ectopic Pregnancy.",
"title_normalized": "persistent human chorionic gonadotropin after methotrexate treatment and an emergency surgical procedure for ectopic pregnancy"
} | [
{
"companynumb": "US-ACCORD-036887",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
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"abstract": "Inferior vena cava syndrome is rare and often difficult to diagnose because of its rarity and consequent low suspicion. We describe the case of a 28-year-old female patient with a history of nephroblastoma of the right kidney, stage IV, with a favourable histology with epidural metastasis (D5-D9), diagnosed at 3 years of age. The patient underwent treatment with surgery, chemotherapy and radiotherapy. The patient suffered from sudden low back pain worsening over 2 weeks, with progressive inability to walk. The pain radiated to the front of the thighs. Concomitantly, oedema of the lower limbs with cephalocaudal progression was observed. At admission to our institution, the physical examination showed peripheral oedema, abdominal wall venous collaterals, an inability to walk due to low back pain in the supine position, with no neurological deficits. Lumbar MRI showed exuberant epidural venous congestion. The hypothesis of inferior vena cava thrombosis (IVCT) was considered and confirmed by angio-CT. IVCT is prevalent in patients with congenital anomalies of the inferior vena cava, occurring in approximately 60-80% of these cases, and most published series on inferior vena cava syndrome refer to thrombotic complications in this subgroup of patients. There are currently no guidelines defined or validated to guide the diagnosis and approach to IVCT. With this case, we would like to draw attention to a rare disease that should be suspected in all patients with inferior vena cava disease, whether resulting from congenital disease or after surgical procedures.\nDiagnosing IVCT can be challenging and a high index of suspicion is needed in presence of abnormalities of the inferior vena cava.In rare instances, IVCT can present with severe lumbar pain due to epidural venous congestion.",
"affiliations": "Department of Medical Oncology, Hospital da Luz, Lisbon, Portugal.;Department of Neurosurgery, Hospital da Luz, Lisbon, Portugal.;Department of Radiology, Hospital da Luz, Lisbon, Portugal.;Department of Internal Medicine, Hospital da Luz, Lisbon, Portugal.",
"authors": "Gantes Padrão|Teresa|T|;Casimiro|Miguel|M|;Gaspar|Augusto|A|;Raimundo|Anabela|A|",
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"doi": "10.12890/2020_001628",
"fulltext": "\n==== Front\nEur J Case Rep Intern Med\nEuropean Journal of Case Reports in Internal Medicine\n2284-2594 SMC Media Srl \n\n10.12890/2020_001628\n1628-1-17652-1-10-20201015\nArticles\nInferior Vena Cava Syndrome: A Rare Complication\nGantes Padrão Teresa 1 Casimiro Miguel 2 Gaspar Augusto 3 Raimundo Anabela 4 \n1 Department of Medical Oncology, Hospital da Luz, Lisbon, Portugal\n\n2 Department of Neurosurgery, Hospital da Luz, Lisbon, Portugal\n\n3 Department of Radiology, Hospital da Luz, Lisbon, Portugal\n\n4 Department of Internal Medicine, Hospital da Luz, Lisbon, Portugal\n2020 \n15 10 2020 \n7 12 00162815 3 2020 19 3 2020 © EFIM 20202020This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseInferior vena cava syndrome is rare and often difficult to diagnose because of its rarity and consequent low suspicion.\n\nWe describe the case of a 28-year-old female patient with a history of nephroblastoma of the right kidney, stage IV, with a favourable histology with epidural metastasis (D5–D9), diagnosed at 3 years of age. The patient underwent treatment with surgery, chemotherapy and radiotherapy.\n\nThe patient suffered from sudden low back pain worsening over 2 weeks, with progressive inability to walk. The pain radiated to the front of the thighs. Concomitantly, oedema of the lower limbs with cephalocaudal progression was observed. At admission to our institution, the physical examination showed peripheral oedema, abdominal wall venous collaterals, an inability to walk due to low back pain in the supine position, with no neurological deficits. Lumbar MRI showed exuberant epidural venous congestion. The hypothesis of inferior vena cava thrombosis (IVCT) was considered and confirmed by angio-CT.\n\nIVCT is prevalent in patients with congenital anomalies of the inferior vena cava, occurring in approximately 60–80% of these cases, and most published series on inferior vena cava syndrome refer to thrombotic complications in this subgroup of patients. There are currently no guidelines defined or validated to guide the diagnosis and approach to IVCT. With this case, we would like to draw attention to a rare disease that should be suspected in all patients with inferior vena cava disease, whether resulting from congenital disease or after surgical procedures.\n\nLEARNING POINTS\nDiagnosing IVCT can be challenging and a high index of suspicion is needed in presence of abnormalities of the inferior vena cava.\n\nIn rare instances, IVCT can present with severe lumbar pain due to epidural venous congestion.\n\nThrombosisinferior vena cava syndromelumbar painnephroblastoma\n==== Body\nINTRODUCTION\nInferior vena cava syndrome (IVCS) is rare and often difficult to diagnose because of its rarity and consequent low suspicion. It is usually suggested by the presence of bilateral oedema and more rarely by low back pain; it may mimic a lumbar hernia and even cauda equina syndrome [1].\n\nNephroblastoma is the most common childhood abdominal malignancy[2].\n\nWe describe the case of a 28-year-old woman with a history of nephroblastoma and a rare surgical complication: cavo-ilio-femoral thrombosis.\n\nCASE DESCRIPTION\nWe describe the case of a 28-year-old female patient with a history of nephroblastoma of the right kidney, stage IV, with a favourable histology with epidural metastasis (D5–D9), diagnosed at 3 years of age. The patient underwent treatment with surgery (right nephrectomy, inferior vena cava thrombectomy, para-aortic lymphadenectomy, laminectomy and epidural tumour removal), chemotherapy (cumulative doses: ifosfamide 22,500 mg/m2, carboplatin 1380 mg/m2, epirubicin 390 mg/m2 and etoposide 780 mg/m2) and radiotherapy (abdominal - 18 Gy and thoracic spine - 30 Gy). The patient attended regular follow-up oncology appointments until the age of 18 years old. Apart from recurrent episodes of dorsolumbar pain due to scoliosis, the patient had never presented signs of neurological or vascular compromise.\n\nAt presentation, she was being medicated with oral contraceptives (gestodene and ethinyl oestradiol).\n\nThe patient suffered from sudden low back pain worsening over 2 weeks, with progressive inability to walk. The pain radiated to the front of the thighs. Concomitantly, she experienced oedema of the lower limbs and ecchymoses on the abdomen, thighs and lower back. For this reason, the patient visited the emergency department twice at another institution, where a CT scan of the lumbosacral spine was performed showing no alterations.\n\nThe patient reported a 16-day car trip, with prolonged immobilization, that ended one week before the onset of symptoms.\n\nAt admission to our institution, the patient presented with a tympanic temperature of 37.8°C, peripheral oedema, the ecchymoses already described, abdominal wall venous collaterals (Fig. 1), an inability to walk due to low back pain in the supine position (numeric pain intensity scale – 10/10), with no neurological deficits or decreased muscle strength.\n\nLaboratory analysis showed elevated inflammatory parameters (CRP 137.5 mg/l, ESR 105 mm/min), normochromic normocytic anaemia (Hb 10.5 g/dl), moderate cholestasis (ALP 140 U/L, GGT 163 U/L), elevated LDH (303 U/L) and haemoglobinuria. Lumbar MRI did not show evidence of spondylodiscitis, but densification of the prevertebral fat and exuberant epidural venous congestion (Fig. 2).\n\nAfter discussing the case with the Neurosurgery and Neuroradiology departments, a diagnosis of inferior vena cava thrombosis (IVCT) was hypothesized. An abdominal angio-CT scan was performed and an absence of continuity of the inferior vena cava with the suprahepatic veins was identified, as well as dilation and absence of permeability of the inferior vena cava and the common and external iliac veins, with slight surrounding densification attributable to thrombosis; in addition, there was permeability of the left renal vein with venous collateral pathway to the mesenteric vein, as well as through the haemorrhoidal plexus, creating a portosystemic shunt and venous collateral circulation through the azygos system (Fig. 3).\n\nOnce the diagnosis of cavo-ilio-femoral thrombosis was made, anticoagulation therapy was started with low molecular weight heparin (LMWH), with progressive improvement of peripheral oedema and pain complaints, with the ability to walk small distances at the time of discharge.\n\nAfter 2 months of anticoagulation therapy with enoxaparin, anticoagulation was started with warfarin. After 6 months, the patient presented complete resolution of all complaints and normal laboratory test results.\n\nDISCUSSION\nIVCT is prevalent in patients with congenital anomalies of the inferior vena cava, occurring in approximately 60–80% of these cases, and most published series on IVCT refer to thrombotic complications in this subgroup of patients. IVCT in the absence of congenital anomalies is rare, and according to different authors, in addition to an acquired anatomical anomaly of the inferior vena cava or adjacent structures a hypercoagulable state is required[1,3,4].\n\nIt presents commonly with pain, oedema, sensation of weight and cramps in the inferior members. In rare instances, paraspinal venous collaterals develop, resulting in severe lumbar pain, sciatica or even cauda equina syndrome, due to the compression of peripheral nerves by dilated veins[1,5].\n\nCT and MRI are essential for the diagnosis, since ultrasound does not always allow a correct visualization of the inferior vena cava [1].\n\nAnticoagulation therapy is the treatment of choice, but there are no specific recommendations to guide anticoagulation management. The most consensual approach is to initiate anticoagulation therapy with an unfractionated heparin or LMWH with conversion to oral therapies such as warfarin[3]. Therapies such as surgical thrombectomy, endovascular or systemic thrombolysis do not yet have well-defined roles in the treatment, with the decision to opt for a more invasive treatment made on a case-by-case basis [1].\n\nNephroblastomas have an incidence of 10 per 1,000,000 children and adolescents before 15 years of age[2]. The therapy instituted depends on tumour staging, but in most cases treatment involves surgery, chemotherapy and radiotherapy. Advances in therapy have led to a 5-year survival rate of approximately 90%, at the cost of long-term sequelae. IVCT is not described as a comorbidity[2,6,7].\n\nIn this clinical case we identify 2 rarities: 1) IVCT as a complication of therapy for nephroblastoma, potentiated by 2 procoagulant factors; the use of oral contraceptives and prolonged immobilization and 2) the less typical presentation with lumbar pain and functional disability which motivated the delay in diagnosis.\n\nThere are currently no guidelines defined or validated to guide the diagnosis and approach to IVCT. As this case illustrates, the diagnosis may be challenging due to the lack of specificity and its rare presentation. This case study is intended to highlight a pathology that should be suspected not only in the context of follow-up of patients with a history of nephroblastoma surgery, but in all patients with inferior vena cava disease.\n\nTo our knowledge this is the first case in which this association is described.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 Abdominal wall and right thigh showing venous collateral circulation\n\nFigure 2 Lumbar spine MRI, axial (A) and sagittal (B), with evidence of epidural venous engorgement (arrows)\n\nFigure 3 Abdominal angio-CT: (A) absence of right kidney and no visualization of inferior vena cava; (B) evidence of multiple tortuous venous structures – portosystemic shunt (circle); (C) inferior vena cava without opacification (arrow)\n==== Refs\nREFERENCES\n1 Alkhouli M Morad M Narins CR Raza F Bashir R Inferior vena cava thrombosis JACC Cardiovasc Interv 2016 9 7 629 643 26952909 \n2 Paulino AC Wilms tumor [Updated 2020 May 21]. Available from: https://emedicine.medscape.com/article/989398-overview#a6 \n3 McAree BJ O’Donnell ME Fitzmaurice GJ Reid JA Spence RA Lee B Inferior vena cava thrombosis: a review of current practice Vasc Med 2013 18 32 43 23439778 \n4 Gayer G Luboshitz J Hertz M Zissin R Thaler M Lubetsky A Congenital anomalies of the inferior vena cava revealed on CT in patients with deep vein thrombosis AJR Am J Roentgenol 2003 180 729 732 12591684 \n5 Paksoy Y Gormus N Epidural venous plexus enlargements presenting with radiculopathy and back pain in patients with inferior vena cava obstruction or occlusion Spine (Phila Pa 1976) 2004 29 21 2419 2424 15507805 \n6 Chintagumpala M Muscal JA Treatment and prognosis of Wilms tumor UpToDate 2019 Available from: https://www.uptodate.com/contents/treatment-and-prognosis-of-wilms-tumor \n7 Termuhlen AM Tersak JM Liu Q Yasui Y Stovall M Twenty-five year follow-up of childhood Wilms tumor: a report from the childhood cancer survivor study Pediatr Blood Cancer 2011 57 7 1210 6 21384541\n\n",
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"keywords": "Thrombosis; inferior vena cava syndrome; lumbar pain; nephroblastoma",
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"abstract": "Exogenous anabolic androgen steroid use is associated with adverse cardiovascular outcomes. A 53-year-old bodybuilder presented with 3 months of exertional dyspnoea. Physical examination showed tachycardia and pan-systolic murmur; an echocardiogram showed a left ventricular ejection fraction (EF) of 15%. Evaluations included normal coronary angiogram, iron panel and thyroid studies, a negative viral panel (human immunodeficiency virus, Lyme disease, and hepatitis), and urine toxicology. He admitted to intramuscular anabolic steroid use; his testosterone level was 30 160.0 ng/dL (normal 280-1100 ng/dL). In addition to discontinuation of anabolic steroid use, he was treated with guideline-directed heart failure medical therapy. Repeat echocardiogram at 6 months showed an EF of 54% and normalized testosterone level of 603.7 ng/dL. Anabolic steroid use is a rare, reversible cause of cardiomyopathy in young, otherwise healthy athletes; a high index of suspicion is required to prevent potentially fatal side effects.",
"affiliations": "Department of Internal Medicine, Aurora Sinai/Aurora St. Luke's Medical Centers, 2801 W. Kinnickinnic River Parkway, Milwaukee, WI, 53215, USA.;Aurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke's Medical Centers, 2801 W. Kinnickinnic River Parkway, Milwaukee, WI, 53215, USA.;Aurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke's Medical Centers, 2801 W. Kinnickinnic River Parkway, Milwaukee, WI, 53215, USA.;Aurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke's Medical Centers, 2801 W. Kinnickinnic River Parkway, Milwaukee, WI, 53215, USA.",
"authors": "Doleeb|Sarah|S|;Kratz|Ann|A|;Salter|Monica|M|;Thohan|Vinay|V|",
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"doi": "10.1002/ehf2.12494",
"fulltext": "\n==== Front\nESC Heart FailESC Heart Fail10.1002/(ISSN)2055-5822EHF2ESC Heart Failure2055-5822John Wiley and Sons Inc. Hoboken 10.1002/ehf2.12494EHF212494ESCHF-18-00247Case ReportCase ReportStrong muscles, weak heart: testosterone‐induced cardiomyopathy Testosterone‐induced cardiomyopathyS. Doleeb et al.Doleeb Sarah \n1\nKratz Ann \n2\nSalter Monica \n2\nThohan Vinay \n2\npublishing112@aurora.org \n1 \nDepartment of Internal Medicine\nAurora Sinai/Aurora St. Luke's Medical Centers\n2801 W. Kinnickinnic River Parkway\nMilwaukee\nWI\n53215\nUSA\n\n2 \nAurora Cardiovascular Services\nAurora Sinai/Aurora St. Luke's Medical Centers\n2801 W. Kinnickinnic River Parkway\nMilwaukee\nWI\n53215\nUSA\n* \nCorrespondence to: Vinay Thohan, Aurora Cardiovascular Services, Aurora St. Luke's Medical Center, 2801 W. Kinnickinnic River Parkway, Ste. 880, Milwaukee, WI 53215, USA. Tel: +1 414 649 3909; Fax: +1 414 649 3578. Email: publishing112@aurora.org\n09 7 2019 10 2019 6 5 10.1002/ehf2.v6.51000 1004 14 11 2018 14 5 2019 11 6 2019 © 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ 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\nExogenous anabolic androgen steroid use is associated with adverse cardiovascular outcomes. A 53‐year‐old bodybuilder presented with 3 months of exertional dyspnoea. Physical examination showed tachycardia and pan‐systolic murmur; an echocardiogram showed a left ventricular ejection fraction (EF) of 15%. Evaluations included normal coronary angiogram, iron panel and thyroid studies, a negative viral panel (human immunodeficiency virus, Lyme disease, and hepatitis), and urine toxicology. He admitted to intramuscular anabolic steroid use; his testosterone level was 30 160.0 ng/dL (normal 280–1100 ng/dL). In addition to discontinuation of anabolic steroid use, he was treated with guideline‐directed heart failure medical therapy. Repeat echocardiogram at 6 months showed an EF of 54% and normalized testosterone level of 603.7 ng/dL. Anabolic steroid use is a rare, reversible cause of cardiomyopathy in young, otherwise healthy athletes; a high index of suspicion is required to prevent potentially fatal side effects.\n\nTestosteroneCardiomyopathyAnabolic hormones source-schema-version-number2.0component-idehf212494cover-dateOctober 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:28.10.2019\n\n\nDoleeb , S. \n, \nKratz , A. \n, \nSalter , M. \n, and \nThohan , V. \n (2019 ) Strong muscles, weak heart: testosterone‐induced cardiomyopathy . ESC Heart Failure , 6 , 1000 –1004 . 10.1002/ehf2.12494 .\n==== Body\nIntroduction\nGender‐based differences in cardiovascular disease incidence, prevalence, and severity may, in part, be related to the difference in endogenous sex hormones. The use of exogenous anabolic androgen steroids (AASs) for bodybuilding is increasing among young athletes in the USA, and some reports link AAS use to adverse cardiovascular outcomes.1, 2, 3 In this report, we highlight the anabolic steroid as a potential cause of cardiomyopathy that resolved upon discontinuation.\n\nCase report\nA 53‐year‐old, otherwise healthy bodybuilder was seen in the emergency department with 3 months of progressive dyspnoea, palpitations, headache, and an episode of syncope. He admitted to a history of fatigue, decreased libido, and erectile dysfunction for which he had been prescribed topical androgen and sildenafil. He is employed as a firefighter, does not smoke tobacco, and uses <6 oz of alcohol per week. He is married with two children and denies any family history of cardiomyopathy. He enjoys 60–90 min of vigorous exercise daily, which predominantly involves heavy weightlifting.\n\nVital signs were remarkable for a regular heart rate of 90 b.p.m. and a blood pressure of 167/95 mmHg. The physical examination demonstrated a muscular man, elevated central venous pressure (12 cm H2O), normal symmetric pulses, a slightly enlarged and laterally displaced cardiac point of maximal impulse, a grade 3/6 holosystolic murmur at the apex, and a positive third heart sound. Chest X‐ray revealed cardiomegaly, and a Doppler echocardiogram demonstrated a dilated left ventricle (6.9 cm) with severe global hypokinesis, left ventricular septal thickness in diastole (LVSthd) of 1.0 cm (normal < 1.2 cm), and a calculated left ventricular ejection fraction (LVEF) of 15% (Figure 1A). Colour Doppler images demonstrated severe mitral regurgitation (Figure\n1\nB); myocardial speckle tracking showed a severely abnormal global longitudinal strain pattern (Figure\n2). Of note, 3 years prior, his LVEF had been 57%.\n\nFigure 1 (A) Parasternal long‐axis view shows the dilated left ventricle (6.9 cm) and severe global hypokinesis with a left ventricular ejection fraction of 15%. (B) Colour Doppler apical four‐chamber view demonstrates severe functional mitral regurgitation.\n\nFigure 2 Myocardial strain assessed with two‐dimensional speckle‐tracking echocardiography shows severe peak systolic longitudinal strain abnormality (−6.7%).\n\nThe patient was admitted for diagnosis of new‐onset heart failure, and subsequent evaluation revealed normal coronary angiogram, iron panel, and thyroid studies and negative blood viral panel (human immunodeficiency virus, Lyme disease, and hepatitis) and urine toxicology panel for illicit drugs. B‐type natriuretic peptide was 303 pg/mL (normal < 100 pg/mL), and high‐sensitivity troponin was 0.05 ng/mL (normal < 0.05 ng/mL) on initial presentation.\n\nThe patient was referred to the Advanced Heart Failure Therapy program at Aurora St. Luke's Hospital, Milwaukee, WI. Upon further questioning, the patient admitted to a 3 year history of routine intramuscular androgen administration for bodybuilding. A testosterone level was obtained and documented at 30 160.0 ng/dL (normal 280–1100 ng/dL). The patient was counselled extensively about the cardiovascular risks associated with AAS use. AAS use was discontinued, and he was started on guideline‐directed medical therapy (GDMT) with comprehensive neurohormonal blockade with a focus on maximum tolerated doses of carvedilol; final doses of therapy were lisinopril 5 mg daily, spironolactone 25 mg daily, and carvedilol 25 mg twice daily. Subsequent outpatient care documented resolution of the patient's symptoms by 3 months. A repeat Doppler echocardiogram at 6 months indicated a normal LV dimension (4.5 cm) with improved cardiac function (LVEF of 53%) and LVSthd of 0.9 cm (normal < 1.2 cm), resolution of mitral regurgitation (Figure\n3\nA,B), and improvement in, but not normalization of, the global longitudinal strain pattern (Figure\n4). Subsequent clinical testing revealed testosterone level of 603.7 ng/dL and normalization of B‐type natriuretic peptide (19 pg/mL).\n\nFigure 3 (A) Parasternal long‐axis view shows normal left ventricular size (4.5 cm) and normal left ventricular ejection fraction of 53%. (B) Colour Doppler apical four‐chamber view demonstrates trace mitral regurgitation.\n\nFigure 4 Myocardial strain assessed with two‐dimensional speckle‐tracking echocardiography shows persistent mild peak systolic longitudinal strain abnormality (−13.9%).\n\nDiscussion\nNormal male physiologic levels of testosterone have been documented to be between 280 and 1100 ng/dL and may vary on the basis of age,4 race, physiologic or emotional stress, incurrent illness,5 and even time of day.6 Experimental and indirect human evidence presumes that testosterone is beneficial for cardiovascular health, as several studies have shown an inverse association of endogenous testosterone level and cardiovascular outcome independent of the traditional risk factors.7 Amid growing public concern and after the US Food and Drug Administration's release of a warning statement about testosterone therapy, a published literature review showed that the normal physiologic testosterone level is beneficial to the cardiovascular health in men and that its deficiency is associated with unfavourable metabolic profile and increased cardiovascular disease events.8\n\n\nExogenous AAS use is a growing public health concern among young athletes; estimates indicate that 3–4 million Americans use AAS, some of which include testosterone preparations.1 Access to various AAS formulations is unregulated, and these formulations can have active metabolites that are 5–15 times more potent than standard testosterone replacement therapies. Animal studies have demonstrated that exogenous AAS administration has deleterious cardiovascular effects including indirect neurohormonal activation and direct androgenic receptor stimulation resulting in hypertension, myocyte hypertrophy and extracellular fibrosis, apoptotic cell death, premature coronary artery disease, and arrhythmogenesis.9 Multiple reports of exogenous AAS have been linked with adverse cardiovascular outcome in humans, and long‐term testosterone use may lead to hypertension10 and stroke, cardiac diastolic and systolic dysfunction,2 coronary artery disease, arrhythmias, and sudden death.3\n\n\nThe diagnosis of AAS‐induced cardiomyopathy requires a thorough history and physical, and exclusion of other common causes of cardiomyopathy. Finally, a high index of suspicion regarding conditioned athletes with cardiovascular disease should prompt questions about exogenous AAS use, and the measurement of blood levels may be diagnostic. Discontinuation of AAS use and the initiation of GDMT are advocated and, as demonstrated in our case, may normalize cardiac structure and function. Further studies are warranted to fully investigate the long‐term use of AAS and its cardiovascular adverse effects.\n\nWe advocate medical societies to raise public awareness of the detrimental cardiovascular effects of AAS use.\n\nConflict of interest\nNone declared.\n\nFunding\nNone.\n==== Refs\nReferences\n1 \n\nPope \nHG \nJr\n, \nWood \nRI \n, \nRogol \nA \n, \nNyberg \nF \n, \nBowers \nL \n, \nBhasin \nS \n. Adverse health consequences of performance‐enhancing drugs: an endocrine society scientific statement . Endocr Rev \n2014 ; 35 : 341 –375 .24423981 \n2 \n\nBaggish \nAL \n, \nWeiner \nRB \n, \nKanayama \nG \n, \nHudson \nJI \n, \nLu \nMT \n, \nHoffmann \nU \n, \nPope \nHG \nJr\n. Cardiovascular toxicity of illicit anabolic‐androgenic steroid use . Circulation \n2017 ; 135 : 1991 –2002 .28533317 \n3 \n\nLichtenfeld \nJ \n, \nDeal \nBJ \n, \nCrawford \nS \n. Sudden cardiac arrest following ventricular fibrillation attributed to anabolic steroid use in an adolescent . Cardiol Young \n2016 ; 26 : 996 –998 .26980272 \n4 \n\nHarman \nSM \n, \nMetter \nEJ \n, \nTobin \nJD \n, \nPearson \nJ \n, \nBlackman \nMR \n. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore longitudinal study of aging . J Clin Endocrinol Metab \n2001 ; 86 : 724 –731 .11158037 \n5 \n\nWoolf \nPD \n, \nHamill \nRW \n, \nMcDonald \nJV \n, \nLee \nLA \n, \nKelly \nM \n. Transient hypogonadotropic hypogonadism caused by critical illness . J Clin Endocrinol Metab \n1985 ; 60 : 444 –450 .3919042 \n6 \n\nBremner \nWJ \n, \nVitiello \nMV \n, \nPrinz \nPN \n. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men . J Clin Endocrinol Metab \n1983 ; 56 : 1278 –1281 .6841562 \n7 \n\nBudoff \nMJ \n, \nEllenberg \nSS \n, \nLewis \nCE \n, \nMohler \nER \n3rd\n, \nWenger \nNK \n, \nBhasin \nS \n, \nBarrett‐Connor \nE \n, \nSwerdloff \nRS \n, \nStephens‐Shields \nA \n, \nCauley \nJA \n, \nCrandall \nJP \n, \nCunningham \nGR \n, \nEnsrud \nKE \n, \nGill \nTM \n, \nMatsumoto \nAM \n, \nMolitch \nME \n, \nNakanishi \nR \n, \nNezarat \nN \n, \nMatsumoto \nS \n, \nHou \nX \n, \nBasaria \nS \n, \nDiem \nSJ \n, \nWang \nC \n, \nCifelli \nD \n, \nSnyder \nPJ \n. Testosterone treatment and coronary artery plaque volume in older men with low testosterone . JAMA \n2017 ; 317 : 708 –716 .28241355 \n8 \n\nElagizi \nA \n, \nKohler \nTS \n, \nLavie \nCJ \n. Testosterone and cardiovascular health . Mayo Clin Proc \n2018 ; 93 : 83 –100 .29275030 \n9 \n\nRieder \nRF \n, \nWolf \nDJ \n, \nClegg \nJB \n, \nLee \nSL \n. Rapid postsynthetic destruction of unstable haemoglobin Bushwick . Nature \n1975 ; 254 : 725 –727 .1124135 \n10 \n\nKuipers \nH \n, \nWijnen \nJA \n, \nHartgens \nF \n, \nWillems \nSM \n. Influence of anabolic steroids on body composition, blood pressure, lipid profile and liver functions in body builders . Int J Sports Med \n1991 ; 12 : 413 –418 .1917227\n\n",
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"title": "Strong muscles, weak heart: testosterone-induced cardiomyopathy.",
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"abstract": "Visceral leishmaniasis is a disease caused by the protozoan Leishmania and is transmitted by Lutzomyia longipalpis (sand fly). It is an endemic parasitic infection in numerous areas around the Mediterranean basin. Though immunocompetent patients may not develop the disease, in transplant recipients the use of corticoids and intensified immunosuppressants to prevent graft rejection may accelerate the disease, causing severe damage to the liver, spleen, and hematopoietic system. We report 2 cases of visceral leishmaniasis with an atypical presentation in transplant recipients. The first patient, who had a kidney transplant, was treated successfully with liposomal amphotericin B, and the second patient, a combined kidney-pancreas transplant recipient, suffered a relapse 3 years after treatment. Visceral leishmaniasis should be considered in the differential diagnosis of pancytopenia or unexplained fever occurring after organ transplantation in patients living in endemic areas or returning from endemic countries.",
"affiliations": "Nephrology Department, Torrecárdenas Hospital Complex, Almería, Spain. Electronic address: fuensantaclavijosanchez@gmail.com.;Nephrology Department, Regional University Hospital of Málaga, Málaga, Spain.;Nephrology Department, Regional University Hospital of Málaga, Málaga, Spain.;Nephrology Department, Regional University Hospital of Málaga, Málaga, Spain.;Nephrology Department, Regional University Hospital of Málaga, Málaga, Spain.;Nephrology Department, Regional University Hospital of Málaga, Málaga, Spain.",
"authors": "Clavijo Sánchez|F|F|;Vázquez Sánchez|T|T|;Cabello Díaz|M|M|;Sola Moyano|V E|VE|;Jironada Gallego|C|C|;Hernández Marrero|D|D|",
"chemical_list": "D000981:Antiprotozoal Agents; D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2017.12.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "50(2)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000981:Antiprotozoal Agents; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D007898:Leishmaniasis, Visceral; D008297:Male; D008875:Middle Aged; D010198:Pancytopenia; D011183:Postoperative Complications",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "581-582",
"pmc": null,
"pmid": "29579858",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Visceral Leishmaniasis in Renal Transplant Recipients: Report of 2 Cases.",
"title_normalized": "visceral leishmaniasis in renal transplant recipients report of 2 cases"
} | [
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"companynumb": "ES-ALKEM LABORATORIES LIMITED-ES-ALKEM-2018-02717",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
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"actiondrug": "5",
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"abstract": "We report 2 fatal exacerbations of systemic capillary leak syndrome (SCLS), also known as Clarkson disease, associated with coronavirus disease (COVID-19) in the United States. One patient carried an established diagnosis of SCLS and the other sought treatment for new-onset hypotensive shock, hemoconcentration, and anasarca, classic symptoms indicative of an SCLS flare. Both patients had only mild-to-moderate symptoms of COVID-19. This clinical picture suggests that these patients succumbed to complications of SCLS induced by infection with severe acute respiratory syndrome coronavirus 2. Persons with known or suspected SCLS may be at increased risk for developing a disease flare in the setting of mild-to-moderate COVID-19 infection.",
"affiliations": null,
"authors": "Cheung|Patricia C|PC|;Eisch|A Robin|AR|;Maleque|Noble|N|;Polly|Derek M|DM|;Auld|Sara C|SC|;Druey|Kirk M|KM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3201/eid2710.211155",
"fulltext": "\n==== Front\nEmerg Infect Dis\nEmerg Infect Dis\nEID\nEmerging Infectious Diseases\n1080-6040\n1080-6059\nCenters for Disease Control and Prevention\n\n34314669\n21-1155\n10.3201/eid2710.211155\nSynopsis\nOriginal Research\nSynopsis\nFatal Exacerbations of Systemic Capillary Leak Syndrome Complicating Coronavirus Disease\nFatal Exacerbations of Systemic Capillary Leak Syndrome Complicating Coronavirus Disease\nSystemic Capillary Leak Syndrome and COVID-19\nCheung Patricia C.\nEisch A. Robin\nMaleque Noble\nPolly Derek M.\nAuld Sara C.\nDruey Kirk M.\nEmory University School of Medicine and Rollins School of Public Health, Atlanta, Georgia, USA (P.C. Cheung, N. Maleque, S.C. Auld);\nNational Institute of Allergy and Infectious Diseases/National Institutes of Health, Bethesda, Maryland, USA (A.R. Eisch, K.M. Druey);\nEmory University Hospital Midtown Department of Pharmacy, Atlanta (D.M. Polly)\nAddress for correspondence: Kirk Druey, National Institute of Allergy and Infectious Diseases/National Institutes of Health, 10 Center Dr, Rm 11N238A, Bethesda, MD 20892, USA; email: kdruey@niaid.nih.gov\n10 2021\n27 10 25292534\nWe report 2 fatal exacerbations of systemic capillary leak syndrome (SCLS), also known as Clarkson disease, associated with coronavirus disease (COVID-19) in the United States. One patient carried an established diagnosis of SCLS and the other sought treatment for new-onset hypotensive shock, hemoconcentration, and anasarca, classic symptoms indicative of an SCLS flare. Both patients had only mild-to-moderate symptoms of COVID-19. This clinical picture suggests that these patients succumbed to complications of SCLS induced by infection with severe acute respiratory syndrome coronavirus 2. Persons with known or suspected SCLS may be at increased risk for developing a disease flare in the setting of mild-to-moderate COVID-19 infection.\n\nKeywords:\n\ncapillary leaks\nClarkson disease\ncoronavirus disease\nCOVID-19\nmultiple organ failure\nrespiratory infections\nSARS-COV-2\nsevere acute respiratory syndrome coronavirus 2\nsystemic capillary leak syndrome\nviruses\n==== Body\npmcSystemic capillary leak syndrome (SCLS), also known as Clarkson disease, is a rare disease of unknown etiology that most commonly develops in adults 50–70 years of age (1). Since SCLS was first characterized in 1960, <500 cases have been described in the medical literature. The current prevalence of SCLS is estimated to be <250 cases worldwide (1), although the disease is likely underdiagnosed.\n\nSCLS is diagnosed clinically on the basis of a characteristic symptomatic triad of hypotension, hemoconcentration (elevated hemoglobin or hematocrit), and serum hypoalbuminemia resulting from fluid extravasation. Patients with SCLS experience transient and reversible episodes of plasma leakage into peripheral tissues, which lead to the acute onset of hypotensive shock and the development of anasarca after intravenous (IV) fluid resuscitation. Severe SCLS flares commonly result in multisystem organ failure and peripheral compartment syndromes (2). Between episodes, patients are typically asymptomatic.\n\nMinor infections, typically of the upper respiratory tract, are common triggers for SCLS, although an infection-related prodrome is identified in only 44%–65% of cases (2,3). Although >80% of SCLS patients have a monoclonal gammopathy of unknown significance (MGUS), the role of this finding in disease pathogenesis remains unclear; the absence of MGUS does not exclude a diagnosis of SCLS (4). Interventions for acute SCLS episodes are limited to supportive measures, but monthly prophylaxis with high dose (1–2 g/kg patient weight) IV immunoglobulin (IVIg) prevents attacks among >90% of patients and provides them with a statistically significant survival advantage compared with those patients who were not treated with IVIg (5,6). Here we report the cases of 2 patients who died of severe SCLS soon after seeking treatment for mild-to-moderate symptoms of COVID-19; neither of them had been receiving IVIg prophylaxis beforehand.\n\nMethods\n\nPatients were referred to the National Institutes of Health (NIH) for evaluation of suspected SCLS. Where applicable, patients provided written informed consent to participate in a natural history protocol (09-I-0184) approved by the NIH institutional review board. We followed the CARE guidelines for writing medical case reports in the preparation of this manuscript.\n\nCase Reports\n\nCase 1\n\nA 59-year-old woman with a history of hypertension but no known history of SCLS or prior episodes of peripheral edema was admitted to a hospital in January 2021 with a 6-day history of cough, shortness of breath, and lower extremity pain. She was hypotensive, with a blood pressure of 96/70 mm Hg, but her initial physical exam was otherwise unremarkable and included normal results for a pulmonary examination. Laboratory examination revealed hemoconcentration (hemoglobin 17.1 g/dL, hematocrit of 52%) and a lactic acid level of 3.7 mmol/L. Despite resuscitation with 5.5 L Ringer’s lactate and 2.5 L normal saline IV fluids over the first 3 days of admission, serum lactate levels remained elevated at 5.7 mmol/L on day 4 of hospitalization (Table 1). Lower extremity pain worsened, and anasarca without hypoxemia developed. SARS-CoV-2 PCR testing of a nasal swab specimen taken at the time of admission returned positive results; daily treatment with 6 mg dexamethasone and 40 mg enoxaparin was initiated. Remdesivir was not administered because of a developing acute kidney injury. The patient’s lung examination results remained unremarkable, but she became intermittently hypoxemic (SpO2 of 88% on 2L nasal cannula), requiring ongoing nasal cannula support. A chest computed tomography revealed bilateral scattered ground glass opacities consistent with mild-to-moderate SARS-CoV-2 infection (Figure). A transthoracic echocardiogram performed on day 3 of hospitalization showed a normal left ventricular ejection fraction (70%–75%), no left ventricular dilation or geometric changes, and no wall motion abnormalities. Other laboratory abnormalities included increased creatinine phosphokinase levels, peaking at 15,094 units/L; elevated lactate at 6.3 mmol/L; and hypoalbuminemia at 2.4 g/dL, which raised concerns for SCLS.\n\nTable 1 Laboratory values during hospitalization for case-patient 1 with systemic capillary leak syndrome and coronavirus disease*\n\nTest\tReference range\tAdmission, 2021 Jan 31\tHospital floor, 2021 Feb 2\tHospital floor/ ICU, 2021 Feb 3\tICU, \n2021 Feb 4\tICU, \n2021 Feb 5\t\nAlbumin\t3.5–5.7 g/dL\t3.8\t3.2\t2.4\t2.1\t2.3\t\nHemoglobin\t11.4–14.4 g/dL\t17.1\t20.3\t17.4\t14.5\t8.7\t\nHematocrit\t33.3%–41.4%\t52.0\t61.0\t52.6\t44.8\t26.7\t\nCreatinine\t0.6–1.2 mg/dL\t0.95\t1.2\t1.42\t1.80\t0.85a\t\nSodium\t136–145 mmol/L\t132\t129\t126\t129\t129\t\nPotassium\t3.5–5.1 mmol/L\t4.3\t4.7\t5.6\t6.1\t6.5\t\nPhosphate\t2.5–5.0 mg/dL\tNA\t6.1\t5.1\t6.9\t8.0\t\nAlanine transaminase\t7–52 unit/L\t32\t26\t92\t299\t7,928\t\nTroponin\t≤0.04 ng/mL\t0.04\t<0.03\tNA\t0.23\t0.50\t\nCreatine kinase\t30–223 unit/L\tNA\t1,851\t15,094\t41,696\t>45,000\t\nC-reactive protein\t≤10 mg/L\tNA\t12.8\t42.2\t41.8\t58.1\t\nLeukocytes\t4.0–10.0 103/μL\t7.0\t9.7\t19.5\t25.3\t12.6\t\nPlatelets\t150–400 103/μL\t184\t158\t145\t170\t71\t\nLactate\t0.5–2.2 mmol/L\t4.6\t6.3\t5.7\t8.2\t10.5\t\nD-dimer\t≤574 ng/mL\t475\tNA\t1,016\t1,271\t9,536\t\nInternational normalized ratio\tNot applicable\tNA\t0.97\tNA\t1.23\t3.29\t\nActivated partial thromboplastin time\t26.5–36.5 s\tNA\tNA\tNA\tNA\t148.9\t\nComplement C3\t81–157 mg/dL\tNA\tNA\tNA\t74\tNA\t\nComplement C4\t13–39 mg/dL\tNA\tNA\tNA\t22\tNA\t\n*ICU, intensive care unit; NA, not available\n\nFigure Chest computed tomography from hospital day 3 for a 59-year-old woman (case-patient 1) with new-onset systemic capillary leak syndrome and coronavirus disease showing A) the upper and B) lower lung fields in axial plane and C) the coronal plane. The scans showed bilateral scattered ground glass opacities consistent with mild-to-moderate infection with severe acute respiratory syndrome coronavirus 2.\n\nThe patient was transferred to the intensive care unit for further monitoring on day 4 of hospitalization. Pain increased in her extremities and tense anasarca developed; however, because compartment pressures were 18 mm Hg in her right arm and 15 mm Hg in her left arm, she did not meet criteria for a diagnosis of compartment syndrome. Apart from edema and tachypnea while on 2 L nasal cannula, her cardiopulmonary examination was otherwise normal. On hospitalization day 5, she suffered a cardiac arrest; spontaneous circulation returned after 2 rounds of cardiopulmonary resuscitation. She was intubated at the time of cardiac arrest and empirically started on vancomycin and cefepime. Because of concern for microvascular thrombi in the setting of SARS-CoV-2 infection, an argatroban infusion was started. Although the patient had remained afebrile and hemodynamically stable up to this point, shock rapidly developed, and she required vasopressor support with norepinephrine, vasopressin, epinephrine, and stress-doses of hydrocortisone. Continuous renal replacement therapy was initiated for oliguric renal failure.\n\nThe next day, edema in the extremities intensified, and creatinine phosphokinase levels increased further to >45,000 units/L, but compartment pressures were 17 mm Hg in her right arm and 16 mm Hg in her left arm, suggestive of rhabdomyolysis without compartment syndrome. No MGUS was detected. Serum SARS-CoV-2 IgG was not detected, prompting treatment with convalescent plasma. Given the patient’s grave condition and lack of proven interventions for acute SCLS, empiric treatments were also administered, including IVIg; methylene blue, an agent that suppresses downstream effects of nitric oxide (7); and icatibant, a bradykinin receptor antagonist used to treat vascular leakage associated with hantavirus infection (8). Bradycardia developed and ultimately required transvenous pacing. Within hours, her hemoglobin decreased to 6.8 g/dL although there was no obvious source of hemorrhage. Because she was anticoagulated with argatroban and had a prolonged activated partial thromboplastin time in the setting of acute liver failure, the patient was transfused with packed erythrocytes. She suffered cardiac arrest, and ventricular fibrillation deteriorated into pulseless electrical activity. Transthoracic echocardiography performed during ACLS revealed no pericardial effusion. The patient received additional units of erythrocytes, IV fluids, fresh frozen plasma, and prothrombin complex concentrate during the cardiac arrest. However, spontaneous circulation was not restored, and the patient died on day 6 of her hospitalization.\n\nCase 2\n\nA 36-year-old man with no notable medical history first sought treatment in 2015 for transient hypotension and severe bilateral lower-extremity edema; laboratory testing showed hemoconcentration (hemoglobin 20.2 g/dL, hemocrit 59.4%) and a serum hypoalbuminemia level of 2.2 g/dL after several days of fevers and upper respiratory symptoms. SCLS was diagnosed on the basis of characteristic clinical presentation and an IgG lambda MGUS. His course was complicated by acute kidney injury and compartment syndromes in both legs, which required bilateral fasciotomies. He also had deep vein thromboses in the right internal jugular and left cephalic veins. He was treated transiently with anticoagulants, but a full evaluation for hypercoagulability was negative. Muscle biopsies taken at the time of fasciotomies provided no evidence of inflammatory myositis. All symptoms resolved before he was discharged from the hospital, although a bilateral sensorimotor neuropathy developed, presumably as a residual effect of compartment syndrome.\n\nThe patient was treated with IVIg (2 g/kg) within 24 hours of the 2015 hospitalization and monthly thereafter with no recurrence of his SCLS-related symptoms. In November 2016, IVIg prophylaxis was discontinued at the patient’s request. In 2017 and 2018, the patient experienced 2 episodes of bilateral lower extremity swelling, in both cases after several days of upper respiratory symptoms. Blood pressure and laboratory tests were normal at the time of these episodes, and swelling resolved without further treatment.\n\nIn February 2020, the patient sought treatment for a several-day history of fevers (40°C) and productive cough. He was noted to be hypoxemic (SpO2 of 87% on room air). Mycoplasma pneumonia was diagnosed on the basis of chest radiographic evidence of lung infiltrates and positive Mycoplasma serologic testing. He was hospitalized and treated with IV antimicrobial drugs and fluids (10.5 L total). Although the fevers and respiratory symptoms resolved, bilateral leg swelling and serum hypoalbuminemia developed, prompting treatment with 1 dose of IVIg (2 g/kg) for empirically presumed SCLS-related edema in the absence of any other proven treatment options. He ultimately recovered and experienced no residual symptoms.\n\nIn January 2021, the patient was transported to the emergency department because of disorientation after several days of upper respiratory symptoms, fever (40.6°C), and back pain. Upon arrival, he was hypotensive, with a blood pressure of 94/20 mm Hg, and tachycardic at 140 beats/min. Upon initial examination, he showed no signs of apparent dyspnea (respiratory rate of 19 breaths/min) or respiratory distress (SpO2 of 99% on room air). A PCR nasal swab test for SARS-CoV-2 performed on the day before he sought treatment was reported by the family to be positive. Laboratory tests taken at the time of hospital admission revealed severe hemoconcentration (hemoglobin >25 g/dL, 75% hemocrit), leukocytosis (leukocyte count 43.3K/μL blood), and lactic acidosis (lactate level 9.2 mmol/L). Other laboratory values included brain natriuretic peptide at 12 pg/mL, troponin at <0.02 ng/mL, and a fingerstick glucose level of 197 mg/dL. There was no ST elevation suggesting myocardial infarction or dysrhythmia on his electrocardiogram.\n\nIn the emergency department, his condition deteriorated rapidly. His blood pressure became unobtainable manually, and he exhibited an Sp02 of 73% on a 15-L nonrebreather mask. A bedside echocardiogram revealed a flat inferior vena cava, intact bilateral ventricular function, and pericardial effusion with no evidence of right heart strain or tamponade. He was intubated emergently but ultimately experienced cardiac arrest with pulseless electrical activity. Despite aggressive cardiopulmonary resuscitation and pharmacological interventions including boluses of epinephrine, bicarbonate, calcium, and magnesium, refractory ventricular tachycardia developed, followed by Torsade de Pointes, and he died shortly thereafter.\n\nDiscussion\n\nWe report 2 cases of SCLS associated with mild-to-moderate COVID-19 infection. Case-patient 1 exhibited the clinical diagnostic triad for SCLS: hypotension, hemoconcentration, and hypoalbuminemia. Case-patient 2 carried a prior diagnosis of SCLS. These findings suggest that patients with SCLS may be at high risk for exacerbations or even death if they contract COVID-19.\n\nInformation from our studies complements the findings of several recent case reports of severe SCLS attacks associated with mild-to-moderate SARS-CoV-2 infection (9–12). In each of the cases in those studies, patients exhibited all the hallmarks of severe SCLS exacerbations after experiencing mild-to-moderate symptoms of COVID-19; 2 of 3 patients died from SCLS-related complications.\n\nBecause COVID-19 had not previously been associated with secondary capillary leak syndrome and there were no other obvious triggers for the episode in case-patient 1 in our study, it is highly likely that she carried latent SCLS even though MGUS was not detected at the time of the episode. Although MGUS is an important clue, it is not detected in all patients with SCLS. In the most recent comprehensive reviews of the literature, which included 290 cases reported during 1960–2016, MGUS was detected in only ≈75% of case-patients (3). Although MGUS was detected in 34 (91%) of 37 patients in a 2017 study (2), the authors emphasized that “the three monoclonal gammopathy-negative patients had typical severe SCLS flares.” Several studies failed to establish any functional role for these monoclonal paraproteins in disease pathogenesis (13–15). Finally, immunofixation may be negative during acute SCLS flares because of IgG extravasation and transient hypogammaglobulinemia (15,16).\n\nSeveral unique clinical and laboratory features of SCLS can be used to differentiate disease flares from the sequelae of severe COVID-19 (Table 2). Most notably, edema of the trunk and extremities is a prominent feature of acute SCLS and can lead to the development of compartment syndromes. Edema in COVID-19 infection is typically peripheral and frequently confined to the fingers and toes in association with chilblains, painful erythematous lesions (17). Pulmonary edema is a feature of SCLS rarely noted at initial observation but is a frequent characteristic of acute COVID-19–associated acute respiratory distress syndrome (18). Furthermore, both patients exhibited severe hemoconcentration despite aggressive fluid resuscitation. Patients who are critically ill with COVID-19 typically exhibit anemia, which is a predictor of a poor clinical outcome (19). Finally, although mildly decreased serum albumin levels of ≈3 g/dL have been reported in patients with severe COVID-19 (20), hypoalbuminemia is typically much more severe in SCLS flares, with an albumin level usually <2 g/dL.\n\nTable 2 Clinical characteristics of acute SCLS compared with severe COVID-19*\n\nParameter\tSCLS\tCOVID-19\t\nBlood pressure\tLow/undetectable, vasopressor-resistant\tNormal/high\t\nHgb/Hct\tVery elevated\tNormal/low\t\nSerum albumin\tVery low\tNormal/low\t\nPulmonary findings\tAbsent\tLung infiltrates, tachypnea, hypoxemia\t\nEdema\tAnasarca, compartment syndrome\tPulmonary edema; no peripheral edema\t\nCreatine kinase\tVery elevated\tNormal/elevated\t\nCreatinine\tElevated, acute kidney injury common\tNormal\t\n*COVID-19, coronavirus disease; Hgb/Hct, hemoglobin/hematocrit ratio; SCLS, systemic capillary leak syndrome.\n\nOf note, SCLS had not previously been diagnosed in case-patient 1, and neither patient was receiving IVIg prophylaxis at the time of COVID-19 infection. Fortunately, we observed no COVID-19–associated SCLS flares in any of the >70 patients in the study cohort who were receiving IVIg prophylaxis (range 0.75–2.00 g/kg/mo). However, a previously published report (11) documented the case of a patient whose disease had been well-controlled by IVIg prophylaxis (0.5 g/kg/mo) but who died of refractory SCLS soon after COVID-19 infection. Nonetheless, in agreement with the authors of that study, we strongly recommend that SCLS patients receive IVIg prophylaxis indefinitely, at the highest recommended dose (2 g/kg/month), until the COVID-19 pandemic is under better control. Because no treatments for acute SCLS flares, including IVIg, have been proven effective, interventions are limited to supportive measures such as IV fluids and albumin, vasopressors, renal replacement therapy, and intubation. However, as noted in recent surveys of critically ill SCLS patients (2), fluid administration must be limited to avoid development of compartment syndromes and limb ischemia. Although case-patient 1 received several empiric treatments, including IVIg, icatibant, and methylene blue, the treatments appeared to have had no effect on her intermediate clinical outcomes.\n\nAlthough the genetic basis of SCLS is not well understood (21,22), our work has provided evidence that patients with SCLS experience intrinsically exaggerated endothelial barrier dysfunction in response to otherwise mundane proinflammatory mediators (23,24). Severe COVID-19 and acute SCLS are both characterized by transient increases in the levels of proinflammatory cytokines in circulation; some of these cytokines, including C-X-C motif chemokine ligand 10, C-C motif chemokine ligand 2 and 3, interleukin -6, and tumor necrosis factor–α (Table 3), directly provoke endothelial barrier disruption (25–27). These results suggest that the cytokine storm associated with mild-to-moderate COVID-19 may lead to an SCLS flare. Alternatively, as suggested elsewhere (9), it is also possible that SARS-CoV-2 may be directly toxic to endothelial cells. This hypothesis suggests that viral factors synergize with host-intrinsic mechanisms to provoke severe SCLS flares. Endothelial cell infection, diffuse inflammatory endothelitis, and microvascular thrombosis are common in COVID-19, although these responses are typically associated with prominent lung involvement (28). Because neither of these patients exhibited prominent pulmonary abnormalities, these mechanisms may not be substantial components of COVID-19–associated SCLS.\n\nTable 3 Typical serum cytokine profiles for acute SCLS compared with severe COVID-19*\n\nCytokine\tSCLS\tCOVID-19\t\nIL-2\tNormal\tElevated\t\nIL-4\tNormal\tElevated\t\nIL-6\tElevated\tElevated\t\nIL-7\tNormal\tElevated\t\nIL-10\tNormal\tElevated\t\nCXCL10\tElevated\tElevated\t\nCCL2\tElevated\tElevated\t\nTNF-α\tVariable\tElevated\t\nIFN-γ\tElevated\tElevated\t\n*COVID-19, coronavirus disease; CCL, C-C motif chemokine ligand; CXCL, C-X-C motif chemokine ligand; IFN, interferon; IL, interleukin; SCLS, systemic capillary leak syndrome; TNF, tumor necrosis factor.\n\nFurther characterization of the immune and inflammatory responses to SARS-CoV-2 will be needed to elucidate its effects on SCLS pathophysiology at the molecular level. However, clinicians should be aware that patients carrying a diagnosis of SCLS or another relapsing-remitting and inflammation-related disease (e.g., autoimmune or autoinflammatory rheumatological diseases) may be at increased risk for severe disease and require increased vigilance for this rare but potentially fatal potential complication of COVID-19 as the pandemic continues.\n\nAcknowledgments\n\nWe thank Helene F. Rosenberg for critical review of the manuscript.\n\nWe dedicate this paper to Kathy Messina, who had SCLS.\n\nFunding for this study was provided by the National Institute of Allergy and Infectious Diseases/National Institutes of Health Intramural Program (Z01-AI-001083).\n\nThe content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US government.\n\nDr. Cheung is an internal medicine resident at Emory University, Atlanta, Georgia, USA. Her research interests include epidemiology and applying implementation science to improve hospitals and health systems.\n\nSuggested citation for this article: Cheung PC, Eisch AR, Maleque N, Polly DM, Auld SC, Druey KM. Fatal exacerbations of systemic capillary leak syndrome complicating coronavirus disease. Emerg Infect Dis. 2021 Oct [date cited]. https://doi.org/10.3201/eid2710.211155\n==== Refs\nReferences\n\n1. DrueyKM, ParikhSM. Idiopathic systemic capillary leak syndrome (Clarkson disease). J Allergy Clin Immunol. 2017;140 :663–70. 10.1016/j.jaci.2016.10.042 28012935\n2. Pineton de ChambrunM, LuytCE, BeloncleF, GousseffM, MauhinW, ArgaudL, et al. ; EurêClark Study Group. EurêClark Study Group. The clinical picture of severe systemic capillary-leak syndrome episodes requiring ICU admission. Crit Care Med. 2017;45 :1216–23. 10.1097/CCM.0000000000002496 28622216\n3. EoTS, ChunKJ, HongSJ, KimJY, LeeIR, LeeKH, et al. Clinical presentation, management, and prognostic factors of idiopathic systemic capillary leak syndrome: a systematic review. J Allergy Clin Immunol Pract. 2018;6 :609–18. 10.1016/j.jaip.2017.07.021 28939140\n4. KapoorP, GreippPT, SchaeferEW, MandrekarSJ, KamalAH, Gonzalez-PazNC, et al. Idiopathic systemic capillary leak syndrome (Clarkson’s disease): the Mayo clinic experience. Mayo Clin Proc. 2010;85 :905–12. 10.4065/mcp.2010.0159 20634497\n5. XieZ, ChanEC, LongLM, NelsonC, DrueyKM. High-dose intravenous immunoglobulin therapy for systemic capillary leak syndrome (Clarkson disease). Am J Med. 2015;128 :91–5. 10.1016/j.amjmed.2014.08.015 25193271\n6. Pineton de ChambrunM, GousseffM, MauhinW, LegaJC, LambertM, RivièreS, et al. EurêClark Study Group. Intravenous immunoglobulins improve survival in monoclonal gammopathy-associated systemic capillary-leak syndrome. Am J Med. 2017;130 :1219.e19–27. 10.1016/j.amjmed.2017.05.023\n7. UmbrelloM, GardinaliM, OttolinaD, ZanforlinG, IapichinoG. Systemic capillary leak syndrome: is methylene blue the silver bullet? Case Rep Crit Care. 2014;2014 :141670. 10.1155/2014/141670 25544902\n8. AntonenJ, LeppänenI, TenhunenJ, ArvolaP, MäkeläS, VaheriA, et al. A severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant. Scand J Infect Dis. 2013;45 :494–6. 10.3109/00365548.2012.755268 23294035\n9. LacoutC, RogezJ, OrvainC, NicotC, RonyL, JulienH, et al. A new diagnosis of systemic capillary leak syndrome in a patient with COVID-19. Rheumatology (Oxford). 2021;60 :e19–20. 10.1093/rheumatology/keaa606 32940700\n10. CaseR, RamaniukA, MartinP, SimpsonPJ, HardenC, AtayaA. Systemic capillary leak syndrome secondary to coronavirus disease 2019. Chest. 2020;158 :e267–8. 10.1016/j.chest.2020.06.049 32622823\n11. Pineton de ChambrunM, Cohen-AubartF, DonkerDW, CariouPL, LuytCE, CombesA, et al. SARS-CoV-2 induces acute and refractory relapse of systemic capillary leak syndrome (Clarkson’s disease). Am J Med. 2020;133 :e663–4. 10.1016/j.amjmed.2020.03.057 32405072\n12. Pineton de ChambrunM, ConstantinJM, MathianA, QuemeneurC, LepereV, CombesA, et al. Clarkson’s disease episode or secondary systemic capillary leak-syndrome: that is the question! Chest. 2021;159 :441. 10.1016/j.chest.2020.07.084 33422212\n13. XieZ, GhoshCC, PatelR, IwakiS, GaskinsD, NelsonC, et al. Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome). Blood. 2012;119 :4321–32. 10.1182/blood-2011-08-375816 22411873\n14. ZhangW, EwanPW, LachmannPJ. The paraproteins in systemic capillary leak syndrome. Clin Exp Immunol. 1993;93 :424–9. 10.1111/j.1365-2249.1993.tb08195.x 8370170\n15. AtkinsonJP, WaldmannTA, SteinSF, GelfandJA, MacdonaldWJ, HeckLW, et al. Systemic capillary leak syndrome and monoclonal IgG gammopathy; studies in a sixth patient and a review of the literature. Medicine (Baltimore). 1977;56 :225–39. 10.1097/00005792-197705000-00004 870792\n16. MathenyM, MalequeN, ChannellN, EischAR, AuldSC, BanerjiA, et al. Severe exacerbations of systemic capillary leak syndrome after COVID-19 vaccination: a case series. Ann Intern Med. 2021;••• :L21-0250; Epub ahead of print. 10.7326/L21-0250 34125573\n17. WollinaU, KaradağAS, Rowland-PayneC, ChiriacA, LottiT. Cutaneous signs in COVID-19 patients: A review. Dermatol Ther (Heidelb). 2020;33 :e13549. 10.1111/dth.13549 32390279\n18. VirotE, MathienC, PointurierV, PoidevinA, LabroG, PintoL, et al. Characterization of pulmonary impairment associated with COVID-19 in patients requiring mechanical ventilation. Rev Bras Ter Intensiva. 2021;33 :75–81.33886855\n19. Faghih DinevariM, SomiMH, Sadeghi MajdE, Abbasalizad FarhangiM, NikniazZ. Anemia predicts poor outcomes of COVID-19 in hospitalized patients: a prospective study in Iran. BMC Infect Dis. 2021;21 :170. 10.1186/s12879-021-05868-4 33568084\n20. HuangJ, ChengA, KumarR, FangY, ChenG, ZhuY, et al. Hypoalbuminemia predicts the outcome of COVID-19 independent of age and co-morbidity. J Med Virol. 2020;92 :2152–8. 10.1002/jmv.26003 32406952\n21. PierceR, JiW, ChanEC, XieZ, LongLM, KhokhaM, et al. Whole exome sequencing of adult and pediatric cohorts of the rare vascular disorder systemic capillary leak syndrome. Shock. 2019;52 :183–90. 10.1097/SHK.0000000000001254 30289850\n22. XieZ, NagarajanV, SturdevantDE, IwakiS, ChanE, WischL, et al. Genome-wide SNP analysis of the systemic capillary leak syndrome (Clarkson disease). Rare Dis. 2013;1 :e27445. 10.4161/rdis.27445 24808988\n23. SekAC, XieZ, TeraiK, LongLM, NelsonC, DudekAZ, et al. Endothelial expression of endothelin receptor A in the systemic capillary leak syndrome. [Erratum in PLoS One. 2015;10:e0137373.]. PLoS One. 2015;10 :e0133266. 10.1371/journal.pone.0133266 26176954\n24. RazaA, XieZ, ChanEC, ChenWS, ScottLM, Robin EischA, et al. A natural mouse model reveals genetic determinants of systemic capillary leak syndrome (Clarkson disease). [Erratum in Commun Biol. 2019;2:439.]. Commun Biol. 2019;2 :398. 10.1038/s42003-019-0647-4 31701027\n25. HuB, HuangS, YinL. The cytokine storm and COVID-19. J Med Virol. 2021;93 :250–6. 10.1002/jmv.26232 32592501\n26. XieZ, GhoshCC, ParikhSM, DrueyKM. Mechanistic classification of the systemic capillary leak syndrome: Clarkson disease. Am J Respir Crit Care Med. 2014;189 :1145–7. 10.1164/rccm.201310-1746LE 24787070\n27. XieZ, ChanE, YinY, GhoshCC, WischL, NelsonC, et al. Inflammatory markers of the systemic capillary leak syndrome (Clarkson disease). J Clin Cell Immunol. 2014;5 :1000213.25405070\n28. PonsS, FodilS, AzoulayE, ZafraniL. The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection. Crit Care. 2020;24 :353. 10.1186/s13054-020-03062-7 32546188\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1080-6040",
"issue": "27(10)",
"journal": "Emerging infectious diseases",
"keywords": "COVID-19; Clarkson disease; SARS-COV-2; capillary leaks; coronavirus disease; multiple organ failure; respiratory infections; severe acute respiratory syndrome coronavirus 2; systemic capillary leak syndrome; viruses",
"medline_ta": "Emerg Infect Dis",
"mesh_terms": "D000086382:COVID-19; D019559:Capillary Leak Syndrome; D006801:Humans; D000086402:SARS-CoV-2; D014481:United States",
"nlm_unique_id": "9508155",
"other_id": null,
"pages": "2529-2534",
"pmc": null,
"pmid": "34314669",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D052060:Research Support, N.I.H., Intramural; D016454:Review",
"references": "23294035;32390279;25193271;20634497;32592501;32405072;25544902;32622823;22411873;32546188;25405070;31701027;28012935;24787070;28939140;32406952;33568084;30289850;28622216;34125573;870792;8370170;28602874;24808988;32940700;33422212;33886855;26176954",
"title": "Fatal Exacerbations of Systemic Capillary Leak Syndrome Complicating Coronavirus Disease.",
"title_normalized": "fatal exacerbations of systemic capillary leak syndrome complicating coronavirus disease"
} | [
{
"companynumb": "US-drreddys-LIT/USA/21/0144774",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ICATIBANT ACETATE"
},
"drugadditional": ... |
{
"abstract": "Therapeutic agents targeting the PD-1/PD-L1 axis have shown durable clinical responses in patients with various cancer types. Although objective responses are common, intrapatient heterogeneous responses have been described, and the mechanism for the different organ responses remains unknown. We present a series of patients in whom a lack of response was noted solely in the adrenal glands. This is the first case series describing 3 patients with heterogeneous patterns of response to pembrolizumab with progression of adrenal metastatic disease despite objective response (complete or partial response) in all other sites of metastatic disease. Two patients, one with melanoma and one with uterine carcinosarcoma, underwent robotic adrenalectomy for enlarging adrenal metastases. An additional patient with melanoma underwent laparotomy with attempted resection, but infiltration of the adrenal tumor into the inferior vena cava prohibited safe excision. This report provides additional insight into the heterogeneous patterns of disease response to anti-PD-1 therapy, highlighting the adrenal gland as a potential sanctuary site for this immunotherapy. These cases display the potential benefit of early surgical resection in this scenario and the pitfalls of delaying referral to a surgeon for assessment of operative intervention.",
"affiliations": null,
"authors": "Nguyen|Michelle C|MC|;Shah|Manisha H|MH|;Liebner|David A|DA|;Backes|Floor J|FJ|;Phay|John|J|;Shirley|Lawrence A|LA|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.6004/jnccn.2018.7059",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1540-1405",
"issue": "16(11)",
"journal": "Journal of the National Comprehensive Cancer Network : JNCCN",
"keywords": null,
"medline_ta": "J Natl Compr Canc Netw",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000311:Adrenal Glands; D000315:Adrenalectomy; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D002296:Carcinosarcoma; D018450:Disease Progression; D005260:Female; D006801:Humans; D008545:Melanoma; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D012878:Skin Neoplasms; D016896:Treatment Outcome; D014594:Uterine Neoplasms",
"nlm_unique_id": "101162515",
"other_id": null,
"pages": "1279-1283",
"pmc": null,
"pmid": "30442730",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The Adrenal Gland as a Sanctuary Site of Metastases After Pembrolizumab Treatment: A Case Series.",
"title_normalized": "the adrenal gland as a sanctuary site of metastases after pembrolizumab treatment a case series"
} | [
{
"companynumb": "US-009507513-1811USA011338",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "We report a patient who presented with acute abdominal pain during the COVID-19 pandemic. His work-up revealed rupture of a 5.8 cm abdominal aortic aneurysm. He also had fever, cough, and shortness of breath and radiologic evidence of COVID-19 infection. After careful consideration, he underwent successful endovascular repair under local anesthesia with good short-term results.",
"affiliations": "Maimonides Medical Center, Division of Vascular and Endovascular Surgery, Brooklyn, NY. Electronic address: mshih@maimonidesmed.org.;Maimonides Medical Center, Division of Vascular and Endovascular Surgery, Brooklyn, NY.;Maimonides Medical Center, Division of Vascular and Endovascular Surgery, Brooklyn, NY.",
"authors": "Shih|Michael|M|;Swearingen|Bruce|B|;Rhee|Robert|R|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.avsg.2020.05.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-5096",
"issue": "66()",
"journal": "Annals of vascular surgery",
"keywords": null,
"medline_ta": "Ann Vasc Surg",
"mesh_terms": "D017544:Aortic Aneurysm, Abdominal; D001019:Aortic Rupture; D000073640:Betacoronavirus; D019917:Blood Vessel Prosthesis Implantation; D000086382:COVID-19; D018352:Coronavirus Infections; D057510:Endovascular Procedures; D006801:Humans; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2",
"nlm_unique_id": "8703941",
"other_id": null,
"pages": "14-17",
"pmc": null,
"pmid": "32437918",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32031570;32289438;29268916;30611580;32291094;32311448;32305387;22563403",
"title": "Ruptured Abdominal Aortic Aneurysm Treated with Endovascular Repair in a Patient with Active COVID-19 Infection during the Pandemic.",
"title_normalized": "ruptured abdominal aortic aneurysm treated with endovascular repair in a patient with active covid 19 infection during the pandemic"
} | [
{
"companynumb": "US-BAYER-2020-177448",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": null,... |
{
"abstract": "OBJECTIVE\nTo better understand the risk of fatal toxic shock caused by Clostridium sordellii in women who had a recent medical abortion with mifepristone and misoprostol.\n\n\nMETHODS\nWe performed active and passive surveillance for cases of toxic shock associated with medical or spontaneous abortion. To identify the cause of toxic shock, immunohistochemical assays for multiple bacteria were performed on formalin-fixed surgical and autopsy tissues. We extracted DNA from tissues, performed Clostridium species-specific polymerase chain reaction assays, and sequenced amplified products for confirmation of Clostridium species.\n\n\nRESULTS\nWe report four patients with toxic shock associated with Clostridium species infection after medical or spontaneous abortion. Two women had fatal Clostridium perfringens infections after medically induced abortions: one with laminaria and misoprostol and one with the regimen of mifepristone and misoprostol. One woman had a nonfatal Clostridium sordellii infection after spontaneous abortion. Another woman had a fatal C sordellii infection after abortion with mifepristone and misoprostol. All four patients had a rapidly progressive illness with necrotizing endomyometritis.\n\n\nCONCLUSIONS\nToxic shock after abortion can be caused by C perfringens as well as C sordellii, can be nonfatal, and can occur after spontaneous abortion and abortion induced by medical regimens other than mifepristone and misoprostol.\n\n\nMETHODS\nIII.",
"affiliations": "Prevention and Response Branch, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA. ALCohen1@cdc.gov",
"authors": "Cohen|Adam L|AL|;Bhatnagar|Julu|J|;Reagan|Sarah|S|;Zane|Suzanne B|SB|;D'Angeli|Marisa A|MA|;Fischer|Marc|M|;Killgore|George|G|;Kwan-Gett|Tao Sheng|TS|;Blossom|David B|DB|;Shieh|Wun-Ju|WJ|;Guarner|Jeannette|J|;Jernigan|John|J|;Duchin|Jeffrey S|JS|;Zaki|Sherif R|SR|;McDonald|L Clifford|LC|",
"chemical_list": "D000019:Abortifacient Agents; D001427:Bacterial Toxins; C073548:toxin L, Clostridium sordellii; D016595:Misoprostol; D015735:Mifepristone",
"country": "United States",
"delete": false,
"doi": "10.1097/01.AOG.0000287291.19230.ba",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-7844",
"issue": "110(5)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D000019:Abortifacient Agents; D000032:Abortion, Therapeutic; D000282:Administration, Intravaginal; D001427:Bacterial Toxins; D003015:Clostridium Infections; D003016:Clostridium perfringens; D047989:Clostridium sordellii; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007795:Laminaria; D015735:Mifepristone; D016595:Misoprostol; D009336:Necrosis; D011247:Pregnancy; D012772:Shock, Septic; D014599:Uterus",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "1027-33",
"pmc": null,
"pmid": "17978116",
"pubdate": "2007-11",
"publication_types": "D002363:Case Reports; D016420:Comment; D016428:Journal Article",
"references": null,
"title": "Toxic shock associated with Clostridium sordellii and Clostridium perfringens after medical and spontaneous abortion.",
"title_normalized": "toxic shock associated with clostridium sordellii and clostridium perfringens after medical and spontaneous abortion"
} | [
{
"companynumb": "US-PFIZER INC-2017160732",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MISOPROSTOL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPrevertebral soft-tissue swelling (PSTS) after anterior cervical spine surgery may result in postoperative catastrophic airway complications and persistent dysphagia. Systemic or local corticosteroids have been used to decrease complications related to PSTS. To date, studies using retropharyngeal steroid (RS) have not reported complications with local steroids such as infection, pseudarthrosis, and other systemic adverse effects.\n\n\nOBJECTIVE\nThe aim was to report delayed esophageal perforation in two patients who underwent anterior cervical spine surgery and RS use.\n\n\nMETHODS\nThis was a case report with a review of literature.\n\n\nMETHODS\nWe presented two cases of delayed esophageal perforation without obvious cause in two patients who underwent anterior cervical spine surgery and RS use.\n\n\nRESULTS\nA 45-year-old woman underwent C5-C6 anterior cervical discectomy and fusion (ACDF) for radiculopathy. Just before closing the wound, one ampule of triamcinolone acetate was placed in the retropharyngeal space. Two months postoperatively, she presented to the emergency department with clinical symptoms of esophageal perforation. Radiographic studies demonstrated a retropharyngeal abscess. A 0.5×1.0-cm sized esophageal defect was identified during the emergency surgery. Complete healing of the esophageal defect was achieved by revision repair with reinforcement using local muscle flap. A 65-year-old man with a history of ankylosing spondylitis presented with severe dysphagia 1 year after C7 pedicle subtraction osteotomy, C2-T4 posterior instrumentation, and C6-C7 ACDF with a plate for a chin-on-chest deformity. Before closure, 1 cc of depomedrol had been placed into the wound. Eleven months postoperatively, he complained of new onset dysphagia. The endoscopic examination demonstrated an esophageal tear with visualization of the anterior cervical plate through the tear. Successful healing was possible with primary repair.\n\n\nCONCLUSIONS\nRetropharyngeal steroids have been shown to decrease PSTS and dysphagia after anterior cervical spine surgery. We believe that it would be prudent to consider avoiding the RS use in patients with a history of chronic corticosteroid use and/or soft-tissue vulnerability or only to use them with caution. Any history of dysphagia that occurs weeks, months, or even years later should be investigated for the possibility of esophageal perforation.",
"affiliations": "Department of Orthopedic Surgery, School of Medicine, Kyung Hee University, Seoul, Korea.;Department of Orthopedic Surgery, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA.;Department of Orthopedic Surgery, School of Medicine, Washington University, 660 S Euclid Ave., Campus Box 8233, St. Louis, MO 63110, USA. Electronic address: riewd@wudosis.wustl.edu.",
"authors": "Lee|Sang-Hun|SH|;Mesfin|Addisu|A|;Riew|K Daniel|KD|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1529-9430",
"issue": "15(10)",
"journal": "The spine journal : official journal of the North American Spine Society",
"keywords": "Anterior cervical fusion; Corticosteroid; Delayed esophageal perforation; Dysphagia; Prevertebral soft-tissue swelling; Retropharyngeal steroid",
"medline_ta": "Spine J",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D002574:Cervical Vertebrae; D004939:Esophageal Perforation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013123:Spinal Fusion",
"nlm_unique_id": "101130732",
"other_id": null,
"pages": "e75-80",
"pmc": null,
"pmid": "26130084",
"pubdate": "2015-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delayed esophageal perforation after anterior cervical fusion and retropharyngeal steroid use: a report of two cases.",
"title_normalized": "delayed esophageal perforation after anterior cervical fusion and retropharyngeal steroid use a report of two cases"
} | [
{
"companynumb": "KR-PFIZER INC-2015335118",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE ACETATE"
},
"drugadditiona... |
{
"abstract": "OBJECTIVE\nThe management of the drug interaction between atazanavir and tacrolimus in a renal transplant recipient is described.\n\n\nCONCLUSIONS\nA 53-year-old African-American man with human immunodeficiency virus (HIV) received a renal transplant and was treated in accordance with a corticosteroid-sparing immunosuppressive protocol and maintenance immunosuppression with mycophenolate mofetil and tacrolimus. His highly active antiretroviral therapy included atazanavir 400 mg daily, abacavir 600 mg daily, and lamivudine 100 mg daily. Because of the potential for a significant interaction between tacrolimus and atazanavir, the tacrolimus dosage was to be based on serum tacrolimus concentrations. The patient was initially administered one dose of tacrolimus 0.5 mg on the morning of postoperative day 2. Evaluation of the tacrolimus profiles revealed that a higher dosage was necessary because serum tacrolimus levels decreased to subtherapeutic levels by 6 hours after dose administration. In an attempt to minimize tacrolimus toxicity and limit the duration of a subtherapeutic tacrolimus level, dosing was adjusted to 1 mg every 8 hours. After 48 hours of this regimen, peak serum tacrolimus levels were lower, and the drug concentrations remained at a relatively steady level throughout the dosing interval. One final dosage adjustment (1.5 mg every 12 hours) was performed to optimize serum tacrolimus levels and patient compliance.\n\n\nCONCLUSIONS\nIn a 53-year-old man with HIV infection who underwent renal transplantation, the drug interaction between atazanavir and tacrolimus was managed by modifying the tacrolimus dosage regimen after determining the patient's blood tacrolimus concentration profile.",
"affiliations": "Department of Pharmacy, Kidney/Pancreas Transplant, New York–Presbyterian Hospital/Columbia University Medical Center, USA. det9021@nyp.org",
"authors": "Tsapepas|Demetra S|DS|;Webber|Allison B|AB|;Aull|Meredith J|MJ|;Figueiro|Jose M|JM|;Saal|Stuart D|SD|",
"chemical_list": "D019380:Anti-HIV Agents; D007166:Immunosuppressive Agents; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp100312",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "68(2)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D019380:Anti-HIV Agents; D000069446:Atazanavir Sulfate; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D011725:Pyridines; D016559:Tacrolimus",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "138-42",
"pmc": null,
"pmid": "21200061",
"pubdate": "2011-01-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Managing the atazanavir-tacrolimus drug interaction in a renal transplant recipient.",
"title_normalized": "managing the atazanavir tacrolimus drug interaction in a renal transplant recipient"
} | [
{
"companynumb": "NVSC2020US013749",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "To assess the prevalence and isotypes of anti-nodal/paranodal antibodies to nodal/paranodal proteins in a large chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cohort, compare clinical features in seronegative vs seropositive patients, and gather evidence of their isotype-specific pathogenic role.\n\n\n\nAntibodies to neurofascin-155 (Nfasc155), neurofascin-140/186 (Nfasc140/186), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1) were detected with ELISA and/or cell-based assay. Antibody pathogenicity was tested by immunohistochemistry on skin biopsy, intraneural injection, and cell aggregation assay.\n\n\n\nOf 342 patients with CIDP, 19 (5.5%) had antibodies against Nfasc155 (n = 9), Nfasc140/186 and Nfasc155 (n = 1), CNTN1 (n = 3), and Caspr1 (n = 6). Antibodies were absent from healthy and disease controls, including neuropathies of different causes, and were mostly detected in patients with European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite CIDP (n = 18). Predominant antibody isotypes were immunoglobulin G (IgG)4 (n = 13), IgG3 (n = 2), IgG1 (n = 2), or undetectable (n = 2). IgG4 antibody-associated phenotypes included onset before 30 years, severe neuropathy, subacute onset, tremor, sensory ataxia, and poor response to intravenous immunoglobulin (IVIG). Immunosuppressive treatments, including rituximab, cyclophosphamide, and methotrexate, proved effective if started early in IVIG-resistant IgG4-seropositive cases. Five patients with an IgG1, IgG3, or undetectable isotype showed clinical features indistinguishable from seronegative patients, including good response to IVIG. IgG4 autoantibodies were associated with morphological changes at paranodes in patients' skin biopsies. We also provided preliminary evidence from a single patient about the pathogenicity of anti-Caspr1 IgG4, showing their ability to penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN1/Caspr1 complex.\n\n\n\nOur findings confirm previous data on the tight clinico-serological correlation between antibodies to nodal/paranodal proteins and CIDP. Despite the low prevalence, testing for their presence and isotype could ultimately be part of the diagnostic workup in suspected inflammatory demyelinating neuropathy to improve diagnostic accuracy and guide treatment.\n\n\n\nThis study provides Class III evidence that antibodies to nodal/paranodal proteins identify patients with CIDP (sensitivity 6%, specificity 100%).",
"affiliations": "From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France. andrea.cortese@ucl.ac.uk.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.;From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico \"Carlo Besta,\" Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples \"Federico II,\" Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi \"Bonino Pulejo\" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences \"Luigi Sacco\" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.",
"authors": "Cortese|Andrea|A|;Lombardi|Raffaella|R|;Briani|Chiara|C|;Callegari|Ilaria|I|;Benedetti|Luana|L|;Manganelli|Fiore|F|;Luigetti|Marco|M|;Ferrari|Sergio|S|;Clerici|Angelo M|AM|;Marfia|Girolama Alessandra|GA|;Rigamonti|Andrea|A|;Carpo|Marinella|M|;Fazio|Raffaella|R|;Corbo|Massimo|M|;Mazzeo|Anna|A|;Giannini|Fabio|F|;Cosentino|Giuseppe|G|;Zardini|Elisabetta|E|;Currò|Riccardo|R|;Gastaldi|Matteo|M|;Vegezzi|Elisa|E|;Alfonsi|Enrico|E|;Berardinelli|Angela|A|;Kouton|Ludivine|L|;Manso|Constance|C|;Giannotta|Claudia|C|;Doneddu|Pietro|P|;Dacci|Patrizia|P|0000-0003-2818-203X;Piccolo|Laura|L|;Ruiz|Marta|M|;Salvalaggio|Alessandro|A|;De Michelis|Chiara|C|;Spina|Emanuele|E|;Topa|Antonietta|A|;Bisogni|Giulia|G|;Romano|Angela|A|;Mariotto|Sara|S|;Mataluni|Giorgia|G|;Cerri|Federica|F|;Stancanelli|Claudia|C|;Sabatelli|Mario|M|;Schenone|Angelo|A|;Marchioni|Enrico|E|;Lauria|Giuseppe|G|;Nobile-Orazio|Eduardo|E|;Devaux|Jérôme|J|0000-0001-6383-4334;Franciotta|Diego|D|",
"chemical_list": "D001323:Autoantibodies; C548669:CNTN1 protein, human; C491323:CNTNAP1 protein, human; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D058967:Contactin 1; D007074:Immunoglobulin G; C054305:NFASC protein, human; D009414:Nerve Growth Factors",
"country": "United States",
"delete": false,
"doi": "10.1212/NXI.0000000000000639",
"fulltext": "\n==== Front\nNeurol Neuroimmunol NeuroinflammNeurol Neuroimmunol NeuroinflammnnnNEURIMMINFLNeurology® Neuroimmunology & Neuroinflammation2332-7812Lippincott Williams & Wilkins Hagerstown, MD 31753915NEURIMMINFL201902190710.1212/NXI.0000000000000639132176181183ArticleAntibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP Clinical relevance of IgG isotypeCortese Andrea MD, PhDScientific Advisory Boards:\nPfizer Polyneuropathy Advisory Board\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nEditorial Advisory Board Member of Journal of the Peripheral Nervous System\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nInherited neuropathy consortium, which is a part of the NIH Rare Diseases Clinical Research Network (RDCRN) (U54NS065712) and Wellcome Trust (204841/Z/16/Z).\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nLombardi Raffaella MAScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nBriani Chiara MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nCallegari Ilaria MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nBenedetti Luana MD, PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nManganelli Fiore MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nLuigetti Marco MD, PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nFerrari Sergio MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nClerici Angelo M. MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nMarfia Girolama Alessandra MDScientific Advisory Boards:\nAdvisory Board Member of: (1) Biogen (2) Genzyme (3) Merck-Serono (4) Novartis (5) Teva\n\n\n\nGifts:\nNONE\n\n\n\nFunding for travel or speaker honoraria:\nTravel funding from the following commercial entities: (1) Almirall (2) Bayer Schering (3) Biogen Idec (4) Genzyme (5) Merck Serono (6) Novartis (7) Teva\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nConsultation fees from (1) Almirall (2) Bayer Schering (3) Biogen Idec (4) Genzyme (5) Merck Serono (6) Novartis (7) Teva\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nRigamonti Andrea MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nCarpo Marinella MD, PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nFazio Raffaella MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nCorbo Massimo MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nMazzeo Anna MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nGiannini Fabio MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for travel or speaker honoraria:\nCommercial entities (Pharmaceutical company: (1)Kedrion, (2)Grifols, (3)CSL, (4)Genzyme, (5)Angelini for payment of travel-related expenses and (6) Italfarmaco for educational activity Non-profit entity:(7)NIBIT Onlus Foundation for educational activity\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther activities:\n(1)Non-profit entity: Istituto Farmacologico\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\n(1) Pharmaceutical company AB Science,investigator in clinical trial(non-principal) (2)Pharmaceutical company CLS: research support for INSTANT project\n\n\n\nResearch Support, Government Entities:\n(1)Ricerca Finalizzata (Ministero Salute)2016: Project Code RF-2016-02363688 - Principal Investigator\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nCosentino Giuseppe MD, PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nZardini Elisabetta MAScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nCurrò Riccardo MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nGastaldi Matteo MD, PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nVegezzi Elisa MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nAlfonsi Enrico MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nBerardinelli Angela MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nKouton Ludivine MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nManso Constance MScScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nGiannotta Claudia MAScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nDoneddu Pietro MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for travel or speaker honoraria:\nTravel grants to attend scientific meetings from Kedrion and CSL Behring\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nhttp://orcid.org/0000-0003-2818-203XDacci Patrizia MD, PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nPiccolo Laura MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nRuiz Marta MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nSalvalaggio Alessandro MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nDe Michelis Chiara MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nSpina Emanuele MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nTopa Antonietta MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nBisogni Giulia MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nRomano Angela MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nMariotto Sara MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for travel or speaker honoraria:\n(1) Support for attending scientific meetings by Merck and Euroimmun\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nMataluni Giorgia MD, PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for travel or speaker honoraria:\nTravel funding from Kedrion, CSL Bering, Almirall, Biogen, Novartis and Sanofi- Genzyme; honoraria for speaking from Biogen. She is subinvestigator in clinical trials being conducted for Biogen, Merck Serono, Novartis, Roche and Teva\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nCerri Federica MD, PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nStancanelli Claudia MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nSabatelli Mario MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nSchenone Angelo MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nFrontiers Neurology, subeditor, 2017\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nMarchioni Enrico MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nLauria Giuseppe MDScientific Advisory Boards:\nGL served on scientific advisory board of Vertex, Biogen, Chromocell, CSL Behring\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nEditor-in-Chief, Journal of the Peripheral Nervous System, 2019-\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nNobile-Orazio Eduardo MDScientific Advisory Boards:\n1) Kedrion, Italy, 2) Baxter, Italy, 3) Novartis, Switzerland, 4) CSL-Behring, Italy and USA, 5) LFB, France, 6) Astellas, the Netherlands\n\n\n\nGifts:\nNONE\n\n\n\nFunding for travel or speaker honoraria:\n1) Kedrion, Italy, speaker honorarium 2) CSL Behring, Italy and USA, speaker honorarium\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\n1) AIFA, Ricerca Indipendente 2016:\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nhttp://orcid.org/0000-0001-6383-4334Devaux Jérôme PhD*Scientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nCSL Behring?s grant in immunology.\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\n1) Agence Nationale pour la Recherche (NECCIN)2) the Association Française contre les Myopathies (21532)\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nFranciotta Diego MD*Scientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nFrom the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico “Carlo Besta,” Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples “Federico II,” Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi “Bonino Pulejo” (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences “Luigi Sacco” (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.Correspondence Dr. Cortese andrea.cortese@ucl.ac.ukGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.\n\n* These authors contributed equally to this work.\n\nThe Article Processing Charge was funded by the MRC and Wellcome Trust.\n\n1 2020 21 11 2019 21 11 2019 7 1 e639Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.2019American Academy of NeurologyThis is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Objective\nTo assess the prevalence and isotypes of anti-nodal/paranodal antibodies to nodal/paranodal proteins in a large chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cohort, compare clinical features in seronegative vs seropositive patients, and gather evidence of their isotype-specific pathogenic role.\n\nMethods\nAntibodies to neurofascin-155 (Nfasc155), neurofascin-140/186 (Nfasc140/186), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1) were detected with ELISA and/or cell-based assay. Antibody pathogenicity was tested by immunohistochemistry on skin biopsy, intraneural injection, and cell aggregation assay.\n\nResults\nOf 342 patients with CIDP, 19 (5.5%) had antibodies against Nfasc155 (n = 9), Nfasc140/186 and Nfasc155 (n = 1), CNTN1 (n = 3), and Caspr1 (n = 6). Antibodies were absent from healthy and disease controls, including neuropathies of different causes, and were mostly detected in patients with European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite CIDP (n = 18). Predominant antibody isotypes were immunoglobulin G (IgG)4 (n = 13), IgG3 (n = 2), IgG1 (n = 2), or undetectable (n = 2). IgG4 antibody-associated phenotypes included onset before 30 years, severe neuropathy, subacute onset, tremor, sensory ataxia, and poor response to intravenous immunoglobulin (IVIG). Immunosuppressive treatments, including rituximab, cyclophosphamide, and methotrexate, proved effective if started early in IVIG-resistant IgG4-seropositive cases. Five patients with an IgG1, IgG3, or undetectable isotype showed clinical features indistinguishable from seronegative patients, including good response to IVIG. IgG4 autoantibodies were associated with morphological changes at paranodes in patients' skin biopsies. We also provided preliminary evidence from a single patient about the pathogenicity of anti-Caspr1 IgG4, showing their ability to penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN1/Caspr1 complex.\n\nConclusions\nOur findings confirm previous data on the tight clinico-serological correlation between antibodies to nodal/paranodal proteins and CIDP. Despite the low prevalence, testing for their presence and isotype could ultimately be part of the diagnostic workup in suspected inflammatory demyelinating neuropathy to improve diagnostic accuracy and guide treatment.\n\nClassification of evidence\nThis study provides Class III evidence that antibodies to nodal/paranodal proteins identify patients with CIDP (sensitivity 6%, specificity 100%).\n\nItalian Ministry of Health “Ricerca Corrente” 2017–2019 GrantRC1812CItalian Ministry of Health “Ricerca Finalizzata 2016RF-2016-02361887Wellcome Trust204841/Z/16/ZInherited Neuropathy Consortium (INC), which is a part of the NIH Rare Diseases Clinical Research Network (RDCRN)U54NS065712OPEN-ACCESSTRUE\n==== Body\nChronic inflammatory demyelinating polyradiculoneuropathy (CIDP), the most commonly acquired inflammatory neuropathy worldwide, is clinically heterogeneous. Proven treatments for CIDP include corticosteroids, plasma exchange, and intravenous immunoglobulin (IVIG). The response rates to treatments were reported to be heterogeneous in subgroups of patients, and the availability of specific biomarkers could provide guidance for patient-tailored immunotherapeutic options.1\n\nAntibodies to cell adhesion molecules of the paranodal complex, neurofascin-155 (Nfasc155), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1), and to nodal neurofascin-140/186 (Nfasc140/186) have been identified in various percentages of patients with CIDP, with IgG4 being the predominant isotype of these antibodies.2–8 Moreover, IgG4-seropositive patients show specific clinical features and a poor response to IVIG.\n\nThe prevalence of anti-CNTN1 and Nfasc155 IgG4 has been well documented in cohorts of Japanese patients.2,5,6,9,10 It has been shown that anti-CNTN1 IgG4 antibodies are pathogenic in animal models and have a function-blocking activity.11,12 Moreover, anti-CNTN1 and Nfasc155 IgG4 are associated with specific alterations of the paranodal axo-glial contacts in nerve biopsies,13,14 suggesting that these antibodies induce conduction defects in patients by altering paranode integrity, hence the term paranodopathy. In Europe, the study of these antibodies has been so far limited to small cohorts of Spanish, French, and German patients with CIDP,3,4,15,16 and there is little information on the role and associated clinical features of antibodies of the IgG1-3 isotype. Moreover, the prevalence of anti-Caspr1 antibodies is still largely unknown, as well as their possible pathogenic role.\n\nHere, we assessed the prevalence and isotypes of antibodies against Nfasc155, Nfasc140/186, CNTN1, and Caspr1 in a large cohort of Italian patients affected by CIDP to better characterize their clinical associations. We also investigated skin biopsies from antibody-reactive patients for morphological abnormalities and the pathogenicity of anti-Caspr1 antibodies using in vitro and in vivo models.\n\nMethods\nPatients and sera\nThe primary research question of this study is to test the frequency of antibodies to nodal/paranodal proteins in CIDP (Class III evidence). Sera from 342 patients fulfilling the diagnostic criteria for CIDP17 (306 typical and 36 atypical) were collected in 11 Italian centers with specific expertise in neuromuscular disorders and were all tested by ELISA and cell-based assay (CBA) for antibodies to Nfasc155 and CNTN1 and by CBA only for antibodies to Nfasc140/186 and Caspr1 by 2 independent laboratories (Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] Mondino Foundation, National Neurological Institute of Pavia, Italy, and Institute for Neurosciences of Montpellier, France). As controls, samples from healthy controls (HCs, n = 60); patients with Guillain-Barré syndrome (GBS, n = 31), multifocal motor neuropathy (MMN, n = 13), inherited neuropathy (n = 18), other noninflammatory neuropathy (n = 52) including paraproteinemic neuropathy (n = 18) and toxic-metabolic neuropathy (n = 34), and patients with MS (n = 60) were tested. Methods for ELISA18 and CBA6,10 were previously reported and are available as supplementary methods, links.lww.com/NXI/A165. Clinical information was collected from seropositive patients with CIDP and from 64 randomly selected seronegative patients with CIDP. Weakness was graded as mild if the medical research council (MRC) score of the weakest muscle considered of either proximal or distal muscle groups was <5 and >3, moderate if MRC = 3, or severe if MRC <3. Disability was graded using the Overall Neuropathy Limitation Scale (ONLS).19 Response to treatment was investigated post hoc and was defined as a persistent improvement of disability with an ONLS change after treatment ≥1. Reactivity of sera to teased fibers from murine sciatic nerves was also evaluated as previously described.2\n\nImmunohistochemistry on skin biopsy\nThree patients with anti-Nfasc155 IgG4 antibodies, 1 patient with anti-CNTN1 IgG3/IgG4 antibodies, 1 patient with anti-Caspr1 IgG4 antibodies, 1 patient with anti-Nfasc155 antibodies of an undetectable isotype, and 6 seronegative patients with CIDP underwent 3-mm punch skin biopsies at 1 distal site of the lower limb as per EFNS/PNS guidelines.20 Nodal/internodal morphological analysis was performed by double immunofluorescence staining for myelin basic protein and Nfasc or myelin basic protein and Caspr1. Detailed methods are available in supplementary methods, links.lww.com/NXI/A165.\n\nPurification of patients' antibodies\nFor in vitro and in vivo studies, IgG1 and IgG4 were purified from the serum of 1 Caspr1-reactive patient and the plasma of a HC and their pathogenicity was tested by intraneural injection on murine sciatic nerve and cell aggregation assay. Methods for in vitro and in vivo studies are detailed in supplementary methods, links.lww.com/NXI/A164.\n\nStatistics\nClinical data were presented as number (%) or mean (min-max). Categorical variables were compared in seronegative and seropositive patients using the χ2 test or Fisher exact test; unpaired 2-tailed Student t test was used for comparing continuous variables. Analysis of clinical variables was performed using STATA. p values inferior to 0.05 were considered significant.\n\nStandard protocol approvals, registrations, and patient consents\nThe study was approved by local institutional ethical committees. Written informed consent was obtained from all patients (or guardians of patients) participating in the study.\n\nData availability\nAnonymized data from this study will be shared by request from any qualified investigator.\n\nResults\nSerologic findings\nOf 342 sera from patients with CIDP tested, 10 (3%) were positive for antibodies to anti-Nfasc155 using ELISA and CBA (figure 1A). IgG isotypes were IgG4 in 7, IgG3 in 1, and undetectable in 2 patients (figure 1B). One of these latter patients showed IgG4 reactivity against Nfasc140/186 and was thus considered a Nfasc140/186-reactive patient. Three patients (1%) tested positive on ELISA and CBA for anti-CNTN1 antibodies (figure 1A). IgG isotypes were IgG4 in 2 patients and mixed IgG3/IgG4 in 1 patient (figure 1B). All sera reactive to Nfasc155 or CNTN1 by ELISA were also confirmed by CBA, and no nonspecific reactivities by ELISA only were identified. Six patients (2%) showed reactivity against Caspr1 on CBA (figure 1C). Three had an IgG4-predominant isotype, 2 had an IgG1 isotype, and 1 did not have a detectable isotype. Overall, 19 patients (6%) had antibodies against one of these 4 targets. None of the HCs and patients with GBS, MMN, hereditary neuropathy, other noninflammatory neuropathies, or MS tested positive, indicating that the presence of antibodies to nodal/paranodal proteins accurately identify patients with CIDP with sensitivity 6% and specificity 100%. Of note, none of the sera from 36 atypical CIDP cases tested positive.\n\nFigure 1 Reactivity to Nfasc155, CNTN1, and Caspr1 in CIDP by ELISA and CBA\n(A) Serum samples from patients with CIDP (n = 342), MMN (n = 13), GBS (n = 31), genetic PN (n = 18), other noninflammatory PN (n = 52), MS (n = 60) and from HCs (n = 60) were tested for autoantibodies to human Nfasc155 (left) and CNTN1 (right) by ELISA. OD are shown after subtraction of the baseline OD reading to bovine serum albumin. The red line represents the mean OD in HCs plus 3 standard deviations. (B) IgG isotype in Nfasc155- and CNTN1-positive patients. (C) The sera (here case 14) were tested on living HEK cells transfected with CNTN1 and Caspr1 (red) and then revealed with mouse antihuman IgG1, IgG2, IgG3, or IgG4 (green) as indicated. Nuclei were stained with DAPI (blue). (D) These are teased fibers from mouse sciatic nerves immunostained for CNTN1 (red) and the serum from case 14, then revealed with mouse antihuman IgG1, IgG2, IgG3, or IgG4 (green) as indicated. IgG1 and IgG4 from this patient reacted against Caspr1 and bound to the paranodal regions. Scale bars: 10 μm. Caspr1 = contactin-associated protein 1; CBA = cell-based assay; CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; CNTN1 = contactin-1; GBS = Guillain-Barré syndrome; HC = healthy control; HEK = human embryonic kidney; MMN = multifocal motor neuropathy; Nfasc155 = neurofascin-155; OD = Optical density; PN = peripheral neuropathy.\n\nSera from patients with IgG4 anti-Nfasc155, anti-CNTN1, or anti-Caspr1 antibodies, but not anti-Nfasc155 of the IgG3 isotype or undetectable isotype, consistently showed reactivity against paranodes when tested on teased fibers from murine sciatic nerves (figure 1D). Sera with anti-Nfasc140/186 IgG4 that co-reacted against Nfasc155 stained the nodes of Ranvier on teased fibers.\n\nClinical features\nPatients with anti-Nfasc155 IgG4 antibodies\nOf patients with anti-Nfasc155 IgG4 antibodies, 4 were men and 3 were women, with an average age at onset of 31 ± 18 years (table e-1, links.lww.com/NXI/A164). The onset of neuropathy was subacute in 5 patients. One case was initially diagnosed with GBS.\n\nAll patients had symmetric 4-limb muscle weakness, which was mild to moderate in the upper limbs and proximal muscles of the lower limbs but severe in 5 patients in the lower limb distal muscles. Pinprick and position sense at the hallux were reduced or abolished in all patients. Tremor was also invariably present, and 6 had sensory ataxia. One patient reported neuropathic pain at onset, and 1 had dysphagia. One of them presented optic neuritis during steroid tapering. Brain MRI was thus performed but did not show evidence of disseminated inflammatory CNS disease. The neuropathy was moderately to severely disabling with an ONLS at onset of 5.8 ± 2.2. Two patients required a wheelchair 1 month after the disease onset. The patients received IVIG (n = 6), steroids (n = 7), azathioprine (n = 1), or rituximab (n = 1). Only 1 patient responded to IVIG and steroids (ONLS 4 → 2), 1 patient showed response to steroids (ONLS 6 → 2), and 1 patient unresponsive to IVIG and steroids had sustained response after rituximab (ONLS 9 → 2).\n\nPatients with anti-CNTN1 IgG4 antibodies\nOf patients with anti-CNTN1 IgG4 antibodies, 3 were men with a mean age at onset of 56 ± 26 years (table e-1, links.lww.com/NXI/A164). The onset of neuropathy was subacute in 2 patients. Strength was impaired in both proximal and distal muscles in the upper and lower limbs, often to a severe degree, and 2 of them required a wheelchair. Pinprick sensation and proprioception were either severely reduced or abolished, and all of them had sensory ataxia. One patient showed cranial nerve involvement and respiratory failure. One patient with anti-CNTN1 IgG3/IgG4 antibodies had a concurrent onset of CIDP and nephrotic syndrome because of membranous glomerulonephritis. A kidney biopsy showed subepithelial deposits of immune complexes and complement deposition. CNTN1 patients had the highest disability at onset with an ONLS of 7.6 ± 2.5. One patient died of cardiac disease 6 months after the disease onset. The patients were treated with IVIG (n = 3), steroids (n = 3), plasma exchange (n = 2), and immunosuppressive drugs (n = 2). None of them had a sustained response to either IVIG or steroids. Cyclophosphamide was effective in 2 patients, leading to significant improvement of the neuropathy in 1 case and complete remission of the neuropathy together with regression of the nephrotic syndrome in the other case, who did not require further treatment.\n\nPatients with anti-Caspr1 IgG4 antibodies\nOf seropositive patients with anti-Caspr1 IgG4 antibodies, 2 were men and 1 was a woman, with a mean age at onset of 43 ± 17 years (table e-1, links.lww.com/NXI/A164). The onset was subacute in 2 patients. Weakness was mild to moderate in proximal muscle groups and moderate to severe in distal muscle groups in both upper and lower limbs. Pinprick sensation was reduced, and position sense was abolished at the hallux in all of them. None of them reported neuropathic pain. One patient complained of dysphagia, and 1 patient had tremor. The disease was severe, with a mean ONLS of 8.3 ± 0.6. The patients were treated with IVIG (n = 3), steroids (n = 3), plasma exchange (n = 1), methotrexate (n = 1), and interferon-alfa (n = 1). A sustained response was observed only in 1 patient receiving steroids and methotrexate (ONLS 9 → 6) and 1 patient treated with interferon-alfa (ONLS 8 → 7).\n\nSeropositive patients with an IgG1-3 isotype or undetectable IgG isotype\nSix patients had IgG1 or IgG3 antibodies or an undetectable IgG isotype against Nfasc155 (n = 3) or Caspr1 (n = 3) (table e-1, links.lww.com/NXI/A164). One of these patients presented antibodies reacting to both Nfasc155 and Nfasc140/186. The clinical features of this patient, mainly consisting in a very early onset IVIG-responsive neuropathy, have been previously detailed.16 We will thus focus here on the 5 other patients, 2 men and 3 women. In 2 of them, both reactive against Caspr1, the disease started in the first decade of life. The mode of onset was subacute in 1 patient only. If present, weakness was graded as mild to moderate in upper limbs and proximal muscles of lower limbs. All 5 patients had weakness in lower limb distal muscles, which was severe in 2 of them. Pinprick sensation was reduced in 3 and position sense was reduced at the hallux in 2 patients, but none had absent proprioception. Sensory ataxia was reported in 4 patients, 2 with anti-Nfasc155 antibodies and 2 with anti-Caspr1 antibodies, whereas tremor was observed in 2 patients with anti-Caspr1 antibodies. Disability was usually low with a mean ONLS at onset of 3.2 ± 1.3. Only 1 case with anti-Caspr1 antibodies needed walking aids. The patients were treated with IVIG (n = 4) and steroids (n = 2). One patient with minimal disability did not require treatment. Three of 4 patients treated with IVIG had a good response.\n\nComparison of seropositive vs seronegative patients\nWe compared the clinical features and responses to treatments of patients with IgG4 antibodies against Nfasc155, CNTN1, or Caspr1 with those of 64 randomly selected patients with CIDP who were negative for antibodies against Nfasc155, Nfasc140/186, CNTN1, or Caspr1. We also compared seropositive patients with an IgG1, IgG3, or undetectable IgG isotype with seronegative patients (table 1).\n\nTable 1 Clinical features of patients with CIDP and antibodies to Nfasc155, CNTN1, and Caspr1\n\nAnti-Nfasc155 and anti-Caspr1 IgG4 seropositive patients had more frequently an early disease onset, before 30 years of age, as opposed to that of anti-CNTN1 IgG4 seropositive patients and seronegative patients. A subacute onset was reported in up to two-thirds of anti-Nfasc155, anti-CNTN1, and anti-Caspr1 IgG4 seropositive patients compared with 28% of seronegative patients. According to the EFNS/PNS criteria, CIDP phenotype was typical in all IgG4-seropositive patients. Tremor was invariably present in patients with anti-Nfasc155 IgG4 antibodies but was also observed in anti-CNTN1 and anti-Caspr1 IgG4 seropositive patients. Severe proprioceptive loss and sensory ataxia were significantly more frequent in IgG4-seropositive patients and were observed in all patients with anti-CNTN1 antibodies, 2 patients with anti-Caspr1 IgG4 antibodies, and 3 patients with anti-Nfasc155 IgG4 antibodies (table 1). In anti-CNTN1 and anti-Caspr1 IgG4 seropositive patients, weakness was usually graded as moderate to severe across proximal and distal muscle groups, whereas in patients with anti-Nfasc155 IgG4 antibodies, motor impairment showed a characteristic distal predominance in the lower limbs.\n\nA higher level of CSF total protein and the presence of temporal dispersion on nerve conduction studies were also characteristic features of patients with autoantibodies of the IgG4 isotype. IgG4-seropositive patients had a higher disability at onset: 5 patients needed a walking aid, and 5 patients required a wheelchair. In particular, patients with anti-CNTN1 or anti-Caspr1 IgG4 antibodies showed the highest disability at onset.\n\nPatients with anti-Nfasc155, CNTN1, or Caspr1 IgG4 antibodies had a lower response rate to IVIG compared with seronegative patients (8% vs 67%, p < 0.001), but there was no remarkable difference in the response to steroids or immunosuppressive treatment. In particular, 1 patient with anti-Nfasc155 IgG4 antibodies was treated with rituximab, 1 patient with anti-Nfasc155 IgG4 antibodies was treated with azathioprine, 2 patients with anti-CNTN1 IgG4 antibodies were treated with cyclophosphamide, and 1 patient with anti-Caspr1 IgG4 antibodies was treated with methotrexate. Four of them who were started on immunosuppressors within 1 year from disease onset showed long-lasting good response.\n\nPatients with antibodies to Nfasc155, CNTN1, or Caspr1 of the IgG1, IgG3, or undetectable isotype did not show distinct clinical features or response to treatments compared with seronegative patients, except for more frequent temporal dispersion on nerve conduction studies.\n\nMorphological changes of the nodes of Ranvier in skin biopsy of seropositive patients\nWe evaluated skin biopsies from 3 patients with anti-Nfasc155 IgG4 antibodies, 1 patient with anti-CNTN1 IgG3/IgG4 antibodies, 1 patient with anti-Caspr1 IgG4 antibodies, 1 patient with anti-Nfasc155 antibodies of an undetectable isotype, and 6 seronegative patients with CIDP. Analysis of myelinated fibers from patients with anti-Nfasc155 and anti-Caspr1 IgG4 showed elongation of the nodes of Ranvier and loss of paranodal Nfasc155 and Caspr1 staining. Moderate elongation of the nodes of Ranvier and loss of Nfasc155 paranodal staining were also observed in myelinated fibers of the patient with anti-CNTN1 IgG3/IgG4 antibodies. Contrarily, we did not observe similar changes in the patient with anti-Nfasc155 antibodies with an undetectable isotype, seronegative patients CIDP, or HCs (figure 2).\n\nFigure 2 Morphological alterations of the nodes of Ranvier in patients with CIDP with IgG4 autoantibodies\nWe evaluated skin biopsies from 3 patients with IgG4 anti-Nfasc155 antibodies, 1 patient with IgG3/IgG4 anti-CNTN1 antibodies, 1 patient with IgG4 anti-Caspr1 antibodies, 1 patient with undetectable isotype IgG anti-Nfasc155, and 6 seronegative patients with CIDP. Analysis of myelinated fibers showed elongation of the nodes of Ranvier and loss of paranodal Nfasc155 staining in skin biopsies from patients with anti-Nfasc155 (C) and Caspr1 (E) IgG4. Moderate elongation of the nodes of Ranvier and loss of Nfasc155 paranodal staining were also observed in myelinated fibers of a CNTN1 IgG3/IgG4-positive patient (D). Contrarily, we did not observe similar changes in the patient with undetectable isotype IgG anti-Nfasc155 antibodies (F), in seronegative patients with CIDP (B), or in HCs (A). A complete loss of Caspr1 staining was observed in biopsies from patients with IgG4 antibodies to paranodal proteins (I, L, M), but not in an Nfasc155 seropositive patient with an undetectable isotype (N) and in seronegative CIDP (H) or healthy patients (G). Caspr1 = contactin-associated protein 1; CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; CNTN1 = contactin-1; HC = healthy control; Nfasc155 = neurofascin-155.\n\nPathogenic effects of anti-Caspr1 IgG4 and IgG1 antibodies\nAnti-CNTN1 IgG4 antibodies were previously found to have function-blocking activity and to disrupt the interaction between CNTN1 and its glial partner Nfasc155.12 We have previously shown that anti-CNTN1 IgG4 and anti-Nfasc155 IgG4 antibodies are pathogenic and disrupt the paranodal regions.11,21 We thus examined whether anti-Caspr1 antibodies also affect the integrity of the CNTN1/Caspr1/Nfasc155 complex. In particular, we purified IgG1 and IgG4 and tested the effects of the different antibody isotypes. First, we tested the impact of IgG4 and IgG1 fractions from Caspr1-positive patients on the interaction of CNTN1/Caspr1 with Nfasc155 by a cell aggregation assay (figure 3). Human embryonic kidney cells were transfected with Nfasc155 and mCherry and incubated for 2 hours with cells coexpressing CNTN1/Caspr1 and green fluorescent protein (GFP). The percentage of cell clusters showing contacts between red and green cells and the percentage of green and red cells per cell clusters were quantified. As a negative control, Nfasc155-mCherry-transfected cells were incubated with cells expressing GFP only. In the absence of CNTN1/Caspr1, Nfasc155-expressing cells do not form significant contact with GFP-expressing cells, and most clusters express only green or red cells. The expression of CNTN1/Caspr1 significantly increases the number of clusters with contacts, and most cell clusters show an average of 50% of CNTN1/Caspr1- and 50% of Nfasc155-expressing cells. The presence of 10 μg of IgG4 from a Caspr1-positive patient, but not IgG1, abolished the interaction between CNTN1/Caspr1- and Nfasc155-expressing cells to the level of negative controls, thus supporting a blocking function of anti-Caspr1 IgG4 antibodies.\n\nFigure 3 IgG4 to Caspr1 disrupt the interaction between Nfasc155 and CNTN1/Caspr1\n(A–D) HEK cells transfected with CNTN1 and Caspr1 (green) or Nfasc155 (red) were incubated together for 2 hours in the presence of control IgG4 (B), anti-Caspr1 IgG1 (C), or anti-Caspr1 IgG4 (D). As negative controls, HEK cells transfected with Nfasc155 (red) were incubated with cells transfected with GFP (A). Anti-Caspr1 IgG4, but not anti-Caspr1 IgG1, abrogated the aggregation of Nfasc155-transfected cells with CNTN1/Caspr1. Scale bar: 10 μm. (E–F) The graphs represent the relative frequency of green cells per aggregates (n = 4 experiments for each condition). The percentage of cell clusters with contacts between green and red cells was quantified (F). The percentage of contacts was significantly decreased in the presence of anti-Caspr1 IgG4 (p < 0.005 by unpaired 2-tailed Student t tests and by one-way ANOVA, followed by Bonferroni post hoc tests). Bars represent mean and SEM. ANOVA = analysis of variance; Caspr1 = contactin-associated protein 1; CNTN1 = contactin-1; GFP = green fluorescent protein; HEK = human embryonic kidney; Nfasc155 = neurofascin-155.\n\nTo further confirm these findings, mouse sciatic nerve segments were incubated in vitro with 10 μg of IgG4 or IgG1 fractions from Caspr1-positive patients for 3 hours, and IgG deposition was monitored. IgG4 but not IgG1 antibodies were found to penetrate the paranodal regions (figure 4). These findings were replicated in vivo by performing intraneural injections. Again, only IgG4 antibodies were found to penetrate the paranodal regions. Of interest, the level of antibody penetration across the paranodal region was similar at 1 or 3 days after intraneural injection, and IgG4 deposition was detected only at the border of the nodes of Ranvier (figure 4). No paranodes presented a complete invasion by IgG4 at 1 or 3 days postinjection.\n\nFigure 4 Anti-Caspr1 IgG4, but not IgG1, invades the paranodal regions\n(A–C) Sciatic nerve fibers were incubated in vitro with purified control IgG4 (A), anti-Caspr1 IgG1 (B), or anti-Caspr1 IgG4 (C) for 3 hours and immunolabeled for IgG (green) and CNTN1 (red). (D–F) Sciatic nerves were fixed 1 or 3 days after intraneural injections of purified control IgG4 (D), anti-Caspr1 IgG4 (E–F), immunolabeled for CNTN1 (red), and human IgG (green). Note that only anti-Caspr1 IgG4 penetrated the paranodes. One or 3 days after injection, IgG4 antibodies were detected at the paranode borders (arrows). Images are representative of 3 independent experiments. Scale bar: 10 μm. Caspr1 = contactin-associated protein 1; CNTN1 = contactin-1.\n\nDiscussion\nAntibodies to nodal/paranodal protein were found, albeit with a low frequency, in Italian patients with CIDP and are associated with target- and isotype-specific clinical features, as previously reported. The prevalence of anti-Nfasc155 and anti-CNTN1 antibodies was similar to that reported by previous studies in European patients but was lower compared with that in Japanese patients.5,10 The discrepancy may be attributable to differences in inclusion criteria, ethnicities, and nonstandardized laboratory techniques. The frequency of anti-Caspr1 IgG4 antibodies was equal to that of antibodies against CNTN1, confirming that Caspr1 may also represent a relevant target of the immune response in Caucasian patients with CIDP. None of the healthy or pathologic controls tested, including patients affected by other neuropathies, showed reactivity against Nfasc155, CNTN1, or Caspr1. These maximum levels of specificity entail that the tests perform very well for the diagnosis of such CIDP subtypes.\n\nIn addition, it is worth noting that the results of antibody testing by ELISA and CBA were concordant in all samples across the 2 testing centers in Pavia and Montpellier, indicating that these techniques, although not broadly available, have a high reproducibility if performed in specialized centers.\n\nOur findings largely confirm previous observations by several groups showing a tight clinical serologic correlation of antibodies to nodal/paranodal proteins and clinical features of seropositive patients with CIDP.\n\nThe patients with anti-Nfasc155 IgG4 antibodies showed earlier onset, distal predominant lower limb weakness, and gait disturbance. Tremor was also present, although only in 1 case this was disabling. One patient with such antibodies developed bilateral optic neuritis during steroid tapering 18 months after the onset of the neuropathy.\n\nThe patients with anti-CNTN1 antibodies were older and showed a subacute or rapidly progressive severe sensory and motor neuropathy. Previous studies found that anti-CNTN1 antibodies were associated with either predominant motor or sensory impairment. Here, both sensory and motor fibers were equally severely affected, and the patients became wheelchair dependent few months after the disease onset. Notably, 1 patient with anti-CNTN1 antibodies of IgG3 and IgG4 subclasses showed the contemporary occurrence of membranous glomerulonephritis. This association had been reported in 3 cases with anti-CNTN1 antibodies,7,22,23 and either a direct damage or indirect damage, after the deposition of immune complexes, can be hypothesized. Of interest, a recent study showed that complement deposition may contribute to the pathophysiology of anti-CNTN1-associated neuropathy, particularly in patients with a predominance of the IgG3 subclass.24\n\nNeuropathy in patients with anti-Caspr1 IgG4 antibodies was also highly debilitating. Pain did not seem to be a clinical feature associated with the presence of anti-Caspr1 antibodies in our series, as opposed to the first report of 2 patients with Caspr1-associated inflammatory neuropathy.8\n\nAs a novel observation of our study, we found that patients with anti-Nfasc155 or Caspr1 antibodies of the IgG1, IgG3, or undetectable IgG isotype did not show clinical features distinct from seronegative patients. Most importantly, patients with anti-Nfasc155, CNTN1, or Caspr1 IgG4 antibodies, but not patients with antibodies to Nfasc155 or Caspr1 of IgG1, IgG3, or undetectable IgG isotype, showed a significantly lower response rate to IVIG compared with seronegative patients.\n\nAnalysis of myelinated fibers in the skin biopsy of patients with anti-Nfasc155, CNTN1, or Caspr1 IgG4 antibodies showed morphological changes of the nodes of Ranvier, including elongation of the node and loss of neurofascin and Caspr1 staining at paranodes, which were absent or less prominent in seronegative CIDP cases or in the case with anti-Nfasc155 antibodies of an undetectable isotype. These data add to other recent histopathologic and neurophysiologic observations in patients with antibodies to nodal/paranodal proteins14,25 and indicate that isotype determination appears to be crucial to correctly identify such patients and to guide treatment.\n\nThe high frequency of anti-Caspr1 antibodies in our series prompted us to further investigate their pathogenic effects. Albeit the experimental setting was limited to the examination of the effects of anti-Caspr1 autoantibodies from a single patient, we found that anti-Caspr1 IgG4, but not anti-Caspr1 IgG1, antibodies affect the interaction between the CNTN1/Caspr1 and Nfasc155 complex using a cell aggregation assay. These findings are in line with the previously reported pathogenic role of anti-CNTN1 IgG4 antibodies11,12 and suggest that IgG4 antibodies targeting the CNTN1/Caspr1 complex may have a function-blocking activity and disrupt the paranodal axo-glial contact. In keeping with this experimental evidence, our data also seem to indicate that anti-Caspr1 IgG4 antibodies can penetrate the paranodal regions. It is worth noting that the pathogenic mechanism of IgG4 antibodies in other diseases implicates the disruption of cell adhesion protein complexes too, by inhibiting protein-protein interaction, and that therapies aiming at downregulating the humoral immune response, such as rituximab, showed some efficacy in anti-Nfasc155- and anti-Caspr1 antibody-associated CIDP, as well as in other IgG4-related diseases, likely because of the depletion of the Nfasc155- or Caspr1-reactive B cells.26\n\nDespite the limitation entailed by the retrospective data collection, in the present series, immunosuppressive treatment, including rituximab, cyclophosphamide, and methotrexate, seemed effective in IVIg-resistant IgG4 seropositive patients if started early in the disease course. Of note, we did not detect a significant difference in the response to steroids between patients with anti-paranodal IgG4 antibodies and seronegative patients, confirming steroids as an effective therapeutic option in CIDP cases, independent from their serologic status for anti-Nfasc155, CNTN1, or Caspr1 antibodies. Low numbers of patients treated with plasma exchange, and the temporal overlap of plasma exchange cycles with other treatments (case 12), prevented us from drawing firm conclusions on its role in patients with antiparanodal IgG4 antibodies.\n\nAlthough patients with antibodies against the nodal/paranodal component often, albeit not always, show additional clinical features, CIDP phenotype was typical in all IgG4 and non-IgG4 seropositive patients according to the EFNS/PNS criteria, whereas none of the sera from atypical CIDP cases or control sera showed the presence of these antibodies. Together, this observation challenges the view that the search for antibodies against the nodal/paranodal component may be limited to atypical CIDP cases.\n\nTesting for the presence of antibodies against Nfasc155, CNTN1, and Caspr1, followed by IgG isotype determination in seropositive cases should be part of the diagnostic workup in inflammatory neuropathies to improve diagnostic accuracy and guide treatment. Moreover, knowledge of the mechanism underlying these CIDP subtypes might shed light on the pathophysiology and help further understanding of this complex and heterogeneous disease.\n\nClass of Evidence: NPub.org/coe\n\nStudy funding\nThis work was supported by the Italian Ministry of Health “Ricerca Corrente” 2017–2019 Grant (Grant code: RC1812C) to the IRCCS Mondino Foundation, GBS/CIDP Foundation Non-profit Grant 2017 Grant code: 501(c)(3) to Fondazione IRCCS Istituto Neurologico Carlo Besta, and Agence Nationale pour la Recherche (NECCIN; JD) and by the Association Française contre les Myopathies (grant#21532; JD), the Italian Ministry of Health “Ricerca Finalizzata 2016 (Grant code: RF-2016-02361887) to Humanitas Clinical and Research Center, IRCCS. Andrea Cortese is funded by MRC (MR/T001712/1) and received funding from Wellcome Trust (204841/Z/16/Z) and the Inherited Neuropathy Consortium (INC), which is a part of the NIH Rare Diseases Clinical Research Network (RDCRN) (U54NS065712).\n\nDisclosure\nThe authors report no disclosures. Go to Neurology.org/NN for full disclosures.\n\nAppendix Authors\n\n\nGlossary\nCaspr1contactin-associated protein 1\n\nCBAcell-based assay\n\nCIDPchronic inflammatory demyelinating polyradiculoneuropathy\n\nCNTN1contactin-1\n\nEFNS/PNSEuropean Federation of Neurological Societies/Peripheral Nerve Society\n\nGBSGuillain-Barré syndrome\n\nGFPgreen fluorescent protein\n\nHChealthy control\n\nIVIGintravenous immunoglobulin\n\nMMNmultifocal motor neuropathy\n\nMRCmedical research council\n\nNfasc155neurofascin-155\n\nONLSOverall Neuropathy Limitation Scale\n\nPNperipheral neuropathy\n==== Refs\nReferences\n1. Doneddu PE , Cocito D , Manganelli F , et al \nAtypical CIDP: diagnostic criteria, progression and treatment response. Data from the Italian CIDP database . J Neurol Neurosurg Psychiatry \n2019 ;90 :125 –132 .30297520 \n2. Devaux JJ , Odaka M , Yuki N \nNodal proteins are target antigens in Guillain-Barré syndrome . J Peripher Nerv Syst \n2012 ;17 :62 –71 .22462667 \n3. Querol L , Nogales-Gadea G , Rojas-Garcia R , et al \nAntibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy . Ann Neurol \n2013 ;73 :370 –380 .23280477 \n4. Querol L , Nogales-Gadea G , Rojas-Garcia R , et al \nNeurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg . Neurology \n2014 ;82 :879 –886 .24523485 \n5. Ogata H , Yamasaki R , Hiwatashi A , et al \nCharacterization of IgG4 anti-neurofascin 155 antibody-positive polyneuropathy . Ann Clin Transl Neurol \n2015 ;2 :960 –971 .26478896 \n6. Miura Y , Devaux JJ , Fukami Y , et al ; CNTN1-CIDP Study Group . Contactin 1 IgG4 associates to chronic inflammatory demyelinating polyneuropathy with sensory ataxia . Brain \n2015 ;138 :1484 –1491 .25808373 \n7. Doppler K , Werner C , Sommer C \nDisruption of nodal architecture in skin biopsies of patients with demyelinating neuropathies . J Peripher Nerv Syst \n2013 ;18 :168 –176 .23781964 \n8. Doppler K , Appeltshauser L , Villmann C , et al \nAuto-antibodies to contactin-associated protein 1 (Caspr) in two patients with painful inflammatory neuropathy . Brain \n2016 ;139 :2617 –2630 .27474220 \n9. Kadoya M , Kaida K , Koike H , et al \nIgG4 anti-neurofascin155 antibodies in chronic inflammatory demyelinating polyradiculoneuropathy: clinical significance and diagnostic utility of a conventional assay . J Neuroimmunol \n2016 ;301 :16 –22 .27852440 \n10. Devaux JJ , Miura Y , Fukami Y , et al \nNeurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy . Neurology \n2016 ;86 :800 –807 .26843559 \n11. Manso C , Querol L , Mekaouche M , Illa I , Devaux JJ \nContactin-1 IgG4 antibodies cause paranode dismantling and conduction defects . Brain \n2016 ;139 :1700 –1712 .27017186 \n12. Labasque M , Hivert B , Nogales-Gadea G , Querol L , Illa I , Faivre-Sarrailh C \nSpecific contactin N-glycans are implicated in neurofascin binding and autoimmune targeting in peripheral neuropathies . J Biol Chem \n2014 ;289 :7907 –7918 .24497634 \n13. Koike H , Kadoya M , Kaida KI , et al \nParanodal dissection in chronic inflammatory demyelinating polyneuropathy with anti-neurofascin-155 and anti-contactin-1 antibodies . J Neurol Neurosurg Psychiatry \n2017 ;88 :465 –473 .28073817 \n14. Vallat JM , Yuki N , Sekiguchi K , et al \nParanodal lesions in chronic inflammatory demyelinating polyneuropathy associated with anti-neurofascin 155 antibodies . Neuromuscul Disord \n2017 ;27 :290 –293 .27986399 \n15. Ng JK , Malotka J , Kawakami N , et al \nNeurofascin as a target for autoantibodies in peripheral neuropathies . Neurology \n2012 ;79 :2241 –2248 .23100406 \n16. Delmont E , Manso C , Querol L , et al \nAutoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy . Brain \n2017 ;140 :1851 –1858 .28575198 \n17. Joint Task Force of the EFNS and the PNS . European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society—first revision . J Peripher Nerv Syst \n2010 ;15 :1 –9 .\n18. Cortese A , Devaux JJ , Zardini E , et al \nNeurofascin-155 as a putative antigen in combined central and peripheral demyelination . Neurol Neuroimmunol Neuroinflamm \n2016 ;3 :e238 \ndoi: 10.1212/NXI.0000000000000238.27308303 \n19. Graham RC , Hughes RA \nA modified peripheral neuropathy scale: the overall neuropathy limitations scale . J Neurol Neurosurg Psychiatry \n2006 ;77 :973 –976 .16574730 \n20. Lauria G , Hsieh ST , Johansson O , et al ; European Federation of Neurological Societies; Peripheral Nerve Society . European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society . Eur J Neurol \n2010 ;17 :903 –912 , e44–49.20642627 \n21. Manso C , Querol L , Lleixà C , et al \nAnti-neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo . J Clin Invest \n2019 ;130 :2222 –2236 .\n22. Taieb G , Le Quintrec M , Pialot A , et al \n“Neuro-renal syndrome” related to anti-contactin-1 antibodies . Muscle Nerve \n2019 ;59 :E19 –E21 .30488516 \n23. Hashimoto Y , Ogata H , Yamasaki R , et al \nChronic inflammatory demyelinating polyneuropathy with concurrent membranous Nephropathy: an anti-paranode and podocyte protein antibody study and literature Survey . Front Neurol \n2018 ;9 :997 .30538665 \n24. Appeltshauser L , Weishaupt A , Sommer C , Doppler K \nComplement deposition induced by binding of anti-contactin-1 auto-antibodies is modified by immunoglobulins . Exp Neurol \n2017 ;287 :84 –90 .27746185 \n25. Uncini A , Vallat JM \nAutoimmune nodo-paranodopathies of peripheral nerve: the concept is gaining ground . J Neurol Neurosurg Psychiatry \n2018 ;89 :627 –635 .29248893 \n26. Querol L , Rojas-García R , Diaz-Manera J , et al \nRituximab in treatment-resistant CIDP with antibodies against paranodal proteins . Neurol Neuroimmunol Neuroinflamm \n2015 ;2 :e149 \ndoi: 10.1212/NXI.0000000000000149.26401517\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2332-7812",
"issue": "7(1)",
"journal": "Neurology(R) neuroimmunology & neuroinflammation",
"keywords": null,
"medline_ta": "Neurol Neuroimmunol Neuroinflamm",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D058967:Contactin 1; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D008297:Male; D009414:Nerve Growth Factors; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating",
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"pmid": "31753915",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "27986399;22462667;26478896;24523485;24497634;26843559;27852440;30297520;27017186;27746185;16574730;20642627;30488516;23100406;30538665;26401517;23280477;29248893;30869655;27308303;28073817;20433600;27474220;25808373;28575198;23781964",
"title": "Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP: Clinical relevance of IgG isotype.",
"title_normalized": "antibodies to neurofascin contactin 1 and contactin associated protein 1 in cidp clinical relevance of igg isotype"
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"abstract": "We report a rare case of severe acute rhabdomyolysis in association with coadministration of levofloxacin and simvastatin in a patient with normal renal function. A 70-year-old Caucasian male was treated due to community acquired pneumonia with levofloxacin in a dosage of 500 mg once and then twice a day. On the 8th day of hospitalization the patient presented with acute severe rhabdomyolysis requiring an intensive care support. After discontinuation of levofloxacin and concomitant medication with simvastatin 80 mg/day, clinical and laboratory effects were totally reversible. Up to now, levofloxacin has been reported to induce rhabdomyolysis mainly in patients with impaired renal function, as the medication has a predominant renal elimination. In our case renal function remained normal during the severe clinical course. According to a recent case report rhabdomyolysis was observed due to interaction of simvastatin and ciprofloxacin. To our best knowledge this is the first case of interaction between simvastatin and levofloxacin to be reported. This case emphasizes the need of close monitoring of creatine kinase in patients under more than one potentially myotoxic medication especially when patients develop muscle weakness.",
"affiliations": "Department of Pulmonary Diseases, General Hospital Kassel, Kassel School of Medicine, Mönchebergstraße 41-43, 53125 Kassel, Germany.;Department of Pulmonary Diseases, General Hospital Kassel, Kassel School of Medicine, Mönchebergstraße 41-43, 53125 Kassel, Germany.;Department of Pulmonary Diseases, General Hospital Kassel, Kassel School of Medicine, Mönchebergstraße 41-43, 53125 Kassel, Germany.",
"authors": "Paparoupa|Maria|M|;Pietrzak|Sebastian|S|;Gillissen|Adrian|A|",
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"doi": "10.1155/2014/562929",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2014/562929Case ReportAcute Rhabdomyolysis Associated with Coadministration of Levofloxacin and Simvastatin in a Patient with Normal Renal Function Paparoupa Maria *Pietrzak Sebastian Gillissen Adrian Department of Pulmonary Diseases, General Hospital Kassel, Kassel School of Medicine, Mönchebergstraße 41-43, 53125 Kassel, Germany*Maria Paparoupa: maria.paparoupa@yahoo.comAcademic Editor: Gerald S. Supinski\n\n2014 22 7 2014 2014 5629298 5 2014 11 7 2014 Copyright © 2014 Maria Paparoupa et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We report a rare case of severe acute rhabdomyolysis in association with coadministration of levofloxacin and simvastatin in a patient with normal renal function. A 70-year-old Caucasian male was treated due to community acquired pneumonia with levofloxacin in a dosage of 500 mg once and then twice a day. On the 8th day of hospitalization the patient presented with acute severe rhabdomyolysis requiring an intensive care support. After discontinuation of levofloxacin and concomitant medication with simvastatin 80 mg/day, clinical and laboratory effects were totally reversible. Up to now, levofloxacin has been reported to induce rhabdomyolysis mainly in patients with impaired renal function, as the medication has a predominant renal elimination. In our case renal function remained normal during the severe clinical course. According to a recent case report rhabdomyolysis was observed due to interaction of simvastatin and ciprofloxacin. To our best knowledge this is the first case of interaction between simvastatin and levofloxacin to be reported. This case emphasizes the need of close monitoring of creatine kinase in patients under more than one potentially myotoxic medication especially when patients develop muscle weakness.\n==== Body\n1. Introduction\nAcute rhabdomyolysis is well-known as a clinical and laboratory syndrome associated with myoglobinuria, electrolyte disorders, and acute renal failure. Its diagnosis is based on the elevated creatine kinase levels after exclusion of myocardial infarction. Although initially described to be induced by crush injury or trauma, more common causes in hospitalized patients include coadministration of interacting drug agents [1]. The identification of a drug-induced rhabdomyolysis is important because the adverse effect is usually reversible after withdrawal of the suspected compound.\n\nParticularly statins are well-known for their myotoxic potential especially in genetically susceptible individuals [2]. The symptoms of the myotoxic effect vary from simple myalgia to severe rhabdomyolysis [3]. Rhabdomyolysis caused by statins is mainly observed at the beginning of the treatment, after changing the agent [4], or even after increasing the dose of the subscribed medication [5]. The mean onset of myopathic side effects is approximately 6 months after initiation of treatment, although symptoms can occur at any time during the statin therapy [6].\n\nLevofloxacin is a widely prescribed antibiotic for the treatment of community acquired pneumonia. It has a predominant renal elimination and dose reduction is necessary in patients with renal dysfunction [7]. Acute rhabdomyolysis due to Levofloxacin has been previously reported in elderly patients [8], in patients under hemodialysis [9], or after renal transplantation [10]. We report a rare case of severe acute rhabdomyolysis associated with coadministration of levofloxacin and simvastatin in a 70-year-old Caucasian male with normal renal function.\n\n2. Case Presentation\nA 70-year-old Caucasian male with previous medical history of coronary artery disease, hypertension, hyperlipidemia, and atrial fibrillation was presented with persistent dyspnea and cough for several days. An externally performed chest X-ray revealed consolidation of the upper lobe of the left lung. Having signs of community acquired pneumonia ampicillin/sulbactam was commenced and after developing diarrhea the antibiotic regime was changed to intravenous levofloxacin 500 mg/day. After 5 days of consecutive treatment respiratory symptoms remained unchanged and the patient was subsequently admitted to our institution for further diagnostic procedures.\n\nAt the day of admission a clinical work up revealed reduced general health but no further clinical abnormalities. He denied back and joint pain or skin rashes. Routine laboratory exams were performed and have shown elevated liver (aspartate aminotransferase [ASAT] 129 U/L, reference range 5–34 U/L and alanine aminotransferase [ALAT] 113 U/L, reference <55 U/L) and muscle enzymes (creatine kinase [CK] 2521 U/L, reference range 30–200 U/L) without signs of myocardial injury (quotient CKMB/CKMM 2). As the inflammatory markers were still significantly high (C-reactive protein [CRP] 182 mg/L, reference <5 mg/L) and the renal function was intact (blood potassium 4.10 mmol/L and creatinine concentrations 0.8 mg/dL, resp.) levofloxacin therapy has been continued in a higher dosage (500 mg/2 ∗ day). Serum brain natriuretic peptide was normal, ruling out cardiogenic dyspnea. Active medication including simvastatin 80 mg/day, metoprolol 25 mg/2 ∗ day, aspirin 100 mg/day, digitoxin 0,07 mg/day, and furosemide 40 mg/day was maintained. About 20 days before the admission of the patient to our department a former dose of simvastatin 40 mg/day was doubled to 80 mg/day as referred from his general physician. The reason for increasing the simvastatin dose was a persistent hypercholesterolemia despite the intake of the former antilipid therapy. \n\nOn the fourth day of hospitalization (overall day 8 of levofloxacin therapy) the patient complained about progressively increased bilateral legs and arms weakness involving both distal and proximal muscle groups. He further reported difficulty to stand up from his bed, dress up, or even use his pen to write. There was no bowel or bladder incontinence or further neurological symptoms. Physical examination revealed diffuse extremity weakness but no other neurological findings or signs of dermatomyositis. At this time muscle enzymes ([CK] 31539 U/L) and parameters of liver toxicity ([ASAT] 486 U/L and [ALAT] 182 U/L) increased dramatically indicating a rhabdomyolysis and the Patient was immediately treated with intravenous crystalloid hypotonic solution (100 mL/h). We also proceded to discontinuation of simvastatin and levofloxacin, urine alkalinization and physical therapy.\n\nA remarkable increase of muscle enzymes during the next days (maximum [CK] 159.450 U/L) and severe generalized weakness, including respiratory insufficiency, made the admission to the ICU necessary, for implementation of noninvasive ventilation. As the renal retention parameters remained normal no hemodialysis was performed. Wide range of serology markers excluded other causes of rhabdomyolysis. A computer tomography of the chest showed withdrawal of the infiltration, although a 2 cm large tumor on the upper left lobe remained. A transbronchial biopsy confirmed the presence of nonsmall cell lung cancer.\n\nWithin a few days his symptoms improved significantly and his muscle and liver enzymes normalized (Figure 1). The patient was discharged at the 26th day of hospitalization with the diagnosis of iatrogenic rhabdomyolysis with acute hepatocellular damage. He presented again to the department of radiotherapy for the treatment of his lung carcinoma and his laboratory parameters were totally normal. The previous dosage of simvastatin 40 mg/day was already resumed by his general physician.\n\n3. Discussion\nThe diagnosis of acute severe rhabdomyolysis in our case is clear. The most probable cause for it is the treatment with levofloxacin, because there was a close temporal sequence between levofloxacin administration and the appearance of the symptoms, as well as clinical and laboratory recovery when the medication was discontinued. The adverse reaction appeared to be more severe when the dosage of levofloxacin was increased. Accordingly to Naranjo's probability scale a probable relationship between levofloxacin and rhabdomyolysis (total score 5) was confirmed even if simvastatin was considered to be an alternative cause of the adverse event (Table 1). Furthermore, all other potential reasons of muscle damage, such as Influenza A and B virus [11], Parainfluenza type 1 and 2 virus [12], Coxsackie virus [13], HIV 1-2 virus [14], endocrinological abnormalities [15], and autoimmune myositis could be serologically excluded. Serum and urinary antigen and antibodies exams excluded Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Streptococcus pneumoniae as potential pathogens of the community acquired pneumonia.\n\nLevofloxacin has a predominant renal elimination and a dose reduction is necessary in patients with impaired renal function [7]. Acute rhabdomyolysis has been previously reported in patients under hemodialysis [9] or after renal transplantation [10]. Petitjeans et al. described in 2003 a case of an elderly patient with severe rhabdomyolysis, suffering from acute renal failure [8]. In our case renal function was normal at the beginning of the therapy and remained intact all along the severe clinical course, indicating that the adverse event is also probable in patients without renal impairment. An ofloxacin-induced rhabdomyolysis in previously healthy individuals has been reported from Hsiao et al. in 2005 [16], while other fluoroquinolones may also lead to this very rare adverse event mostly associated with acute kidney injury [17]. The histological effect of fluoroquinolones on the muscle cell has been demonstrated several years ago in juvenile rats, where no necrosis or lysis was seen, but the muscle fibers became atrophic [18].\n\nThe role of simvastatin in our case has to be also considered, as the medication has a very well confirmed myotoxicity especially when coadministrated with antibiotics, such as macrolides [19], fusidic acid [20], and azole antifungals [21]. According to a recent case report rhabdomyolysis was observed due to interaction of simvastatin and ciprofloxacin [22]. To the best of our knowledge, this is the first case of interaction between simvastatin and levofloxacin to be reported. Simvastatin is metabolized mainly in the liver by cytochrome CYP 3A4 and its active metabolite simvastatin acid is metabolized by cytochrome CYP 2C8 [23]. Levofloxacin is a weak inhibitor of cytochrome CYP 1A2 and has no effect on cytochromes CYP 3A4 and CYP 2C8. As approximately 80% of levofloxacin is eliminated as unchanged drug in the urine through glomerular filtration and tubular secretion and only minimal metabolism occurs with the formation of no active metabolites [24], most likely other mechanisms are involved in the drug interaction of our case. Statins are substrates and strong inhibitors of P-glycoprotein (P-gp), also known as MDR1, which is a cellular drug efflux-transporter, responsible for the bioavailability of lots of medications [25]. In vitro studies have shown that levofloxacin is a potent inhibitor of P-gp-mediated efflux system [26]. According to this knowledge, levofloxacin may have blocked the metabolism of simvastatin leading to increased toxicity.\n\n4. Conclusion\nOur case report highlights the importance of close monitoring in patients under more than one potentially myotoxic medication, especially when patients develop new muscle weakness, by checking the serum creatine kinase and performing liver function tests.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Serum creatinine, creatine kinase [CK], and aspartate aminotransferase [ASAT] during the severe clinical course. Notice the same curve morphology regarding the CK and ASAT evolution.\n\nTable 1 Naranjo's probability scale for our case.\n\nNaranjo's algorithm questions\tAnswer\tScore\t\n(1) Are there previous conclusive reports of this reaction? \tYes\t+1\t\n\n\n\t\n(2) Did the adverse event appear when the drug was administered?\tYes\t+2\t\n\n\n\t\n(3) Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? \tYes\t+1\t\n\n\n\t\n(4) Did the adverse reaction reappear when the drug was readministered?\tDo not know\t0\t\n\n\n\t\n(5) Are there alternative causes (or other drugs) that could on their own explain the adverse reaction? \tYes\t−1\t\n\n\n\t\n(6) Did the adverse reaction reappear when a placebo was given? \tNo\t+1\t\n\n\n\t\n(7) Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? \tNo\t0\t\n\n\n\t\n(8) Was the reaction more severe when the dose was increased or less severe when the dose was decreased? \tYes\t+1\t\n\n\n\t\n(9) Did the patient have a similar reaction to the same or similar drugs in any previous exposure? \tDo not know\t0\t\n\n\n\t\n(10) Was the adverse event confirmed by any objective evidence? \tNo\t0\t\n\n\n\t\n \tTotal score:\t5\t\nThe total score calculated from this table defines the category to which an adverse event belongs to.\n\nThe categories are defined as shown below:\n\ndefinite (certain): >8;\n\nprobable: total score 5–8;\n\npossible: total score 1–4;\n\ndoubtful (unlikely): total score <1.\n==== Refs\n1 Zimmerman JL Shen MC Rhabdomyolysis Chest 2013 144 3 1058 1065 24008958 \n2 Needham M Mastaglia FL Statin myotoxicity: a review of genetic susceptibility factors Neuromuscular Disorders 2014 24 1 4 15 24176465 \n3 Tomaszewski M Stepien KM Tomaszewska J Czuczwar SJ Statin-induced myopathies Pharmacological Reports 2011 63 4 859 866 22001973 \n4 Khanna S Mundell WC Rhadbomyolysis associated with co-administration of danazol and lovastatin British Journal of Clinical Pharmacology 2011 72 1 166 167 2-s2.0-79958744470 21223355 \n5 Tayal U Carroll R Should anyone still be taking simvastatin 80 mg? BMJ Case Reports 2013 \n6 Hansen KE Hildebrand JP Ferguson EE Stein JH Outcomes in 45 patients with statin-associated myopathy Archives of Internal Medicine 2005 165 22 2671 2676 2-s2.0-28944444047 16344427 \n7 Czock D Hüsig-Linde C Langhoff A Pharmacokinetics of moxifloxacin and levofloxacin in intensive care unit patients who have acute renal failure and undergo extended daily dialysis Clinical Journal of the American Society of Nephrology 2006 1 6 1263 1268 2-s2.0-34548567819 17699357 \n8 Petitjeans F Nadaud J Perez JP A case of rhabdomyolysis with fatal outcome after a treatment with levofloxacin European Journal of Clinical Pharmacology 2003 59 10 779 780 2-s2.0-0347991796 14576967 \n9 Gupta A Guron N Harris M Bell R Levofloxacin-induced rhabdomyolysis in a hemodialysis patient Hemodialysis International 2012 16 1 101 103 2-s2.0-84863399672 22098607 \n10 Korzets A Gafter U Dicker D Herman M Ori Y Levofloxacin and rhabdomyolysis in a renal transplant patient Nephrology Dialysis Transplantation 2006 21 11 3304 3305 2-s2.0-33749996210 \n11 Fearnley RA Lines SW Lewington AJP Bodenham AR Influenza A-induced rhabdomyolysis and acute kidney injury complicated by posterior reversible encephalopathy syndrome Anaesthesia 2011 66 8 738 742 2-s2.0-79960350185 21539531 \n12 Douvoyiannis M Kielbasa JM Chandrasekharan GM Holmes CL Gomez MR Rhabdomyolysis associated with parainfluenza virus Case Reports in Infectious Diseases 2013 2013 4 pages 650965 \n13 Wang Y Zhang Y Ye Z Rhabdomyolysis following recent severe coxsackie virus infection in patient with chronic renal failure: one case report and a review of the literature Renal Failure 2006 28 1 89 93 2-s2.0-32644486633 16526325 \n14 Douvoyiannis M Litman N Acute encephalopathy and multi-organ involvement with rhabdomyolysis during primary HIV infection International Journal of Infectious Diseases 2009 13 5 e299 e304 2-s2.0-68949165678 19324581 \n15 Ardalan MR Ghabili K Mirnour R Shoja MM Hypothyroidism-induced rhabdomyolysis and renal failure Renal Failure 2011 33 5 553 554 2-s2.0-79956281874 21500981 \n16 Hsiao S Chang C Tsao C Lee YJ Hsu M Wu T Acute rhabdomyolysis associated with ofloxacin/levofloxacin therapy Annals of Pharmacotherapy 2005 39 1 146 149 2-s2.0-11144225236 15562138 \n17 Qian Q Nasr SH Akogyeram CO Sethi S Myoglobin-associated acute kidney injury in the setting of ciprofloxacin administration The American Journal of Kidney Diseases 2012 59 3 462 466 2-s2.0-84857358451 22261117 \n18 Kashida Y Kato M Toxic effects of quinolone antibacterial agents on the musculoskeletal system in juvenile rats Toxicologic Pathology 1997 25 6 635 643 2-s2.0-0031443891 9437810 \n19 Wagner J Suessmair C Pfister HW Rhabdomyolysis caused by co-medication with simvastatin and clarithromycin Journal of Neurology 2009 256 7 1182 1183 2-s2.0-67650499611 19252767 \n20 Burtenshaw AJ Sellors G Downing R Presumed interaction of fusidic acid with simvastatin Anaesthesia 2008 63 6 656 658 2-s2.0-43549126635 18477279 \n21 Omar MA Wilson JP FDA adverse event reports on statin-associated rhabdomyolysis Annals of Pharmacotherapy 2002 36 2 288 295 2-s2.0-0036163750 11847951 \n22 Sawant RD Rhavdomyolysis due to an uncommon interaction of ciprofloxacin with simvastatin Canadian Journal of Clinical Pharmacology 2009 16 1 e78 e79 2-s2.0-60849102788 19151423 \n23 Neuvonen PJ Niemi M Backman JT Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance Clinical Pharmacology and Therapeutics 2006 80 6 565 581 2-s2.0-33845420011 17178259 \n24 Fish DN Chow AT The clinical pharmacokinetics of levofloxacin Clinical Pharmacokinetics 1997 32 2 101 119 2-s2.0-0031055732 9068926 \n25 Williams D Feely J Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors Clinical Pharmacokinetics 2002 41 5 343 370 2-s2.0-0036291921 12036392 \n26 Pal D Mitra AK MDR- and CYP3A4-mediated drug-drug interactions Journal of Neuroimmune Pharmacology 2006 1 3 323 339 2-s2.0-33747352798 18040809\n\n",
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"title": "Acute rhabdomyolysis associated with coadministration of levofloxacin and simvastatin in a patient with normal renal function.",
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"abstract": "Immune checkpoint inhibitors (ICPIs) are a breakthrough therapy in oncology and have been approved by the Food and Drug Administration for the treatment of several malignancies. ICPIs have been reported to cause immune-mediated damage of islet cells leading to ICPI-induced type 1 diabetes mellitus (T1DM). These reports described patients presenting with severe diabetic ketoacidosis (DKA). We present a case of a 69-year-old Caucasian male with type 2 diabetes suffering from non-small cell lung cancer and undergoing treatment with pembrolizumab, an anti-programmed cell death protein-1 antibody, who presented to our emergency department with complaints of nausea, vomiting, polyuria, and polydipsia. He was found to have high anion gap metabolic acidosis with ketosis and elevated blood glucose levels consistent with DKA. Lab workup was consistent with T1DM. Despite being on a tailored insulin regimen, his blood glucose remained elevated, necessitating the addition of metformin to his regimen which effectively controlled his blood glucose.",
"affiliations": "Department of Internal Medicine, AMITA Health Saint Joseph Hospital, Chicago, IL 60657, USA.;Department of Internal Medicine, AMITA Health Saint Joseph Hospital, Chicago, IL 60657, USA.;Department of Internal Medicine, AMITA Health Saint Joseph Hospital, Chicago, IL 60657, USA.;Department of Internal Medicine, AMITA Health Saint Joseph Hospital, Chicago, IL 60657, USA.;Department of Internal Medicine, Saint Catherine Hospital, East Chicago, IN 46312, USA.;Khyber Medical College, Peshawar, Pakistan.;Department of Endocrinology, AMITA Health Saint Joseph Hospital, Chicago, IL 60657, USA.",
"authors": "Alrifai|Taha|T|https://orcid.org/0000-0002-2268-9529;Ali|Faisal Shaukat|FS|;Saleem|Sameer|S|https://orcid.org/0000-0003-3763-0906;Ruiz|Diana Carolina Miranda|DCM|;Rifai|Dana|D|;Younas|Sundas|S|;Qureshi|Faisal|F|",
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"country": "United States",
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"doi": "10.1155/2019/8781347",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2019/8781347Case ReportImmune Checkpoint Inhibitor Induced Diabetes Mellitus Treated with Insulin and Metformin: Evolution of Diabetes Management in the Era of Immunotherapy https://orcid.org/0000-0002-2268-9529Alrifai Taha tahaalrifai@gmail.com\n1\nAli Faisal Shaukat \n1\nhttps://orcid.org/0000-0003-3763-0906Saleem Sameer \n1\nRuiz Diana Carolina Miranda \n1\nRifai Dana \n2\nYounas Sundas \n3\nQureshi Faisal \n4\n\n1Department of Internal Medicine, AMITA Health Saint Joseph Hospital, Chicago, IL 60657, USA\n2Department of Internal Medicine, Saint Catherine Hospital, East Chicago, IN 46312, USA\n3Khyber Medical College, Peshawar, Pakistan\n4Department of Endocrinology, AMITA Health Saint Joseph Hospital, Chicago, IL 60657, USAAcademic Editor: Jose I. Mayordomo\n\n2019 4 11 2019 2019 878134727 5 2019 26 10 2019 Copyright © 2019 Taha Alrifai 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.Immune checkpoint inhibitors (ICPIs) are a breakthrough therapy in oncology and have been approved by the Food and Drug Administration for the treatment of several malignancies. ICPIs have been reported to cause immune-mediated damage of islet cells leading to ICPI-induced type 1 diabetes mellitus (T1DM). These reports described patients presenting with severe diabetic ketoacidosis (DKA). We present a case of a 69-year-old Caucasian male with type 2 diabetes suffering from non-small cell lung cancer and undergoing treatment with pembrolizumab, an anti-programmed cell death protein-1 antibody, who presented to our emergency department with complaints of nausea, vomiting, polyuria, and polydipsia. He was found to have high anion gap metabolic acidosis with ketosis and elevated blood glucose levels consistent with DKA. Lab workup was consistent with T1DM. Despite being on a tailored insulin regimen, his blood glucose remained elevated, necessitating the addition of metformin to his regimen which effectively controlled his blood glucose.\n==== Body\n1. Background\nSince the approval of immune checkpoint inhibitors (ICPIs), several case reports have emerged describing adverse outcomes pertaining to the activation of patients' immune systems. These immune-related adverse events (irAEs) can theoretically affect any organ system [1]. Several case reports have been published describing new onset diabetes mellitus in cancer patients receiving programmed cell death protein-1 (PD-1) inhibitors which is thought to be a consequence of immune-mediated beta islet cell dysfunction, resulting in a type 1 diabetes mellitus (T1DM) [2–6]. However, data regarding management of new onset T1DM, particularly among patients with a history of T2DM, is scarce. We report a case of a 69-year-old cancer patient with a history of T2DM who developed T1DM after undergoing treatment with pembrolizumab, a PD-1 inhibitor, which was effectively managed with insulin and metformin.\n\n2. Case Presentation\nA 69-year-old male with a medical history of T2DM and stage IV NSCLC presented to our ED with complaints of nausea, vomiting, polyuria, polydipsia, and weakness of 4 days duration. His T2DM was diagnosed 4 years prior to his presentation and had been managed with oral antidiabetic drugs (OADs); his glycohemoglobin levels ranged between 5.9 and 7.3%. He had been undergoing chemotherapy with carboplatin, pemetrexed, and pembrolizumab and had completed his 4th cycle 20 days prior to this presentation.\n\nOn physical examination, he had dry oral mucosa and was tachypneic with a respiratory rate of 30 respirations per minute. Laboratory workup revealed a pH of 6.95, a serum bicarbonate level of 3 mmol/L with an anion gap of 39 mmol/L. Serum osmolality was elevated at 342 mOsm/kg. Blood glucose was 907 mg/dL, and serum ketones were 5.3 mmol/L. His serum potassium level was 7.5 mmol/L, and his serum creatinine level was elevated to 2.72 mg/dL from a normal baseline. Glycohemoglobin was 9.2%. The patient was admitted to the intensive care unit (ICU), where he was started on an intravenous (IV) insulin infusion and IV fluids with serial monitoring of his blood glucose, pH, and potassium levels. His DKA resolved and he was started on long-acting and short-acting insulin.\n\nWorkup for potential precipitating events leading to DKA was done. After exclusion of infectious and common metabolic etiologies, it was thought that the patient's treatment with pembrolizumab may have led to new-onset ICPI-induced T1DM presenting with DKA. Subsequently, C-peptide levels were checked and were undetectable (<0.1 mg/mL). Anti-glutamic acid decarboxylase antibody (Anti-GAD) titers were elevated at 61 U/mL, both of which were consistent with a diagnosis of T1DM. His pembrolizumab was held for one cycle and resumed thereafter.\n\nFollowing his discharge from the hospital, the patient was maintained on a regimen of long- and short-acting insulin with insulin degludec and insulin aspart. However, it became challenging to achieve adequate glycemic control despite the patient's compliance with insulin therapy. His glycohemoglobin was persistently high and was 8.7% after being on insulin for 15 months. His insulin regimen was subsequently supplemented with metformin, which led to a decrease in his glycohemoglobin from 8.7% to 7.7% one month after the change in regimen. He remains on maintenance therapy with pembrolizumab for his NSCLC and has not had further ICPI-associated complications on his last follow-up.\n\n3. Discussion\nICPIs evolved the paradigm of cancer therapy, proving efficacious for a myriad of cancers including metastatic melanoma, NSCLC, and renal cell carcinoma, with a plethora of clinical trials underway to assess the safety and efficacy of this drug class in various other cancers [7]. Owing to the immune-mediated mechanism of action of ICPIs, they have led to a wide spectrum of irAEs. ICPI-induced islitis and subsequent development of ICPI-induced T1DM or evolution of T2DM into ICPI-induced T1DM is a rare entity and may be difficult to identify upon presentation. The first case of ICPI-induced T1DM was reported in 2015 with the use of pembrolizumab [8]. Subsequently, multiple case reports of ICPI-induced T1DM associated with the use of PD-1 inhibitors [2–6], as well as cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors [9], emerged, shedding light on this uncharacterized entity. To date, the largest case series are comprised of less than 30 patients, highlighting the scarcity of data concerning ICPI-induced T1DM [10].\n\nImmune-mediated islet injury has been thought to be a consequence of T-cell modulation, evident by the presence of GAD-65 antibodies, though these have not been reported in all cases of ICPI-induced T1DM to date, highlighting the inadequacy of the T-cell immunomodulation theory [11]. However, an upregulation of CD-8 T-cell-mediated response to T1DM antigens, as has been reported in a fraction of cases, weighs in favor of a T-cell-mediated injury. Nonetheless, the current hypotheses identify pieces of the puzzle which, when put together, may provide an all-inclusive understanding of the mechanisms behind this rare entity.\n\nSerial blood glucose monitoring of patients being treated with ICPIs on regular intervals is crucial for recognition of ICPI-induced T1DM. In patients with a history of T2DM, ICPI-induced T1DM may be masked and overlooked as a manifestation of uncontrolled T2DM, highlighting the importance of a low threshold for suspicion and initiation of further workup. Wright et al. suggested obtaining GAD antibody levels in patients with T2DM prior to initiating therapy with ICPI to identify those who might be at risk for developing immune-mediated DM [12]. Patients with ICPI-induced T1DM which has gone unrecognized may develop DKA which is potentially fatal if not recognized and treated in a timely manner. The National Comprehensive Cancer Network (NCCN) recommends holding ICPI therapy among patients who present with a blood glucose of >250 m/dL or DKA, as was done in our case [13].\n\nThe management of ICPI-induced T1DM is not well characterized and is currently stemming from our understanding of T2DM, T1DM, and DKA. ICPI-induced insulin deficiency may warrant therapy with a tailored insulin regimen, as is done for patients with T1DM. However, among patients with a history of T2DM, this may not address the insulin resistance, highlighting the need for studies addressing the management of ICPI-induced T1DM. Among patients with a history of T2DM, the treatment of ICPI-induced T1DM may constitute a combination of OACs to tackle insulin resistance, along with a customized insulin regimen to address the acquired insulin deficiency. The OACs which our patient was taking prior to presentation were held temporarily and he was started on insulin degludec and insulin aspart. However, due to his history of T2DM and difficulty in achieving adequate glycemic control despite being on a tailored insulin regimen for 15 months, metformin was reintroduced to his regimen which led to a noticeable improvement in glycemic control. Hence, ICPI-induced T1DM among patients with a history of T2DM represents a new entity requiring an evolved treatment approach where a baseline insulin regimen may be supplemented with OACs such as metformin to counteract insulin resistance and achieve better glycemic control.\n\nSeveral irAEs have been reported to spontaneously resolve with the discontinuation of immunotherapy [14]. This might not prove true for the majority of ICPI-induced endocrinopathies [15]. Further large-scale studies concerning the reversibility of ICPI-induced endocrinopathies are urgently needed.\n\nIn conclusion, ICPI-induced T1DM is a rare irAE. Clinicians involved in the care of cancer patients on ICPI therapy should be mindful and maintain a high clinical index of suspicion for this rare entity. In patients with preexisting T2DM, ICPI-induced T1DM can be treated with an insulin regimen supplemented with OACs to counter the insulin resistance and achieve better glycemic control. Further large-scale studies are needed to characterize the management of ICPI-induced T1DM in patients with preexisting T2DM further.\n\nConflicts of Interest\nThe authors declare that there is no conflict of interest regarding the publication of this paper.\n\nAuthors' Contributions\nF.A. and T.A. have both contributed equally to the writing of the manuscript. S.S., D.M., D.R., and S.Y. have all contributed to the conception of the work, data collection, drafting the article, critical review of the article, and final approval of the version to be published. F.Q. has contributed to the conception of the work, drafting the article, critical review of the article, and final approval of the version to be published. Taha Alrifai and Faisal Shaukat Ali are co-first authors.\n==== Refs\n1 Humayun M. A. Poole R. A case of multiple immune toxicities from Ipilimumab and pembrolizumab treatment HORMONES 2016 15 2 303 306 10.14310/horm.2002.1656 2-s2.0-84976483958 27376434 \n2 Chae Y. K. Chiec L. Mohindra N. Gentzler R. Patel J. Giles F. A case of pembrolizumab- induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes Cancer Immunology, Immunotherapy 2017 66 1 25 32 10.1007/s00262-016-1913-7 2-s2.0-84991785839 27761609 \n3 Hansen E. Sahasrabudhe D. Sievert L. A case report of insulin-dependent diabetes as immune-related toxicity of pembrolizumab: presentation, management and outcome Cancer Immunology, Immunotherapy 2016 65 6 765 767 10.1007/s00262-016-1835-4 2-s2.0-84962798338 27067877 \n4 Cheema A. Makadia B. Karwadia T. Bajwa R. Hossain M. Autoimmune diabetes associated with pembrolizumab: a review of published case reports World Journal of Oncology 2018 9 1 1 4 10.14740/wjon1085w 29581809 \n5 Li S. Zhang Y. Sun Z. Hu J. Fang C. Anti-PD-1 pembrolizumab induced autoimmune diabetes in Chinese patient: a case report Medicine (Baltimore) 2018 97 45 p. e12907 10.1097/MD.0000000000012907 2-s2.0-85056411685 30407284 \n6 Gaudy C. Clévy C. Monestier S. Anti-PD1 pembrolizumab can induce exceptional fulminant type 1 diabetes Diabetes Care 2015 38 11 e182 e183 10.2337/dc15-1331 2-s2.0-84962385750 26310693 \n7 Park Y. J. Kuen D. S. Chung Y. Future prospects of immune checkpoint blockade in cancer: from response prediction to overcoming resistance Experimental & Molecular Medicine 2018 50 8 1 13 10.1038/s12276-018-0130-1 2-s2.0-85056450926 29563495 \n8 Hughes J. Vudattu N. Sznol M. Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy Diabetes Care 2015 38 4 e55 e57 10.2337/dc14-2349 2-s2.0-84962198249 25805871 \n9 Tsiogka A. Jansky G. L. Bauer J. W. Koelblinger P. Fulminant type 1 diabetes after adjuvant ipilimumab therapy in cutaneous melanoma Melanoma Research 2017 27 5 524 525 10.1097/cmr.0000000000000384 2-s2.0-85054248134 28858175 \n10 Stamatouli A. M. Quandt Z. Perdigoto A. L. Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors Diabetes 2018 67 8 1471 1480 10.2337/dbi18-0002 2-s2.0-85050445745 29937434 \n11 Byun D. J. Wolchok J. D. Rosenberg L. M. Girotra M. Cancer immunotherapy — immune checkpoint blockade and associated endocrinopathies Nature Reviews Endocrinology 2017 13 4 195 207 10.1038/nrendo.2016.205 2-s2.0-85009968823 28106152 \n12 Wright L. A.-C. Ramon R. V. Batacchi Z. Hirsch I. B. Progression to insulin dependence post-treatment with immune checkpoint inhibitors in pre-existing type 2 diabetes AACE Clinical Case Reports 2017 3 2 e153 e157 10.4158/EP161303.CR \n13 Thompson J. A. Schneider B. J. Brahmer J. Management of Immunotherapy-Related Toxicities, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology Journal of the National Comprehensive Cancer Network 2019 17 3 255 289 10.6004/jnccn.2019.0013 2-s2.0-85062877270 30865922 \n14 Weber J. S. Yang J. C. Atkins M. B. Disis M. L. Toxicities of immunotherapy for the practitioner Journal of Clinical Oncology 2015 33 18 2092 2099 10.1200/JCO.2014.60.0379 2-s2.0-84937605130 25918278 \n15 Ryder M. Callahan M. Postow M. A. Wolchok J. Fagin J. A. Endocrine- related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution Endocrine-Related Cancer 2014 21 2 371 381 10.1530/ERC-13-0499 2-s2.0-84899873585 24610577\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2019()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
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"nlm_unique_id": "101581035",
"other_id": null,
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"pmid": "31781446",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "25918278;24610577;28106152;27067877;28858175;30865922;30135516;27761609;25805871;26310693;30407284;29937434;29581809;27376434",
"title": "Immune Checkpoint Inhibitor Induced Diabetes Mellitus Treated with Insulin and Metformin: Evolution of Diabetes Management in the Era of Immunotherapy.",
"title_normalized": "immune checkpoint inhibitor induced diabetes mellitus treated with insulin and metformin evolution of diabetes management in the era of immunotherapy"
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"abstract": "RTX could be an effective and safe alternative treatment for refractory EF. Rituximab (RTX) is a successful therapeutic option for various autoimmune diseases. Our aim is to report our experience with RTX in eosinophilic fasciitis (EF) and review published data on its efficacy for the treatment of EF. We reviewed the medical charts of all patients with a diagnosis of EF treated with RTX from 2008 to 2020 in the Department of Rheumatology and Clinical Immunology in the University Hospital of Heraklion, Crete, Greece. We also reviewed the English literature for cases of EF treated with RTX. Demographics, clinical manifestations, laboratory findings, prior treatments, response to RTX, cumulative RTX dose, duration of treatment and follow-up are reported. We report three cases of EF refractory to conventional DMARDs (cDMARDs) that responded to RTX. Furthermore, literature review revealed five cases. In our case series in all patients, RTX was the first biologic. RTX could be effective in cases of (EF) refractory to standard immunosuppressive treatment.",
"affiliations": "Department of Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Heraklion, Greece. nkougas@yahoo.gr.;Department of Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Heraklion, Greece.;Department of Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Heraklion, Greece.;Department of Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Heraklion, Greece.;Department of Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Heraklion, Greece.;Department of Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Heraklion, Greece.",
"authors": "Kougkas|Nikolaos|N|http://orcid.org/0000-0001-5275-8639;Bertsias|George|G|;Papalopoulos|Ioannis|I|;Repa|Argiro|A|;Sidiropoulos|Prodromos|P|;Avgoustidis|Nestor|N|",
"chemical_list": null,
"country": "Germany",
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"issue": "41(10)",
"journal": "Rheumatology international",
"keywords": "Eosinophilic fasciitis; Refractory; Review; Rituximab; Treatment",
"medline_ta": "Rheumatol Int",
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"other_id": null,
"pages": "1833-1837",
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"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D016454:Review",
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"title": "Rituximab for refractory eosinophilic fasciitis: a case series with long-term follow-up and literature review.",
"title_normalized": "rituximab for refractory eosinophilic fasciitis a case series with long term follow up and literature review"
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"abstract": "Cytomegalovirus is an opportunistic virus that commonly affects immunosuppressed patients. Cutaneous involvement by this virus is rare and occurs in significantly immunocompromised hosts, with a poor prognosis. Skin ulcers may represent the first sign of systemic infection by cytomegalovirus in these patients. Herein, a case of a systemic infection by Cytomegalovirus presenting as genital and oral ulcers in a kidney-transplant recipient is reported.",
"affiliations": "Hospital Federal de Bonsucesso, Rio de Janeiro, RJ, Brazil.;Hospital Federal de Bonsucesso, Rio de Janeiro, RJ, Brazil.;Hospital Federal de Bonsucesso, Rio de Janeiro, RJ, Brazil.;Hospital Federal de Bonsucesso, Rio de Janeiro, RJ, Brazil.",
"authors": "Neumann|Antonielle Borges Faria|AB|;Daxbacher|Egon Luiz Rodrigues|EL|;Chiaratti|Francielle Chiavelli|FC|;Jeunon|Thiago|T|",
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"fulltext": "\n==== Front\nAn Bras DermatolAn Bras DermatolabdAnais Brasileiros de Dermatologia0365-05961806-4841Sociedade Brasileira de Dermatologia 10.1590/abd1806-4841.20163989Case ReportCutaneous involvement by cytomegalovirus in a renal transplant\nrecipient as an indicator of severe systemic infection*\n Neumann Antonielle Borges Faria 1Daxbacher Egon Luiz Rodrigues 1Chiaratti Francielle Chiavelli 1Jeunon Thiago 11 Hospital Federal de Bonsucesso (HFB) - Rio de Janeiro\n(RJ), Brazil.Mailing address: Thiago Jeunon, Rua General Roca, 778/1005 Tijuca,\n20521-070 - Rio de Janeiro - RJ Brazil.\nthiago.jeunon@gmail.comJan-Feb 2016 Jan-Feb 2016 91 1 80 83 16 9 2014 13 10 2014 © 2016 by Anais Brasileiros de\nDermatologia2016This is an Open Access article distributed under the terms of the\nCreative Commons Attribution Non-Commercial License which permits\nunrestricted non-commercial use, distribution, and reproduction in any\nmedium provided the original work is properly cited.Cytomegalovirus is an opportunistic virus that commonly affects immunosuppressed\npatients. Cutaneous involvement by this virus is rare and occurs in\nsignificantly immunocompromised hosts, with a poor prognosis. Skin ulcers may\nrepresent the first sign of systemic infection by cytomegalovirus in these\npatients. Herein, a case of a systemic infection by Cytomegalovirus presenting\nas genital and oral ulcers in a kidney-transplant recipient is reported.\n\nCytomegalovirusImmunocompromised hostInfectionKidney transplantationSkin ulcer\n==== Body\nINTRODUCTION\nCytomegalovirus (CMV), also known as human herpesvirus type 5, is a DNA virus that\nbelongs to the betaherpes subfamily of the herpesviridae family, which are\ncharacterized by their latency ability.1 It may be transmitted by saliva, urine, sexual contact,\nplacental transfer, breastfeeding, blood transfusion, solid organ or hematopoietic\nstem cell transplantations. After primary infection, the virus goes through a long\nlatency period in the host. In immunocompetent individuals, primary infection is\noftentimes asymptomatic, but it may manifest as a mononucleosis-like syndrome. On\nthe other hand, in immunodepressed individuals, primary infection, reactivation of\nlatent infection or reinfection by a different serotype usually cause the\ndisease.2\n\nHerein, a case of disseminated infection initially manifested only by worsening of\nrenal function and the onset of skin and mucosa ulcers caused by the CMV is\nreported.\n\nCASE REPORT\nA 68-year-old male patient after a long time of essential hypertension progressed\nwith hypertensive nephropathy, terminal renal failure and renal transplantation. He\nwas in use of prednisone, tacrolimus and mycophenolate mofetil since the\ntransplantion and presented decrease of renal function after two months requiring\nhospitalization. After admission, clean-based ulcers were noticed, one on the\nlateral border of the tongue and another on the dorsum of the penis (Figures 1 and 2). CMV infection was suspected and the work-up included antigenemia\nassay in peripheral blood and biopsies of the penile ulcer; one sample was submitted\nto histopathology and the other to polymerase chain reaction (PCR) for CMV. The\nhistopathological examination revealed ulceration, occlusion of some vessels by\nthrombi and prominent endothelial cells with conspicuous cytoplasm and markedly\nenlarged nuclei containing CMV inclusion corpuscles, resulting in diagnosis of\ncytomegalovirus infection (Figures 3, 4 and 5.\nThe qualitative PCR for DNA of the CMV was positive in skin samples, as well as the\nantigenemia assay on peripheral blood (Figure\n6). The treatment with intravenous ganciclovir was started, with the dose\nadjusted in accordance with the renal function, but the patient died after 41 days\nof admission in consequence of pulmonary sepsis.\n\n\nFigure 1 Clean-based, well-delimited ulcer on the lateral border of the tongue\n\n\n\n\n\nFigure 2 Clean-based, well-delimited ulcer on the dorsum of the penis\n\n\n\n\n\nFigure 3 Partial surface ulceration and vessels with endothelial cells with large\nnuclei and ample cytoplasm, assuming an epithelioid aspect. In the lower\npart of the photomicrograph, a vessel occluded by a thrombus can be\nseen. HE, 100X\n\n\n\n\n\nFigure 4 Endothelial cells with markedly augmented nuclei, rough nucleoli and\nample cytoplasm. HE, 400X\n\n\n\n\n\nFigure 5 Eosinophilic corpuscle of viral inclusion, surrounded by a light halo in\nthe cytoplasm of an endothelial cell with an epithelioid aspect. HE,\n400X\n\n\n\n\n\nFigure 6 Agarose gel image after electrophoresis, with positive PCR results for\nDNA of CMV in the penile ulcer. M: Marker of molecular weight. C -:\nNegative control. C +: Positive control. A: Sample of the penile ulcer\nwith a band at the level compared to positive control, which confirms\nthe presence of DNA of the CMV in this sample\n\n\n\n\nDISCUSSION\nCytomegalovirus (CMV) is an opportunistic virus that frequently affects\nimmunosuppressed patients, such as those with HIV infection/acquired\nimmunodeficiency syndrome and kidney transplant recipients.3,4 Active disease by CMV occurs most of the times in the first\nhundred days after transplant, at the moment of greater immunosuppression,\nrepresenting an important morbimortality factor.24 It may manifest as a\nsyndrome characterized by fever, atypical lymphocytosis, neutropenia or\nthrombocytopenia and malaise or as an invasive tissue disease.2,5 Although visceral manifestations by CMV are frequently reported,\nskin lesions caused by this virus are rare.3,5 In the present case,\nthe patient in day 60 presented worsening of the renal function and ulcers of oral\nmucosa and skin of the penis.\n\nThe most frequent infectious dermatoses in renal transplant recipients are caused by\nfungi, followed by virus and bacteria; among the viral infections, there is a marked\npredominance of herpesvirus infection in the first year after transplantation, while\nwarts usually appear later.6,7 It seems that the dermis is\nrelatively inhospitable for the CMV and that the rare cutaneous involvement occurs\nonly in significantly immunodepressed patients. Consequently, cutaneous lesions are\nusually associated with disseminated disease and predict a poor prognosis.3,4,5 CMV infection\nusually presents at the skin as a generalized maculopapulous eruption, but ulcers,\nnodules, vesicles, petechiae and plaques may come into being, mimicking other\ndermatoses, especially other infections. Ulcerations involving mainly the genital,\nperineal and perianal areas, as well as necrosis of mucosal membranes, may occur in\nmore severe cases.4,8 Contrasting with what happens in lesions caused by\nherpes simplex or varicella-zoster, in which the cytopathic alterations\n(karyomegaly, peripheral chromatin margination and multinucleation) take place\npreferably in the epidermis and in the epithelium of hair follicles, the cellular\nalterations characteristic of infection by CMV involve preferentially the\nendothelial cells that line the small capillary vessels in the dermis.9 These present large nuclei and ample\ncytoplasm, assuming an epithelioid aspect, and exhibit a rough eosinophilic\ninclusion corpuscle surrounded by a light halo, which may be present in the nucleus\nof the cell or located in the cytoplasm. Neutrophilic invasion of vessel walls is\noften observed, although unequivocal leukocytoclastic vasculitis is rare. Less\nfrequently, the cytopathic alterations characteristic of CMV infection may be found\nin fibroblasts and macrophages, as well as in the epithelium of eccrine ducts and\nhair follicles. In congenital infections, extramedullar hematopoiesis may be found\nin the skin.8,9,10\n\nThere are two possible explanations for oral-genital ulcers caused by the CMV: the\nlatent virus in the gastrointestinal tract, when reactivated, infects the skin of\nthe perineum via fecal elimination, or reactivation of the latent virus in\nendothelial cells during the course of hematogenic dissemination.4 Infection by CMV also produces a\nvast range of indirect effects, such as decrease in function of the transplanted\nkidney, susceptibility to rejection and opportunistic infections.2 In the present report, the patient\ndeveloped symptoms of pulmonary sepsis despite the use of intravenous ganciclovir.\nBecause it was not possible to exclude a associated bacterial infection, systemic\nantibiotic therapy was promptly started. Nevertheless, the patient died after 41\ndays of admission in the hospital.\n\nThe infection is diagnosed based on the presence of typical clinical signs and\nsymptoms and identification of characteristic inclusion corpuscles in\nhistopathology, combined with detection of CMV in the blood and/or involved\norgans.3,4 At present, the methods of choice for such detection\nare antigenemia or PCR.1-4 Antigenemia is a fast assay of\nsemiquantitative immunofluorescence that detects phosphoprotein 65 produced by\npolymorphonuclear cells infected by CMV in peripheral blood. PCR detects viral DNA\nin total blood, leukocytes, plasma, serum or in the affected organ.2 In this case, we diagnosed the\ninfection through histopathologic examination, antigenemia in peripheral blood and\nqualitative PCR in the affected skin. The infection should be treated with\nintravenous valganciclovir or ganciclovir until the replication of CMV is no longer\ndetected, with a minimum of two weeks of treatment. Viral load monitoring should be\ndone on a weekly basis, by means of PCR or antigenemia in peripheral\nblood.2\n\nThe dermatologist is of fundamental importance in a hospital where there is a renal\ntransplant service. This case is an example of our role in the diagnosis and early\ntreatment of severe diseases in the transplanted patient.\n\nConflict of Interest: None.\n\nFinancial Support: None.\n\n* Study carried out at the Hospital Federal de Bonsucesso (HFB) - Rio de Janeiro\n(RJ), Brazil.\n==== Refs\nREFERENCES\n1 García-Testal A Olague Díaz P Bonilla Escobar BA Criado-Álvarez JJ Sanchez Plumed J Análisis de infección por citomegalovirus y sus\nconsecuencias en el transplante renal: revision de uma\ndécada Med Clin (Barc) 2011 137 335 339 21513959 \n2 De Keyzer K Van Laecke S Peeters P Vanholder R Human cytomegalovirus and kidney transplantation: A clinician's\nupdate Am J Kidney Dis 2011 58 118 126 21684438 \n3 Toome BK Bowers KE Scott GA Diagnosis of cutaneous cytomegalovirus infection: A review and\nreport of a case J Am Acad Dermatol 1991 24 860 867 1646834 \n4 Moscarelli L Zanazzi M Rosso G Farsetti S Caroti L Annunziata F Can skin be the first site of CMV involvement preceding a\nsystematic infection in a renal transplant recipient? NDT Plus 2011 4 53 55 25984104 \n5 Prasad N Jain M Gupta A Sharma RK Agarwal V An unusual case of CMV cutaneous ulcers in a renal transplant\nrecipient and review of literature NDT Plus 2010 3 379 382 25949436 \n6 Lima AM Rocha SP Reis EG Filho Eid DR Reis CM Study of dermatoses in kidney transplant patients An Bras Dermatol 2013 88 361 367 23793196 \n7 Vettorato G Carvalho AVE Lecompte SM Trez EG Garcia VD Keitel E Frequency of infectious dermatosis in 208 renal transplant\nrecipients An Bras Dermatol 2003 78 283 288 \n8 Lesher JL Jr Cytomegalovirus infections and the skin J Am Acad Dermatol 1988 18 1333 1338 2838537 \n9 Requena L Requena C Histopathology of the more common viral skin\ninfections Actas Dermosifiliogr 2010 101 201 216 20398595 \n10 Resnik KS DiLeonardo M Maillet M Histopathologic findings in cutaneous cytomegalovirus\ninfection Am J Dermatopathol 2000 22 397 407 11048974\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0365-0596",
"issue": "91(1)",
"journal": "Anais brasileiros de dermatologia",
"keywords": null,
"medline_ta": "An Bras Dermatol",
"mesh_terms": "D000368:Aged; D003586:Cytomegalovirus Infections; D006801:Humans; D007121:Immunocompetence; D016030:Kidney Transplantation; D008297:Male; D016133:Polymerase Chain Reaction; D017193:Skin Diseases, Viral; D012883:Skin Ulcer",
"nlm_unique_id": "0067662",
"other_id": null,
"pages": "80-3",
"pmc": null,
"pmid": "26982783",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23793196;11048974;20398595;1646834;25949436;21513959;21684438;2838537;25984104",
"title": "Cutaneous involvement by cytomegalovirus in a renal transplant recipient as an indicator of severe systemic infection.",
"title_normalized": "cutaneous involvement by cytomegalovirus in a renal transplant recipient as an indicator of severe systemic infection"
} | [
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"companynumb": "BR-ALKEM LABORATORIES LIMITED-BR-ALKEM-2022-01143",
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"abstract": "To describe the features of chronic sinusitis associated with the use of tumour necrosis factor (TNF) inhibitors.\n\n\n\nA retrospective review of the medical records between 2003 and 2011 revealed that five patients had developed chronic sinusitis after the start of TNF inhibitor administration and required rhinological evaluation and treatment.\n\n\n\nThe incidence of refractory sinusitis associated with TNF inhibitors was approximately 2%. Of the five patients identified, four patients were medicated with etanercept and one with infliximab. The maxillary sinus was most commonly involved and cultures of the sinus discharge revealed Pseudomonas aeruginosa in three cases. Two patients showed improvement of sinusitis with antibiotic medication, despite the continuous use of TNF inhibitor, while in two other patients, sinusitis was resistant to antibiotic medication. Another patient who had developed recurrence of sinusitis after complete remission of previous chronic sinusitis by endoscopic sinus surgery showed remission only after cessation of TNF inhibitor.\n\n\n\nChronic sinusitis associated with TNF inhibitors is considered to be a new disease entity, and it will become more common due to the increasing use of TNF inhibitors.",
"affiliations": null,
"authors": "Yoshihara|S|S|;Kondo|K|K|;Kanaya|K|K|;Suzukawa|K|K|;Baba|S|S|;Toma-Hirano|M|M|;Kikuta|S|S|;Iwasaki|Y|Y|;Fujio|K|K|;Yamasoba|T|T|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068800:Etanercept",
"country": "Netherlands",
"delete": false,
"doi": "10.4193/Rhino13.074",
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"issn_linking": "0300-0729",
"issue": "52(3)",
"journal": "Rhinology",
"keywords": null,
"medline_ta": "Rhinology",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D002908:Chronic Disease; D004198:Disease Susceptibility; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D000069285:Infliximab; D015523:Maxillary Sinusitis; D008875:Middle Aged; D011859:Radiography; D018124:Receptors, Tumor Necrosis Factor; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0347242",
"other_id": null,
"pages": "246-51",
"pmc": null,
"pmid": "25271530",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tumour necrosis factor inhibitor-associated sinusitis.",
"title_normalized": "tumour necrosis factor inhibitor associated sinusitis"
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"abstract": "The goal of the present cohort study was to review outcomes of patients exposed to interferon beta-1b during pregnancy.\nPregnancy cases with exposure to interferon beta-1b reported to Bayer's pharmacovigilance (PV) database from worldwide sources from January 1995 through February 2018 were retrieved for evaluation. Only cases where pregnancy outcomes were unknown at the time of reporting (i.e. prospective cases) were included in the analysis of this retrospective cohort study.\nAs of February 2018, 2581 prospective pregnancies exposed to interferon beta-1b were retrieved from the database; 1348 pregnancies had documented outcomes. The majority of outcomes [1106 cases (82.0%)] were live births. Health status was known for 981 live births (no known health status for 125). Most of the prospective pregnancies with known outcomes corresponded to live births with no congenital anomalies [896 cases (91.3%)]. Spontaneous abortion occurred in 160 cases (11.9%). Congenital birth defects were observed in 14/981 live births with known health status [1.4%, 95% confidence interval (CI) 0.78-2.38]. No consistent pattern in the type of birth defect was identified. Rates of both spontaneous abortion and birth defects were not higher than the general population.\nThese PV data, the largest sample of interferon beta-1b-exposed patients reported to date, suggest no increase in risk of spontaneous abortion or congenital anomalies in women exposed during pregnancy.",
"affiliations": "Department of Neurology, St. Joseph and St. Elisabeth Hospital, Ruhr University, Bleichstrasse 15, Bochum, 44787, Germany.;Bayer, Whippany, NJ, USA.;Bayer AG, Berlin, Germany.;Bayer, Whippany, NJ, USA.;Bayer AG, São Paulo, Brazil.",
"authors": "Hellwig|Kerstin|K|https://orcid.org/0000-0003-4467-9011;Duarte Caron|Fernando|F|;Wicklein|Eva-Maria|EM|;Bhatti|Aasia|A|;Adamo|Alessandra|A|",
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"doi": "10.1177/1756286420910310",
"fulltext": "\n==== Front\nTher Adv Neurol Disord\nTher Adv Neurol Disord\nTAN\nsptan\nTherapeutic Advances in Neurological Disorders\n1756-2856 1756-2864 SAGE Publications Sage UK: London, England \n\n10.1177/1756286420910310\n10.1177_1756286420910310\nNeurological Disorders in Women\nOriginal Research\nPregnancy outcomes from the global pharmacovigilance database on interferon beta-1b exposure\nhttps://orcid.org/0000-0003-4467-9011Hellwig Kerstin Department of Neurology, St. Joseph and St. Elisabeth Hospital, Ruhr University, Bleichstrasse 15, Bochum, 44787, Germany\n Duarte Caron Fernando Bayer, Whippany, NJ, USA\n Wicklein Eva-Maria Bayer AG, Berlin, Germany\n Bhatti Aasia Bayer, Whippany, NJ, USA\n Adamo Alessandra Bayer AG, São Paulo, Brazil\n k.hellwig@klinikum-bochum.de\n9 3 2020 \n2020 \n13 175628642091031018 9 2019 6 1 2020 © The Author(s), 20202020SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (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).Background:\nThe goal of the present cohort study was to review outcomes of patients exposed to interferon beta-1b during pregnancy.\n\nMethods:\nPregnancy cases with exposure to interferon beta-1b reported to Bayer’s pharmacovigilance (PV) database from worldwide sources from January 1995 through February 2018 were retrieved for evaluation. Only cases where pregnancy outcomes were unknown at the time of reporting (i.e. prospective cases) were included in the analysis of this retrospective cohort study.\n\nResults:\nAs of February 2018, 2581 prospective pregnancies exposed to interferon beta-1b were retrieved from the database; 1348 pregnancies had documented outcomes. The majority of outcomes [1106 cases (82.0%)] were live births. Health status was known for 981 live births (no known health status for 125). Most of the prospective pregnancies with known outcomes corresponded to live births with no congenital anomalies [896 cases (91.3%)]. Spontaneous abortion occurred in 160 cases (11.9%). Congenital birth defects were observed in 14/981 live births with known health status [1.4%, 95% confidence interval (CI) 0.78–2.38]. No consistent pattern in the type of birth defect was identified. Rates of both spontaneous abortion and birth defects were not higher than the general population.\n\nConclusions:\nThese PV data, the largest sample of interferon beta-1b-exposed patients reported to date, suggest no increase in risk of spontaneous abortion or congenital anomalies in women exposed during pregnancy.\n\nincidence studiesmultiple sclerosisneonatalobservational studyBayerhttps://doi.org/10.13039/100004326cover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nMultiple sclerosis (MS), a chronic demyelinating disease, more common in women than in men, is frequently diagnosed in young patients during their peak reproductive years.1 Although MS has not been shown to increase the rate of adverse pregnancy outcomes,2 information regarding the risk associated with exposure to disease-modifying therapies (DMTs) has been limited. Animal data suggested an increased risk of early pregnancy losses. Studies in humans had sample sizes too small to draw firm conclusions; therefore, we aim to use a pharmacovigilance (PV) database as an alternative source of information on exposure during pregnancy, which is crucial for guiding decision-making during this time period.\n\nCurrent data on DMT exposure during pregnancy are limited by small sample sizes and the potential for reporting bias. As such, guidelines for the treatment offer little guidance on DMTs during pregnancy, suggesting that patients consider deferring DMTs until after pregnancy.3,4 Discontinuation of DMTs for several months by patients who intend to become pregnant might also precipitate the reactivation of well-controlled MS, which could result in accumulated neurological disability. Concerns also arise when patients have an unplanned pregnancy during treatment.5\n\nInterferon beta-1b (Betaferon®/Betaseron®, Bayer AG; Extavia, Novartis Pharmaceuticals Corporation) demonstrated a favorable safety and efficacy profile in patients with clinically isolated syndrome suggestive of MS, relapsing MS, and secondary progressive MS.6–13 Some preliminary evidence on the effects of exposure during pregnancy has been reported, suggesting a relatively low risk of abnormal outcomes.14,15 In the present study, we aimed to strengthen the data regarding interferon beta-1b exposure during pregnancy by analyzing a large sample size from a PV database.\n\nMethods\nPregnancy cases with exposure to interferon beta-1b reported to Bayer from worldwide sources up to February 2018 were retrieved from Bayer’s global PV database for this retrospective cohort study. All cases were assessed for medical confirmation (confirmed versus unconfirmed), as the medically confirmed cases would present to be more reliable sources of information than patient-reported cases. However, all cases received the same level of surveillance with similar follow-up processes. The database contains data on more than 3800 pregnancies with exposure to interferon beta-1b collected over more than 20 years since January 1995, making it the largest dataset available on interferon beta-1b exposure to date, and the source of many cases that can be assessed for patterns of outcomes.\n\nIn order to limit the potential for recall bias in the dataset, only prospective cases (patients who have been exposed to interferon beta-1b but whose data were entered into the database prior to the knowledge of the pregnancy outcome or prior to the detection of a congenital malformation)16,17 were included in the present analysis as retrospective pregnancy cases (data acquired after the outcome of the pregnancy is known or after the detection of a congenital malformation) have an inherent reporting bias toward adverse outcomes as normal outcomes are less likely to be reported.16,17 This may lead to a higher proportion of abnormal outcomes that does not reflect the ‘true’ prevalence rate.16 All considered cases were consistent with the European Medicines Agency guidelines on exposure to medicinal products during pregnancy.16 The database included pregnancies that were reported spontaneously, during clinical trials, in registries, or through patient support programs, where patients were supervised by nursing staff when the pregnancies were confirmed. Outcomes and follow-up information were collected from patients and their health care providers. Institutional Review Board (IRB) approval was not required for the analysis of these PV data.\n\nThe calculations of rates for pregnancy losses were based on the total number of known pregnancies outcomes and the rates of outcomes after birth were based among the total number of cases with known live birth outcomes. Calculations of outcomes were conducted using the following formulas:\n\nRate of live births = (total live births/total number known pregnancy outcomes) × 100\n\nRate of spontaneous abortions = (total number of spontaneous abortions/total number of known pregnancy outcomes) × 100\n\nRate of congenital anomalies = (total pregnancies with congenital anomaly/total number of live births with known outcomes) × 100\n\nFor these calculations, live births included those classified as a healthy child, nonhealthy child, congenital anomaly, and live birth with missing information on health status. The congenital anomalies were registered in the safety database and described ‘as reported,’ and were classified as per ICD-10 exclusively for this study by the authors with the intention to facilitate and group the terms. Pregnancy losses included ectopic pregnancies, spontaneous abortions, stillbirth/fetal death. We defined spontaneous abortions as pregnancy losses occurring at less than 22 weeks gestation without elective medical or surgical intervention, which includes the subdivision of threatened abortions, incomplete abortions, inevitable abortions, missed abortions, septic abortions, complete abortions, and recurrent spontaneous abortions.16,18 After 22 weeks, live births, or stillbirths, were defined as the complete expulsion or extraction of products of conception at any point during gestation.16\n\nSpontaneous abortions were compared with reference rates of abnormal pregnancy outcomes from the general population. Rates of pregnancies resulting in congenital disorders in the database were compared with rates from the general population using the EUROCAT database, a European network of population-based registries for the epidemiologic surveillance of congenital anomalies (2012–2016),19 and the Metropolitan Atlanta Congenital Defects Program (MACDP) database, a US population–based system that records birth defects (1978–2005).20 Approximately 80% of the case reports came from the United States and Europe, and, therefore, these American and European databases were considered appropriate for comparison. The exact Clopper Pearson method was used to calculate 95% confidence intervals (95% CIs). The standardized incidence ratio (SIR) for birth defects was calculated as the ratio of observed to expected events, with 95% CI calculated using the exact Poisson method by Owen. Any SIR smaller than 1.00 indicated a lower than expected number of birth defects.\n\nResults\nAs of February 2018, there were a total of 3884 pregnancy cases in the database, of which 2581 prospective pregnancies exposed to interferon beta-1b were retrieved from 2548 individual case safety reports (Figure 1). A total of 1348 pregnancies had documented outcomes and were included in the data analyses regardless of gestational age. The majority of cases came from North America (43%, including 37% from the US) and Europe (41%, including 22% from Germany) (Figure 2). Most of the cases (83%) were solicited from observational studies and Patient Support Programs. From the remaining spontaneous reports (17%), 62% were medically confirmed. Most exposures (59.6%) occurred during the first trimester (Table 1).\n\nFigure 1. Distribution of cases.\n\nFigure 2. Distribution of pregnancy cases by country.\n\nTable 1. Timing of interferon beta-1b exposure.\n\nTime of exposure, n (%)\tBefore\nconception\nn = 6\tFirst\ntrimester\nn = 909\tSecond\ntrimester\nn = 38\tThird\ntrimester\nn = 9\tTiming\nunknown\nn = 386\tTotal\nn = 1348\t\n\nn\n\t% (95% CI)\t\nTotal live births\t4 (66.7)\t745 (82.0)\t36 (94.7)\t9 (100)\t312 (80.8)\t1106\t82.0 (79.89, 84.06)\t\nTotal live birth with known health statusa\t3 (50.0)\t675 (74.3)\t32 (84.2)\t8 (88.9)\t263 (68.1)\t981\t72.8 (70.31, 75.14)\t\nLive birth, missing information for health status\t1 (16.7)\t70 (0.08)\t4 (10.5)\t1 (11.1)\t49 (12.7)\t125\t9.3 (7.78, 10.95)\t\nTotal known pregnancy outcomesb\t6 (17.1)\t909 (61.9)\t38 (52.8)\t9 (52.9)\t386 (39.1)\t1348\t100.0\t\n Pregnancy loss\t2 (33.3)\t164 (18.0)\t2 (5.3)\t0 (0.0)\t74 (19.2)\t242\t18.0 (15.94, 20.11)\t\n Ectopic pregnancies\t0 (0.0)\t3 (0.003)\t0 (0.0)\t0 (0.0)\t4 (1.0)\t7\t0.5 (0.21, 1.07)\t\n Spontaneous abortion\t2 (33.3)\t110 (12.1)\t1 (2.6)\t0 (0.0)\t47 (12.2)\t160\t11.9 (10.19, 13.72)\t\n Elective abortion\t0 (0.0)\t26 (2.9)\t0 (0.0)\t0 (0.0)\t16 (4.1)\t42\t3.1 (2.25, 4.19)\t\n Therapeutic abortion\t0 (0.0)\t10 (1.1)\t0 (0.0)\t0 (0.0)\t3 (0.8)\t13\t1.0 (0.51, 1.64)\t\n Stillbirth/fetal death\t0 (0.0)\t15 (1.7)\t1 (2.6)\t0 (0.0)\t4 (1.0)\t20\t1.5 (0.91, 2.28)\t\n Live birth, child healthy\t3 (100.0)\t607 (89.9)\t30 (93.8)\t8 (100.0)\t248 (94.3)\t896\t91.3 (89.40, 93.02)\t\n Live birth, child not healthy\t0 (0.0)\t57 (8.4)\t2 (6.3)\t0 (0.0)\t12 (4.6)\t71\t7.2 (5.70, 9.04)\t\n Live birth with congenital anomaly\t0 (0.0)\t11 (1.6)\t0 (0.0)\t0 (0.0)\t3 (1.1)\t14\t1.4 (0.78, 2.38)\t\nPregnancy outcome unknown\t29 (82.9)\t560 (38.1)\t34 (47.2)\t8 (47.1)\t602 (60.9)\t1233\t47.8 (45.83, 49.72)\t\nTotal cases\t35 (1.4)\t1469 (56.9)\t72 (2.8)\t17 (0.7)\t988 (38.3)\t2581\t100.0\t\na This total was used to calculate the percentage of live birth events.\n\nb This total was used to calculate the percentage of pregnancy losses.\n\nCI, confidence interval.\n\nThe majority of the outcomes [1106/1348, 82.0% (95% CI 79.89, 84.06)] were live births (Figure 3). A total of 896 cases [91.3% (95% CI 89.40, 93.02)] were live births of healthy children with no congenital anomalies.\n\nFigure 3. Pregnancy outcomes.\n\naIncluding live births that reported events which are not congenital anomalies (for example, neonatal jaundice).\n\nbLive births where there was no complete information on child health status so congenital anomalies could not be excluded.\n\nSpontaneous abortion occurred in 160 cases [11.9% (95% CI 10.19, 13.72)]. Patient age at abortion varied from 16 to 48 years (median of 31 years). Gestational age information was available in 43% (69/190) of the spontaneous abortions prospectively reported, which varied from 3 to 18 weeks (median of 8 weeks). Six patients reported history of previous spontaneous abortion and two had previous elective abortions. Alternative explanations were available for six cases, and included car accident, thyroid disease, myoma, metabolic, and cardiac disorder. Four patients reported to be taking several concomitant drugs at the time of the abortion, including bupropion, venlafaxine, solumedrol, clonazepam, trazodone, lioresal, and antiepileptics.\n\nOne fetal death at the second trimester of gestation was related to chromosomal anomaly (Trisomy 21), and three patients opted for therapeutic/elective abortion due to congenital anomalies of the fetus: spina bifida and diaphragmatic hernia, gastroschisis, and anencephaly. For most of the spontaneous, elective, and therapeutic abortions, information about congenital anomalies was either not observed or not reported.\n\nCongenital anomalies (Table 2) were observed in 14 of 981 live births with known health status [1.4% (95% CI 0.78, 2.38)]. Maternal age at birth varied from 23 to 38 years (median 31 years). This rate of birth defects (1.4%) was comparable to both the MACDP database reference rate of major congenital anomalies in the US population (2.8%) and to the EUROCAT database (2.4%) (Table 3).19,20 The SIR for birth defects was 0.61 (95% CI 0.31, 0.94). No consistent pattern in the type of birth defect was identified. Six patients reported pregnancy history of prematurity and spontaneous or elective abortions. A congenital heart defect was observed in one neonate of a gemellar gestation, with the other neonate healthy.\n\nTable 2. Congenital anomalies from live birth outcomes with known health status.\n\nPatient information\tGestational information\tChild information\t\nAge\tMedical history\tConcomitant drugs\tPregnancy history\tGestational age at drug exposure\tGestational age at delivery\tCongenital anomaly as reported/MedDRA PT\tClassification by ICD 10 system\t\n24\tHPV\tEthinylestradiol, etonogestrel, oxycocet\tG3P3. Premature newborn death 3 weeks postpartum\t7 weeks\t36 weeks\tPlagiocephaly/Plagiocephaly\tCongenital musculoskeletal deformities of head, face, spine and chest\n(Q67)\t\n31\tN/A\tZolpidem, tretinoin, benzoyl peroxide with clindamycin, prednisone, temazepam, acyclovir, baclofen, ibuprofen, naproxen\tG2P1A1. Previous spontaneous abortion\tFirst trimester\tN/A\tCongenital knee dislocation/Congenital knee dislocation\tOther congenital musculoskeletal deformities\n(Q68)\t\n25\tN/A\tN/A\tG2P2\tFirst trimester\tN/A\tRight hand 6th digit/Polydactyly\tPolydactyly\n(Q69)\t\n31\tN/A\tN/A\tN/A\t6 weeks\t39 weeks, 4 days\t2 hamartomas in left ear/Hamartoma\tPhakomatoses, not elsewhere classified\n(Q85)\t\n34\tN/A\tOxycocet\tN/A\tN/A\t38 weeks\tDouble outlet ventricle anomaly/Double outlet right ventricle\tCongenital malformations of cardiac chambers and connections\n(Q20)\t\n38\tN/A\tHeparin-fraction, progesterone in oil\tG3P3. Cervical incompetence\tN/A\t34 weeks\tDown’s syndrome/Trisomy 21\tDown syndrome\n(Q90)\t\n35\tN/A\tN/A\tN/A\tN/A\t35 weeks, 4 days\tTrisomy 21 and duodenal atresia/Trisomy 21, Duodenal atresia\tDown syndrome\n(Q90)/Congenital absence, atresia and stenosis of small intestine\n(Q41)\t\n36\tN/A\tImmunoglobulin\tN/A\tFirst trimester\t38 weeks, 3 days\tRenal dysgenesis/Renal aplasia\tRenal agenesis and other reduction defects of kidney\n(Q60)\t\n31\tN/A\tAcetylsalicylic acid, Wobenzyme®a\tN/A\t6 weeks\tN/A\tRenal reflux II and left auricular dysplasia/Congenital vesicoureteric reflux, ear malformation\tCongenital obstructive defects of renal pelvis and congenital malformations of ureter (Q62)/Other congenital malformations of ear\n(Q17)\t\nN/A\tMS exacerbation, UTI during pregnancy\tMacrobid and recreational marijuana\tG4P1 with 3 elective abortions due to MS\t1 week\tN/A\tRight renal pyelectasis/Pyelocaliectasis\tCongenital obstructive defects of renal pelvis and congenital malformations of ureter\n(Q62)\t\n34\tN/A\tN/A\tN/A\tFirst trimester\tN/A\tCleft palate/Cleft palate\tCleft palate\n(Q35)\t\n29\tObesity, HTN\tNifedipine\tN/A\tFirst trimester\tN/A\tSpina bifida/Spina bifida\tSpina bifida\n(Q05)\t\n23\tHTN during pregnancy\tSertraline\tG1P1\t5 weeks\t38 weeks\tVentriculoseptal defect, patent ductus arteriosus, patent foramen ovale, hip dysplasia/Ventricular septal defect, Patent ductus arteriosus, developmental hip dysplasia, Atrial septal defect\tCongenital malformations of cardiac septa\n(Q21)/Congenital malformations of great arteries\n(Q25)/Congenital malformations of cardiac septa\n(Q21)/Congenital deformities of hip\n(Q65)\t\n32\tHTN, previous conisation\tFerrous sulfate\tN/A\t4 weeks\t38 weeks\tVentricular septal defect/Ventricular septal defect\tCongenital malformations of cardiac septa\n(Q21)\t\na Wobenzyme is a blend of pancreatin, protease, chymotrypsin, bromelaine, papain, and rutosid.\n\nGPA, gravida, para, abortus; HTN, hypertension; MS, multiple sclerosis; N/A, not available; UTI, urinary tract infection.\n\nTable 3. Congenital anomalies in the interferon beta-1b sample versus the MACDP and EUROCAT databases.\n\nInterferon beta-1b database sample\n\nRate of congenital anomalies\tMACDP database\n\nRate of major congenital anomalies\t\n1.4%a\t2.8%b\t\nInterferon beta-1b database sample\n\nObserved number of cases\tEUROCAT database\n\nExpected number of cases\t\n14c\t25d\t\na Proportion of sample from prospective cases of pregnancies with exposure to interferon beta-1b.\n\nb Number of infants and fetuses with a major birth defect that were delivered during a specified period divided by the number of live births during that period.\n\nc Number of pregnancies with congenital anomalies in the sample from prospective cases of pregnancies with exposure to interferon beta-1b.\n\nd Calculated per the EUROCAT reference prevalence rate of congenital anomalies (2012–2016): 2558.2/100,000 births. Rate calculated as the number of cases with congenital anomalies, divided by the number of cases resulting in birth (live birth, fetal death/stillbirth, and termination of pregnancy for fetal anomaly after prenatal diagnosis).\n\nEUROCAT, European network of population-based registries for the epidemiologic surveillance of congenital anomalies; MACDP, Metropolitan Atlanta Congenital Defects Program.\n\nA separate analysis was conducted to assess the potential for bias in retrospectively reported cases within the database. A total of 1303 cases were retrospectively reported to the database (i.e. after pregnancy outcome was already known). Within the retrospective subset, 1219 cases (93.6%) included known pregnancy outcomes, compared with 47.8% of prospective cases. Timing of interferon beta-1b exposure was unknown in 58.8% of retrospective cases. The percentage of live births in the retrospective subset was 69.2% (compared with 82.0% in the prospective subset). Negative pregnancy outcomes were reported more frequently in the retrospective cohort than in the prospective cohort, including spontaneous abortions (21.2% versus 11.9%) and congenital anomalies (5.6% versus 1.4%).\n\nDiscussion\nIn this study containing the largest worldwide sample of patients exposed to interferon beta-1b during pregnancy reported in the global PV database, we did not find an increase in the rate of abnormal pregnancy outcomes. Rates of spontaneous abortion and major or minor birth defects were not higher than background estimates from the general population. Therefore, our data provide important information showing that first-trimester exposure to interferon beta-1b did not increase the risk of adverse pregnancy outcomes.\n\nIt is important to note that the rates of birth defects in the present analysis were lower than those reported in population data, and the SIR suggested a lower than expected rate of birth defects. However, the 95% CIs for these calculations were relatively wide and the upper limits were close to the expected population range, suggesting that there is no meaningful difference between the present study and the MADCP or EUROCAT data. While these wide CIs were likely driven by the relatively small number of congenital anomalies, this study still captured the largest sample of interferon beta-1b-exposed patients to date, and, therefore, had the highest statistical power to measure these outcomes.\n\nOnly prospective cases were used to estimate prevalence rates of abnormal pregnancy outcomes. A strength of using prospective cases is that it allows for the calculation of an estimated risk, as the occurrence of adverse events and total number of exposure pregnancies are known.17 Retrospective pregnancy cases have an inherent reporting bias because they may be influenced by the outcome itself, distorting the actual rates of these adverse outcomes, and may lead to unfounded fears among pregnant women who could benefit from the continuation of the treatment.17,21–23 Indeed this potential bias is shown in the higher rates of spontaneous abortion and congenital anomalies in retrospectively reported cases relative to the prospectively reported cases in the interferon beta-1b PV database. Consequently, this prospective sample, the largest sample of patients with exposure to interferon beta-1b during pregnancy reported to date, more accurately reflects the effects of interferon beta-1b on pregnancy outcomes.\n\nResults similar to this study have been reported in other analyses of beta interferon exposure during pregnancy. The 99 interferon beta-1b-exposed pregnancies captured in the prospective US Betaseron Pregnancy Registry resulted in 83 (86.4%) live births, 11 (11.5%) spontaneous abortions, and 5 (5.8%) cases with birth defects.14 An additional registry that collected data from patients in Italy exposed to interferon beta during pregnancy found that only 7 of 88 pregnancies (8%) resulted in spontaneous abortion, and no significant fetal complications were observed in live births.24 Recent registries with interferon beta in pregnancy have shown rates for congenital anomalies that vary from 1.8% to 3.08%.25,26 A study using 445 pregnancies (251 exposed interferon beta, 194 unexposed to DMTs) data from the German Multiple Sclerosis Pregnancy Registry observed that the congenital anomaly rates in live births from interferon beta exposed patients versus patients without DMT exposure to be 3.08% (7/226) versus 5.52% (10/179) (p = 0.197), respectively.25 Additionally, data regarding pregnancy outcomes from interferon beta exposure collected from population-based registers in Finland and Sweden demonstrated that interferon beta exposure during pregnancy was associated with 1.8% [12/683, 95% CI 0.91–3.05] of live births with congenital anomalies, and 3.3% [49/1506, 95% CI 2.42–4.28] in the unexposed cohort.26\n\nIn the past decade, the shift toward preventing disease activity as a goal of treatment has renewed the interest of patients in family planning because patients with MS may face a future with reduced disease-related neurological disability. In fact, pregnancy rates in women with MS have increased over the past several years, in contrast to the trend in the general population of North America of decreasing pregnancy rates.27 Available data suggest that the rate of relapses may decrease during pregnancy; however, natural history studies showed that relapse rates increase after birth.28 There is also evidence to suggest that the risk of postpartum relapses and disability is higher in women with more disease activity before and during pregnancy.29,30\n\nThe findings from these studies examining relapse and disability before, during, and after pregnancy underline the importance of controlling disease activity with DMTs until pregnancy starts. Therefore, it is crucial to assess which DMTs for MS can be considered as having a positive benefit–risk ratio when used during conception, pregnancy, and/or breastfeeding.31,32 The results of the present database analysis suggest that the rates of abnormal pregnancy outcomes in women exposed to interferon beta-1b until conception, and during the first trimester of pregnancy, did not exceed those of the general population. This information is important when a patient plans a pregnancy, taking into consideration the balance between the potential harms that may arise from discontinuation of treatment with interferon beta-1b against the benefit of continuing the treatment until pregnancy is confirmed.\n\nThe characteristics of the interferon beta-1b molecule may limit the possibility of harmful effects during pregnancy. For example, the relatively large size of the molecule may prevent it from crossing the placental barrier.33,34 In addition, the half-life may be relatively short, such that it limits the opportunities for interferon beta-1b molecules to come in contact with the developing fetus.\n\nLimitations of the present study include generally known limitations inherent in data from PV databases, namely the lack of a direct comparator group, the potential for underreporting,35 or for inaccurate or incomplete records, as records are based partly on voluntary reporting from health care professionals and patients. Consequently, the data depend on the individual quality of reports, which is a well-known limitation of spontaneous reporting.17 The data included in our study are ‘as reported,’ and, therefore, rely on the reporters’ accuracy. Furthermore, we cannot disregard the fact that some patients may have been exposed to numerous medications, and the possibility of incorrectly making the association of the pregnancy outcome with the other various treatments the patients were taking. Although spontaneous abortions are commonly said to occur in 15–20% of pregnancies, total spontaneous abortions could be much higher if losses that occur prior to clinical recognition are taken into consideration.36 Patient records in this analysis also primarily reflect exposure to interferon beta-1b during the first trimester of pregnancy; data on exposure during the second and third trimesters were collected from a limited number of patients. However, the first 22 weeks are those most critical with the highest risk of congenital anomalies as well as the most likely clinical scenario for patients on interferon beta-1b. Comparisons to unexposed patients with MS, and/or non-MS controls, would have been helpful, and such comparisons are difficult when working with PV data. Consequently, analyses of PV with comparisons to population data have been implemented successfully in the past.37,38 Furthermore, the comparison with population data should take into consideration that PV data represents reporting rates while SIR uses incidence rates.\n\nThis PV data review is the largest interferon beta-1b dataset evaluated for pregnancy exposure. The data presented here provide evidence that interferon beta-1b exposure during pregnancy did not lead to a pattern of negative pregnancy outcomes. The results of this analysis should add to the body of knowledge to help physicians and patients in their benefit–risk evaluation, and to make a more informed decision on treatment when planning pregnancy.\n\nWe are grateful to the patients and their physicians for contributing data to the database. Jong Jun Shin, of VMLY&R Health, provided medical writing assistance that was funded by Bayer.\n\nFunding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Bayer.\n\nConflict of interest statement: KH has received honoraria and research support from Bayer, Biogen, Teva, Novartis, Sanofi Genzyme, and Merck. FDC, EW, AB, and AA are salaried employees at Bayer AG.\n\nORCID iD: Kerstin Hellwig \nhttps://orcid.org/0000-0003-4467-9011\n==== Refs\nReferences\n1 \nCoyle PK Christie S Fodor P , et al\nMultiple sclerosis gender issues: clinical practices of women neurologists\n. Mult Scler \n2004 ; 10 : 582 –588\n.15471377 \n2 \nVaughn C Bushra A Kolb C , et al\nAn update on the use of disease-modifying therapy in pregnant patients with multiple sclerosis\n. 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Neurology \n2006 ; 67 : 1242 –1249\n.16914693 \n11 \nThe IFNB Multiple Sclerosis Study Group . Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial\n. Neurology \n1993 ; 43 : 655 –661\n.8469318 \n12 \nThe IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group . Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial\n. Neurology \n1995 ; 45 : 1277 –1285\n.7617182 \n13 \nMS ESGoib-bisp . Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis\n. Lancet \n1998 ; 352 : 1491 –1497\n.9820296 \n14 \nCoyle PK Sinclair SM Scheuerle AE , et al\nFinal results from the Betaseron (interferon beta-1b) pregnancy registry: a prospective observational study of birth defects and pregnancy-related adverse events\n. BMJ Open \n2014 ; 4 : e004536 .\n15 \nRomero RS Lunzmann C Bugge JP \nPregnancy outcomes in patients exposed to interferon beta-1b\n. J Neurol Neurosurg Psychiatry \n2015 ; 86 : 587 –589\n.25185209 \n16 \nEuropean Medicines Agency . Guideline on the exposure to medicinal products during pregnancy: need for post-authorisation data\n, https://www.ema.europa.eu/documents/regulatory-procedural-guideline/guideline-exposure-medicinal-products-during-pregnancy-need-post-authorisation-data_en.pdf. (accessed 15 January 2019 ).\n17 \nKennedy DL Uhl K Kweder SL \nPregnancy exposure registries\n. Drug Saf \n2004 ; 27 : 215 –228\n.15003034 \n18 \nGriebel CP Halvorsen J Golemon TB , et al\nManagement of spontaneous abortion\n. Am Fam Physician \n2005 ; 72 : 1243 –1250\n.16225027 \n19 \nEUROCAT . Prevalence tables\n, http://www.eurocat-network.eu/accessprevalencedata/prevalencetables. (accessed 7 December 2018 ).\n20 \nUS Centers for Disease Control . Update on overall prevalence of major birth defects - Atlanta, Georgia, 1978–2005\n, https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5701a2.htm. (accessed 7 December 2018 ).\n21 \nU.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research . FDA guidance for industry: postapproval pregnancy safety studies\n, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/postapproval-pregnancy-safety-studies-guidance-industry (accessed 25 February 2020 ).\n22 \nBar-Oz B Moretti ME Mareels G , et al\nReporting bias in retrospective ascertainment of drug-induced embryopathy\n. Lancet \n1999 ; 354 : 1700 –1701\n.10568577 \n23 \nKoren G Nickel S \nSources of bias in signals of pharmaceutical safety in pregnancy\n. Clin Invest Med \n2010 ; 33 : E349 –E355\n.21134336 \n24 \nAmato MP Portaccio E Ghezzi A , et al\nPregnancy and fetal outcomes after interferon-beta exposure in multiple sclerosis\n. Neurology \n2010 ; 75 : 1794 –1802\n.21079181 \n25 \nThiel S Langer-Gould A Rockhoff M , et al\nInterferon-beta exposure during first trimester is safe in women with multiple sclerosis-A prospective cohort study from the German Multiple Sclerosis and Pregnancy Registry\n. Mult Scler \n2016 ; 22 : 801 –809\n.26920382 \n26 \nHellwig K Geissbuhler Y Sabido M , et al\nPregnancy and infant outcomes with interferon beta: data from the European Interferon Beta Pregnancy Registry and population based registries in Finland and Sweden\n. Poster presented at the Annual Meeting of the European Committee for Treatment and Research in Multiple Sclerosis \n10–12 October 2018 , Berlin, Germany .\n27 \nHoutchens MK Edwards NC Schneider G , et al\nPregnancy rates and outcomes in women with and without MS in the United States\n. Neurology \n2018 ; 91 : e1559 –e1569\n.30266889 \n28 \nConfavreux C Hutchinson M Hours MM , et al\nRate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group\n. N Engl J Med \n1998 ; 339 : 285 –291\n.9682040 \n29 \nHughes SE Spelman T Gray OM , et al\nPredictors and dynamics of postpartum relapses in women with multiple sclerosis\n. Mult Scler \n2014 ; 20 : 739 –746\n.24107309 \n30 \nPortaccio E Ghezzi A Hakiki B , et al\nPostpartum relapses increase the risk of disability progression in multiple sclerosis: the role of disease modifying drugs\n. J Neurol Neurosurg Psychiatry \n2014 ; 85 : 845 –850\n.24403285 \n31 \nFragoso YD Adoni T Brooks JBB , et al\nPractical evidence-based recommendations for patients with multiple sclerosis who want to have children\n. Neurol Ther \n2018 ; 7 : 207 –232\n.30167914 \n32 \nVukusic S Marignier R \nMultiple sclerosis and pregnancy in the ‘treatment era’\n. Nat Rev Neurol \n2015 ; 11 : 280 –289\n.25896084 \n33 \nChallier JC Guerre-Millo M Nandakumaran M , et al\nClearance of compounds of different molecular size in the human placenta in vitro\n. Biol Neonate \n1985 ; 48 : 143 –148\n.2413911 \n34 \nWaysbort A Giroux M Mansat V , et al\nExperimental study of transplacental passage of alpha interferon by two assay techniques\n. Antimicrob Agents Chemother \n1993 ; 37 : 1232 –1237\n.8328774 \n35 \nLopez-Gonzalez E Herdeiro MT Figueiras A \nDeterminants of under-reporting of adverse drug reactions: a systematic review\n. Drug Saf \n2009 ; 32 : 19 –31\n.19132802 \n36 \nBrown S \nMiscarriage and its associations\n. Semin Reprod Med \n2008 ; 26 : 391 –400\n.18825607 \n37 \nGeissbuhler Y Vile J Koren G , et al\nEvaluation of pregnancy outcomes in patients with multiple sclerosis after fingolimod exposure\n. Ther Adv Neurol Disord \n2018 ; 11 : 1 –9\n.\n38 \nSandberg-Wollheim M Alteri E Moraga MS , et al\nPregnancy outcomes in multiple sclerosis following subcutaneous interferon beta-1a therapy\n. Mult Scler \n2011 ; 17 : 423 –430\n.21220368\n\n",
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"title": "Pregnancy outcomes from the global pharmacovigilance database on interferon beta-1b exposure.",
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"abstract": "A 49-year-old man with chronic obstructive pulmonary disease (COPD) presented with significant tachypnoea, fevers, productive cough and increased work of breathing for the previous 4 days. Laboratory data showed elevated lactate of 3.2 mEq/L. Continuous inhaled ipratropium and albuterol nebuliser treatments were administered. Lactate levels increased to 5.5 and 3.9 mEq/L, at 6 and 12 h, respectively. No infectious source was found and the lactic acidosis cleared as the patient improved. The lactic acidosis was determined to be secondary to respiratory muscle fatigue and inhaled β-agonist therapy, two under-recognised causes of lactic acidosis in patients presenting with respiratory distress. Lactic acidosis is commonly used as a clinical marker for sepsis and shock, but in the absence of tissue hypoperfusion and severe hypoxia, alternative aetiologies for elevated levels should be sought to avoid unnecessary and potentially harmful medical interventions.",
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"authors": "Lau|Emily|E|;Mazer|Jeffrey|J|;Carino|Gerardo|G|",
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"title": "Inhaled β-agonist therapy and respiratory muscle fatigue as under-recognised causes of lactic acidosis.",
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"abstract": "Exposure to hydrocarbon compounds, such as benzene may cause injury to several organ systems. It occurs accidentally or intentionally by ingestion, inhalation, cutaneous exposure and either subcutaneous injection or intravenous injection. We report a patient who injected benzene into the left hemithorax and secondly attempted to commit suicide with paracetamol.\nA 52-year old man was admitted in the hospital because of an attempted suicide with an injection of benzene in the left hemithorax and ingestion of 50 tablets of 500 mg paracetamol. He developed a hydro-tensionpneumothorax due to inflammatory pleural effusion as a reaction to intrathoracic benzene. Therefore a chest-tube was inserted. A few days later he developed an empyema in the left lung and secondly a pectoral abscess, which required surgical debridement. After surgery, recovered fully and after 23 days of hospitalisation he was discharged to a psychiatric care facility.\nHydrocarbon poisoning is either accidentally or intentionally and leads to thoracic pathology in rare cases. The most affected organ system is the respiratory system, and the cytotoxic effects of hydrocarbons can manifest as respiratory failure, pneumonitis and even acute respiratory distress syndrome (ARDS).",
"affiliations": "Department of Surgery, Franciscus Gasthuis & Vlietland, Rotterdam/Schiedam, The Netherlands.;Department of Emergency Medicine, Franciscus Gasthuis & Vlietland, Rotterdam/Schiedam, The Netherlands.;Department of Emergency Medicine, Franciscus Gasthuis & Vlietland, Rotterdam/Schiedam, The Netherlands.;Department of Surgery, Franciscus Gasthuis & Vlietland, Rotterdam/Schiedam, The Netherlands.;Department of Surgery, Franciscus Gasthuis & Vlietland, Rotterdam/Schiedam, The Netherlands.",
"authors": "Pouwels|Sjaak|S|;Nijdam|Chris|C|;Zwinkels|Manon L|ML|;Struijs|Marie-Chantal|MC|;Kortekaas|Robert|R|",
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(17)30231-910.1016/j.rmcr.2018.04.010Case ReportThoracic empyema and pectoral abscess resulting from attempting suicide by injection of benzene in the pleural cavity Pouwels Sjaak Sjaakpwls@gmail.coma∗Nijdam Chris bZwinkels Manon L. bStruijs Marie-Chantal aKortekaas Robert aa Department of Surgery, Franciscus Gasthuis & Vlietland, Rotterdam/Schiedam, The Netherlandsb Department of Emergency Medicine, Franciscus Gasthuis & Vlietland, Rotterdam/Schiedam, The Netherlands∗ Corresponding author. Department of Surgery, Franciscus Vlietland, Vlietlandplein 2, 3118 JH, Schiedam, The Netherlands. Sjaakpwls@gmail.com20 4 2018 2018 20 4 2018 24 74 76 5 7 2017 15 4 2018 18 4 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/).Background\nExposure to hydrocarbon compounds, such as benzene may cause injury to several organ systems. It occurs accidentally or intentionally by ingestion, inhalation, cutaneous exposure and either subcutaneous injection or intravenous injection. We report a patient who injected benzene into the left hemithorax and secondly attempted to commit suicide with paracetamol.\n\nCase presentation\nA 52-year old man was admitted in the hospital because of an attempted suicide with an injection of benzene in the left hemithorax and ingestion of 50 tablets of 500 mg paracetamol. He developed a hydro-tensionpneumothorax due to inflammatory pleural effusion as a reaction to intrathoracic benzene. Therefore a chest-tube was inserted. A few days later he developed an empyema in the left lung and secondly a pectoral abscess, which required surgical debridement. After surgery, recovered fully and after 23 days of hospitalisation he was discharged to a psychiatric care facility.\n\nConclusion\nHydrocarbon poisoning is either accidentally or intentionally and leads to thoracic pathology in rare cases. The most affected organ system is the respiratory system, and the cytotoxic effects of hydrocarbons can manifest as respiratory failure, pneumonitis and even acute respiratory distress syndrome (ARDS).\n\nKeywords\nBenzene intoxicationThoracic empyemaHydrocarbon poisoning\n==== Body\n1 Background\nExposure to hydrocarbon compounds, such as benzene may cause injury to several organ systems. It occurs accidentally or intentionally by ingestion, inhalation, cutaneous exposure and either subcutaneous injection or intravenous injection [1]. Most poisoning cases with these compounds occur in children via ingestion; however inhalation poisoning is more common in young adults [1]. Petroleum and gasoline are the most common hydrocarbons that cause poisoning, but self-injection of these hydrocarbons is rare and are purposed by suicidal intent. The clinical manifestation of such injection can vary between respiratory distress, arrhythmia, soft tissue necrosis, thrombophlebitis, abscess formation and chronic bone injury [[1], [2], [3], [4]]. In this article, we report a patient who injected benzene into the left hemithorax and consequently attempted to commit suicide with paracetamol.\n\n2 Case report\nA 52-year old man was admitted in a general hospital because of an attempted suicide (at 11 p.m. the night before) with an injection of benzene in the left hemithorax and ingestion of 50 tablets of 500mg paracetamol. His medical history reports severe alcohol and nicotin abusis, chronic lower back pain and several transient ischaemic events (TIA). Initial evaluation at the Emergency Room revealed no signs of hemodynamic or respiratory instability e.g. the vital signs were tympanic temperature 37.5° Celsius; 90 beats per minute, respiratory rate of 14 breaths per minute, oxygen saturation of 98% and blood pressure of 166/140. Physical examination revealed two small injection marks on the left hemithorax without any subcutaneous swelling of emphysema. His blood work revealed a paracetamol level of 38 mg/L and no signs cardiac abnormalities (normal EKG and troponin levels). He was admitted to the Internal Medicine ward for intraveneous treatment of his paracetamol intoxication with acetylcystein. On day 2, he developed a small pneumothorax at the left upper quadrant of the lung (Fig. 1). Due to a fever (temperature of 39.5° Celsius) and a tachycardia of 125 beats per minute, intravenous antibiotic treatment and prednisone (due to existing chemical pleuritis) was started. The day after the patient developed a respiratory insufficiency because of a hydro-pneumothorax (Fig. 2), therefore a chest tube was inserted in the left hemithorax and he was transferred to the Intensive Care Department for hemodynamic and respiratory monitoring and stabilisation. Secondly on the left hemithorax in the region of the pectoral muscle a subcutaneous swelling of approximately 7 cm was seen for the first time. On the same day a pressure measurement of pectoral muscle compartment was performed and showed a normal intra-compartment pressure. In the next few days, the patient was stabilized and his clinical situation improved, therefore after two days he was transferred to the surgical ward. The following chest x-rays showed improvement of his pulmonary situation, with a small residual pneumothorax left (Fig. 3), therefore the chest tube was removed. Antibiotic treatment was continued intravenously. However in the following two days, the patient developed a fever (temperature of 38.5° Celsius) and his C-reactive protein levels increased from 208 to 304 mg/L. On day 9 (Fig. 4), the chest X-ray revealed a suspect lesion in the basal lobe of the left lung. A CT-scan showed an empyema in the left lung and secondly a pectoral abscess (Fig. 5). On day 11, a Video Assisted Thoracoscopic Surgical (VATS) procedure was performed to evacuate the empyema for the left hemi-thorax and the pectoral abscess was drained. Two chest tubes were inserted during the operation, one at the dorsal side and one at the ventral side. After a few days, our patient significantly improved and the chest tubes were removed. Finally after 23 days of hospitalisation the patient was recovered completely and was discharged to a psychiatric care facility.Fig. 1 Chest X-ray on day 2, showing a small pneumothorax at the left upper quadrant of the left lung.\n\nFig. 1Fig. 2 Chest X-ray on day 3, showing a hydro-tensionpneumothorax of the left lung.\n\nFig. 2Fig. 3 Chest X-ray's on day 4, 5 and 6, showing improvement of the pneumothorax.\n\nFig. 3Fig. 4 Chest X-ray's on day 9, showing an empyema in the left lower lobe of the left lung.\n\nFig. 4Fig. 5 CT-scan images of an empyema of the left lung and a pectoral abscess.\n\nFig. 5\n\n3 Discussion\nHydrocarbon poisoning can lead to thoracic pathology in rare cases [5,6]. Hydrocarbons include three major groups; aliphatics, aromatics and halogenics. Aliphatic hydrocarbons are mostly associated with human poisoning [1]. Hydrocarbon poisoning occurs usually through inhalation or by percutaneous exposure, in rare cases these compounds are injected into the human. Hydrocarbons have detrimental cytotoxic effects and can cause injury to soft-tissues, fat and the nervous system. The most affected organ system is the respiratory system and the cytotoxic effects of hydrocarbons can manifest as respiratory failure, pneumonitis and even acute respiratory distress syndrome (ARDS) [1,7]. Subcutaneous injection of hydrocarbon compounds can cause swelling, redness, tenderness, crepitation and abscess formation according to the volume, the depth and the impregnation time after the injection [[1], [2], [3], [4], [5], [6], [7], [8], [9]].\n\nBronchopleural fistulas are also a frequent complication of intrathoracic injections of hydrocarbon compounds. In the report of Eskandarlou et al. [6] a similar case was presented and they needed frequent surgical procedures and debridements and eventually a segmentectomy and chest wall reconstruction due to the empyema and bronchopleural fistulas formed after such a intoxication attempt.\n\nThe initial evaluation of our patient showed no significant abnormalities besides the high paracetamol level in the blood work. However, the initial evaluation of a patient after intrathoracic injection of a chemical substance needs to be done with extreme caution because changes in the clinical situation can occur rapidly. Firstly, such an injection site should include inspection and palpation of the injection area, and secondly early local treatment in terms of incision, drainage and frequent debridement of necrotic tissue (if needed). Thirdly, irrespective of the injection area, always be cautious for symptoms of possible respiratory failure. When having any doubts about the clinical symptoms and/or presentation of the patient, do make an additional ultrasound and/or chest x-ray.\n\nConflicts of interest\nNone.\n\nFunding\nNone.\n\nContributions\nInitial idea, drafting and finalising manuscript: SP, CN, MZ, MCS, RK.\n\nFinal approval\nSP, CN, MZ, MCS, RK.\n\nAppendix A Supplementary data\nThe following is the supplementary data related to this article:Multimedia component 1\nMultimedia component 1 \n\nAppendix A Supplementary data related to this article can be found at https://doi.org/10.1016/j.rmcr.2018.04.010.\n==== Refs\nReferences\n1 Porraga M. West J.M. Hydrocarbons Bania T. Brent J. Hoffman R.S. Emergency Toxicology 1998 Lippinscott Raven Philadelphia, Pennsylvania 299 313 \n2 Rush M.D. Schoenfeld C.N. Watson W.A. Skin necrosis and venous thrombosis from subcutaneous injection of charcoal lighter fluid (naptha) Am. J. Emerg. Med. 16 5 1998 508 511 9725968 \n3 Paul R. Talukdar A. Bhattacharya R. Santra G. gamma-Benzene hexachloride poisoning leading to acute hepatorenal decompensation BMJ Case Rep. 2013 2013 \n4 Solak I. Cankayali I. Aksu H. Moral A.R. An interesting thinner intoxication case: intrathoracic injection Adv. Ther. 23 3 2006 502 505 16912033 \n5 Bushe C.J. Attempted suicide by intravenous injection of lighter fuel presenting as an unusual cause of crepitus Hum. Toxicol. 5 5 1986 347 3770772 \n6 Eskandarlou M. Moaddab A.H. Chest wall necrosis and empyema resulting from attempting suicide by injection of petroleum into the pleural cavity Emerg. Med. J. EMJ 27 8 2010 616 618 20558490 \n7 Domej W. Mitterhammer H. Stauber R. Kaufmann P. Smolle K.H. Successful outcome after intravenous gasoline injection J. Med. Toxicol. Off. J. Am. Coll. Med. Toxicol. 3 4 2007 173 177 \n8 Federmann G. Fohlinger J. Kurtz V. When necrosis smells of heating oil... what damage fuels can do MMW - Fortschritte Med. 142 5 2000 39 40 \n9 Thaha M.A. McKinnell T.H. Graham K.E. Naasan A.N. Early intervention reduces morbidity in extravasation injuries from 'lighter fuel' injection J. Plast. Reconstr. Aesthetic Surg. JPRAS 60 12 2007 1342 1344\n\n",
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"issue": "24()",
"journal": "Respiratory medicine case reports",
"keywords": "Benzene intoxication; Hydrocarbon poisoning; Thoracic empyema",
"medline_ta": "Respir Med Case Rep",
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"title": "Thoracic empyema and pectoral abscess resulting from attempting suicide by injection of benzene in the pleural cavity.",
"title_normalized": "thoracic empyema and pectoral abscess resulting from attempting suicide by injection of benzene in the pleural cavity"
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"abstract": "BACKGROUND\nData regarding clinical characteristics, therapy, maternal and fetal outcomes of pregnancy-associated acute leukemia are limited.\n\n\nMETHODS\nWe herein, present the data of 27 pregnancy associated acute leukemia [18 acute myeloid leukemia (AML) and 9 acute lymphatic leukemia (ALL)]. Their data were compared to an age matched group of 75 non-pregnant acute leukemia patients admitted and treated during the same period [53 AML and 22 ALL].\n\n\nRESULTS\nComplete remission rates, induction failure and induction deaths showed insignificant differences in pregnant versus non pregnant patients in both types of acute leukemia. Similarly, OS and DFS showed no significant difference between pregnant versus non pregnant patients in both types of acute leukemia. Cox regression analysis was conducted for prediction of OS and DFS in all the studied patients applying age, WBCs, BM blasts, LDH, cytogenetic abnormalities and pregnancy as covariates, Pregnancy was not considered as a risk factor for OS or PFS in univariate or multivariate analysis.\n\n\nCONCLUSIONS\nOur report to the best of our knowledge is the first to present direct evidence that pregnancy has no significant impact on outcome of acute leukemia compared to non-pregnant patients. These results are limited by the small number of cases and should be confirmed in a prospectively larger cohort of patients.",
"affiliations": "The Hematology Unit, Oncology Center, Mansoura University, Egypt. Electronic address: mohmabed@mans.edu.eg.;The Hematology Unit, Oncology Center, Mansoura University, Egypt.;The Hematology Unit, Oncology Center, Mansoura University, Egypt.;The Hematology Unit, Oncology Center, Mansoura University, Egypt.",
"authors": "Mabed|Mohamed|M|;Eisa|Noha|N|;El-Ashwah|Shaimaa|S|;Talaab|Mona|M|",
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"country": "England",
"delete": false,
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"issue": "16()",
"journal": "Cancer treatment and research communications",
"keywords": "Acute leukemia; Chemotherapy; Outcome; Pregnancy",
"medline_ta": "Cancer Treat Res Commun",
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"other_id": null,
"pages": "53-58",
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"pmid": "31299003",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pregnancy associated acute leukemia: Single center experience.",
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"abstract": "Clozapine has proved to be an effective antipsychotic for the treatment of refractory schizophrenia - characterised by the persistence of symptoms despite optimal treatment trials with at least two different antipsychotics at adequate dose and duration - but its use is hampered by adverse effects. The development of clozapine-induced diabetes is commonly considered to arise as part of a metabolic syndrome, associated with weight gain, and thus evolves slowly. We present the case of an individual with refractory schizophrenia and metformin-controlled diabetes who developed rapid-onset insulin-dependent hyperglycaemia immediately after starting clozapine. Given the refractory nature of his illness, the decision was made to continue clozapine and manage the diabetes. This case supports the existence of a more direct mechanism by which clozapine alters glycaemic control, aside from the more routine slow development of a metabolic syndrome.\n\n\nBACKGROUND\nS.S.S. is supported by a European Research Council Consolidator Award (Grant Number 311686) and the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The funders had no role in study design, data collection, data analysis, data interpretation or writing of the report.\n© The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.",
"affiliations": ", MD, University of Granada, Granada, Spain.;, MD, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; National Psychosis Unit, Bethlem Royal Hospital, South London and Maudsley NHS Foundation Trust London, London, UK.;, MBBS PhD, National Psychosis Unit, Bethlem Royal Hospital, South London and Maudsley NHS Foundation Trust London, London, UK.;, BSc, Hull York Medical School, University of York, York, UK.;, MBCHP MRCPsych, National Psychosis Unit, Bethlem Royal Hospital, South London and Maudsley NHS Foundation Trust London, London, UK.;, RMN, National Psychosis Unit, Bethlem Royal Hospital, South London and Maudsley NHS Foundation Trust London, London, UK.;, PhD FRCPsych, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; National Psychosis Unit, Bethlem Royal Hospital, South London and Maudsley NHS Foundation Trust London, London, UK.",
"authors": "Porras-Segovia|Alejandro|A|;Krivoy|Amir|A|;Horowitz|Mark|M|;Thomas|George|G|;Bolstridge|Mark|M|;Ion|Dragos|D|;Shergill|Sukhwinder S|SS|",
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"fulltext": "\n==== Front\nBJPsych OpenBJPsych OpenbjporcpsychbjporcpsychBJPsych Open2056-4724The Royal College of Psychiatrists bjporcpsych00448110.1192/bjpo.bp.117.004481Short ReportRapid-onset clozapine-induced loss of glycaemic control: case report Rapid-onset clozapine-induced diabetesPorras-Segovia et alPorras-Segovia Alejandro Krivoy Amir Horowitz Mark Thomas George Bolstridge Mark Ion Dragos Shergill Sukhwinder S. Alejandro Porras-Segovia, MD, University of Granada, Granada, SpainAmir Krivoy, MD, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK; National Psychosis Unit, Bethlem Royal Hospital, South London and Maudsley NHS Foundation Trust London, London, UKMark Horowitz, MBBS PhD, National Psychosis Unit, Bethlem Royal Hospital, South London and Maudsley NHS Foundation Trust London, London, UKGeorge Thomas, BSc, Hull York Medical School, University of York, York, UKMark Bolstridge, MBCHP MRCPsych, National Psychosis Unit, Bethlem Royal Hospital, South London and Maudsley NHS Foundation Trust London, London, UKDragos Ion, RMN, National Psychosis Unit, Bethlem Royal Hospital, South London and Maudsley NHS Foundation Trust London, London, UKSukhwinder S. Shergill, PhD FRCPsych, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK; National Psychosis Unit, Bethlem Royal Hospital, South London and Maudsley NHS Foundation Trust London, London, UKCorrespondence: Amir Krivoy, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Box PO63, De Crespigny Park, SE5 8AF London, UK. E-mail: amir.krivoy@kcl.ac.uk11 5 2017 5 2017 3 3 138 140 4 1 2017 3 4 2017 5 4 2017 © 2017 The Royal College of Psychiatrists2017The Royal College of PsychiatristsThis is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Clozapine has proved to be an effective antipsychotic for the treatment of refractory schizophrenia – characterised by the persistence of symptoms despite optimal treatment trials with at least two different antipsychotics at adequate dose and duration – but its use is hampered by adverse effects. The development of clozapine-induced diabetes is commonly considered to arise as part of a metabolic syndrome, associated with weight gain, and thus evolves slowly. We present the case of an individual with refractory schizophrenia and metformin-controlled diabetes who developed rapid-onset insulin-dependent hyperglycaemia immediately after starting clozapine. Given the refractory nature of his illness, the decision was made to continue clozapine and manage the diabetes. This case supports the existence of a more direct mechanism by which clozapine alters glycaemic control, aside from the more routine slow development of a metabolic syndrome.\n\nDeclaration of interest\nS.S.S. is supported by a European Research Council Consolidator Award (Grant Number 311686) and the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The funders had no role in study design, data collection, data analysis, data interpretation or writing of the report.\n\nCopyright and usage\n© The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.\n==== Body\nClozapine is an atypical antipsychotic medication used in the treatment of refractory schizophrenia, a condition defined as the persistence of symptoms despite optimal treatment trials with at least two different antipsychotics at adequate dose and duration. Despite its unique benefits, it can also cause severe side-effects, most notably agranulocytosis, and as a consequence its use is strictly regulated in most countries and requires routine monitoring of full blood count.1\n\nAlthough many atypical antipsychotics, such as quetiapine or olanzapine, can induce type 2 diabetes mellitus,2,3 clozapine is believed to pose a higher risk of developing this metabolic disorder.4 This diabetes is conventionally thought to be associated with the development of a broader metabolic syndrome accompanied by an increase in obesity. However, could there be a more directly acting mechanism influencing glycaemic control? There are some data that suggest that antagonism of M3 cholinergic receptors, a feature shared by clozapine and olanzapine, can cause beta-cell dysfunction5; whereas Smith et al6 have suggested clozapine could directly increase the secretion of glucagon, leading to a rapid elevation of glucose levels; and others have proposed direct mitochondrial damage to insulin-responsive cells.7 It is of note that there are instances of acute loss of glycaemic control reported with other atypical antipsychotic compounds.8–10\n\nNevertheless, the onset of diabetes mellitus poses a serious challenge to practitioners and is a significant reason for clozapine discontinuation11–13; however, given the lack of alternative treatments, there is an argument for aggressive treatment of the diabetes mellitus to allow clozapine to be continued or reinitiated.12\n\nHere, we present the case of an individual with refractory schizophrenia who developed rapid-onset insulin dependence at the commencement of his clozapine therapy – too short a time frame for an acute worsening of a metabolic syndrome, implicating a direct mechanism for rapid loss of glycaemic control – and in whom diabetes was treated successfully without discontinuing clozapine.\n\nCase presentation\nMr A is a 48-year-old male of African origin with a diagnosis of treatment-resistant paranoid schizophrenia. He was transferred to the National Psychosis Unit, a tertiary referral in-patient service, for re-titration of clozapine after cessation because of side-effects.\n\nMr A was first known to UK psychiatric services in 1993, the year of his arrival in this country, at the age of 25. He presented with paranoid and grandiose delusions, as well as auditory hallucinations. His symptoms persisted despite treatment and were often associated with violent behaviour, requiring several involuntary admissions to psychiatric wards over the years. Various medications were trialled, including olanzapine (15 mg daily for approximately 4 years), risperidone (up to 9 mg daily for approximately 5 years), paliperidone palmitate (150 mg monthly for approximately 2 years), flupentixol depot (40 mg three times a week for approximately 10 years) and clozapine (up to 400 mg a day for 2 non-consecutive years).\n\nClozapine proved to be the most effective treatment for symptom control, but was stopped on two occasions after a rapid loss of glycaemic control, requiring insulin treatment.\n\nShortly after both clozapine cessations, his diabetes had improved to the point that insulin administration was no longer necessary, and his glycaemic control was maintained with metformin 1 g twice daily. He also suffered from hypertension (average blood pressure: 165/101 mmHg) and hypercholesterolemia (low-density lipoprotein (LDL) levels: 270 mg/dL). He was a one-pack-per-day smoker and was overweight (body mass index (BMI) of 28.7 at the time of admission).\n\nOn admission to the unit, Mr A was irritable, often shouting and at times intimidating towards staff. He presented with paranoid and grandiose delusions and was grossly thought-disordered. Perceptual abnormalities were suspected, as he was often observed responding to unseen stimuli.\n\nThe antipsychotic treatment on admission – risperidone – was switched to lurasidone because of a more benign metabolic side-effect profile.14 However, this was not effective in controlling symptoms and was later changed to amisulpride, which also produced no improvement in his mental state. Finally, given the lack of any progress, it was decided to commence clozapine.\n\nAt this stage, it was decided to seek collaboration with the local endocrinologists to safely manage the risk of emergent loss of glycaemic control. The individual’s fasting blood glucose levels were measured before commencing clozapine to establish a baseline (4–6 mmol/L). Despite using a slow-titration approach, 6 days after commencing clozapine his glucose levels started to increase linearly (see Fig. 1). HbA1c values also increased over a short period of time (from 7.3 to 12.1% in the course of 2 months). Interestingly, clozapine dose was only 100 mg (serum levels: 65 ng/ml) at the time his glucose levels were becoming elevated. This elevation was associated with the increase of clozapine dose.\n\nFig. 1 Correlation of clozapine daily dose with fasting blood sugar and HbA1c levels, prior to the administration of insulin.\nHe was commenced on insulin therapy, at an initial dose of four units of fast-acting insulin once daily. Clozapine was slowly titrated upwards in increments of 25 mg, once the blood glucose levels had stabilised for 2–3 days, until a dose of 700 mg/day (serum levels: 460 ng/ml) was reached. The dose of insulin was increased slowly until he achieved glycaemic control while being treated with 52 units of medium-acting insulin twice daily. He continued taking metformin 1 g twice a day and commenced on a 2 mg weekly injection of long-acting exenatide – a glucagon-like peptide-1 agonist.\n\nThe individual’s mental state improved considerably during his admission. His thought and speech disorders were ameliorated, although still noticeable in a prolonged conversation. Perceptual abnormalities were no longer noted, although he continued to experience paranoid delusions to a lower degree. He started to engage in art activities, showing some talent in this area, and retained a calm demeanour for increasing periods of time. He gained partial insight, identifying the need for medications and follow-up. His weight increased slightly (from a BMI of 28.7 to 28.9) and his smoking was reduced by half.\n\nAfter 5 months of treatment, the individual’s psychotic symptoms were significantly reduced and glycaemic control was stable. He was discharged from hospital, with his care taken over by his local mental health team; his diabetes care was managed by his general practitioner with specialist input from the endocrinologists.\n\nDiscussion\nThis case supports the existence of a direct mechanism by which clozapine may alter the glycaemic control pathways. Our patient developed rapid loss of glycaemic control within days of starting the medication, meaning it was unlikely to be caused by intermediate factors such as increased appetite, weight gain or insulin resistance. He was not taking any other medication likely to cause hyperglycaemia. Clozapine produced a linear dose-related increase in glycaemic levels during the first 2 months of treatment, which from 400 mg onwards seemed to reach a plateau. Although there is an apparent dose-dependence, treatment duration-dependence as a contributing factor cannot be excluded.\n\nGiven the lack of any effective symptom management with other antipsychotic medication and the complexity of the clinical presentation, it was decided to continue clozapine, but to manage the hyperglycaemia while continuing with the medication.\n\nTo do this, we followed the Maudsley prescribing guidelines’ recommendations for treatment of antipsychotic-related diabetes.15 Of equal importance was the collaboration with a clinical pharmacist specialising in mental health and with endocrinologists, who oversaw the individual’s treatment. This approach requires vigorous baseline and follow-up monitoring of glucose levels and HbA1c values, slower clozapine titration schedule, and full control of glycaemic levels before every dose increase of clozapine.\n\nClinicians should also monitor weight gain and lipid levels, as well as considering other potential risk factors for diabetes5; one such factor being African ethnicity, which some studies suggest is associated with a higher risk of diabetes mellitus.16 There are several pharmacological treatment options for diabetes mellitus; in this case, we used insulin and long-acting exenatide – a recently introduced glucagon-like peptide-1 (GLP-1) agonist that requires a weekly injection – added to his existing metformin. The reason for using exenatide is based on recent research, which suggests that hyposecretion of incretin hormone GLP-1 may partially account for the rapid diabetogenic effect of clozapine.17\n\nClearly, it may still be necessary to discontinue clozapine in the event of a severe diabetes mellitus complication, such as ketoacidosis.12\n\nOur case illustrates the successful management of insulin dependence in an individual with refractory schizophrenia and diabetes mellitus previously controlled by metformin. In people with refractory schizophrenia, the effectiveness of clozapine must be balanced against the risks posed by side-effects. In such cases, a personalised plan is required to support the aggressive treatment of the iatrogenic side-effects while continuing clozapine treatment.\n==== Refs\nReferences\n1 Nielsen \nJ , Young \nC , Ifteni \nP , Kishimoto \nT , Xiang \nY , Schulte \nP , et al\nWorldwide differences in regulations of clozapine use . CNS Drugs \n2016 ; 30 : 149 –61 .26884144 \n2 Deng \nC . Effects of antipsychotic medications on appetite, weight, and insulin resistance . Endocrinol Metab Clin North Am \n2013 ; 42 : 545 –63 .24011886 \n3 Jin \nH , Meyer \nJM , Jeste \nDV . Atypical antipsychotics and glucose dysregulation: a systematic review . Schizophr Res \n2004 ; 71 : 195 –212 .15474892 \n4 Foley \nDL , Mackinnon \nA , Morgan \nVA , Watts \nGF , Castle \nDJ , Waterreus \nA , et al\nEffect of age, family history of diabetes, and antipsychotic drug treatment on risk of diabetes in people with psychosis: a population-based cross-sectional study . Lancet Psychiatry \n2015 ; 2 : 1092 –8 .26477242 \n5 Stahl \nS , Mignon \nL , Meyer \nJ . Which comes first: atypical antipsychotic treatment or cardiometabolic risk? \nActa Psychiatr Scand \n2009 ; 119 : 171 –9 .19178394 \n6 Smith \nGC , Zhang \nZY , Mulvey \nT , Petersend \nN , Lach \nS , Xiuc \nP , et al\nClozapine directly increases insulin and glucagon secretion from islets: implications for impairment of glucose tolerance . Schizophr Res \n2014 ; 157 : 128 –33 .24906220 \n7 Contreras-Shannon \nV , Heart \nDL , Paredes \nRM , Navaira \nE , Catano \nG , Kaushal Maffi \nS , et al\nClozapine-induced mitochondria alterations and inflammation in brain and insulin-responsive cells . PLoS ONE \n2013 ; 8 (suppl 3 ): e59012 .23527073 \n8 Duiverman \nML , Cohen \nD , Van Oven \nW , Nioboer \nP . A patient treated with olanzapine developing diabetes de novo: proposal for hyperglycaemia screening . Neth J Med \n2007 ; 65 : 346 –8 .17954954 \n9 Madsen \nK . Fatal hypertriglyceridaemia, acute pancreatitis and diabetic ketoacidosis possibly induced by quetiapine . Case Rep \n2014 ; doi: 10.1136/bcr-2013-202039 .\n10 Takahashi \nM , Ohishi \nS , Katsumi \nC , Moriya \nT , Miyaoka \nH . Rapid onset of quetiapine-induced diabetic ketoacidosis in an elderly patient . Pharmacopsychiatry \n2005 ; 38 : 183 –4 .16025424 \n11 Mustafa \nF , Burke \nJ , Abukmeil \nS , Scanlon \nJ , Cox \nM . ‘Schizophrenia past clozapine’: reasons for clozapine discontinuation, mortality, and alternative antipsychotic prescribing . Pharmacopsychiatry \n2014 ; 48 : 11 –4 .25376977 \n12 Nielsen \nJ , Correll \nC , Manu \nP , Kane \nJ . Termination of clozapine treatment due to medical reasons . J Clin Psychiatry \n2013 ; 74 : 603 –13 .23842012 \n13 Taylor \nD , Douglas-Hall \nP , Olofinjana \nB , Whiskey \nE , Thomas \nA . Reasons for discontinuing clozapine: matched, case-control comparison with risperidone long-acting injection . Br J Psychiatry \n2009 ; 194 : 165 –7 .19182180 \n14 Meyer \nJM , Mao \nY , Pikalov \nA , Cucchiaro \nJ , Loebel \nA . Weight change during long-term treatment with lurasidone: pooled analysis of studies in patients with schizophrenia . Int Clin Psychopharmacol \n2015 ; 30 : 342 –50 .26196189 \n15 Taylor \nD , Kapur \nS . The Maudsley Prescribing Guidelines in Psychiatry . Wiley , 2015 .\n16 Krakowski \nM , Czobor \nP , Citrome \nL . Weight gain, metabolic parameters, and the impact of race in aggressive inpatients randomized to double-blind clozapine, olanzapine or haloperidol . Schizophr Res \n2009 ; 110 : 95 –102 .19269139 \n17 Mayfield \nK , Siskind \nD , Winckel \nK , Russell \nAW , Kisel \nS , Smith \nG , et al\nGlucagon-like peptide-1 agonists combating clozapine-associated obesity and diabetes . J Psychopharmacol \n2016 ; 30 (suppl 3 ): 227 –36 .26801056\n\n",
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"title": "Rapid-onset clozapine-induced loss of glycaemic control: case report.",
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"abstract": "Eccrine poromas arise from the intraepidermal region of the eccrine sweat duct and most often occur as a benign solitary tumor. There are few reports of the occurrence of multiple lesions, defined as poromatosis, which may present in patients who have undergone radiotherapy and/or polychemotherapy. We report the case of a 43-year-old male with a history of mantle cell lymphoma who had undergone 6 cycles of polychemotherapy. He presented to the dermatology clinic for multiple painful lesions on his palms and soles. Several biopsies were performed consistent with eccrine poromas. The patient was successfully treated with a combination of excision, imiquimod cream, and cryosurgery. This case adds to the literature regarding the pathogenesis and treatment options of eccrine poromatosis. Herein, we report a case of eccrine poromatosis that developed after 6 cycles of chemotherapy.",
"affiliations": "Department of Dermatology, University of Alabama at Birmingham, Birmingham, Ala., USA.;Department of Dermatology, University of Alabama at Birmingham, Birmingham, Ala., USA.;Department of Dermatology, University of Alabama at Birmingham, Birmingham, Ala., USA.",
"authors": "Mayo|Tiffany T|TT|;Kole|Lauren|L|;Elewski|Boni|B|",
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"title": "Eccrine Poromatosis: Case Report, Review of the Literature, and Treatment.",
"title_normalized": "eccrine poromatosis case report review of the literature and treatment"
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"abstract": "The effectiveness of the tumor necrosis-α (TNF-α) blockade has changed the treatment of several chronic inflammatory diseases, including inflammatory bowel disease; however, this treatment also has disadvantages. The use of immunosuppressants in combination with infliximab has been associated with greater risk of developing malignant neoplasms. Herein, we report the case of a 33-year-old ethnic Korean man with Crohn disease (CD) who developed papillary thyroid carcinoma (PTC) and, subsequently, T-cell acute lymphoblastic leukemia (ALL) after approximately 16.0 years of immunosuppressant therapy and 5.5 years of infliximab therapy. To our knowledge, this is the first case described in the literature of 2 different malignant neoplasms, 1 of hematologic origin and the other involving the solid organs, in a patient with CD. Through a systematic literature review, we found 28 cases of acute leukemia in adult patients with CD, of whom 22 had myeloid leukemia and 6 had lymphoid leukemia. Half of the patients with ALL underwent TNF-α-blocker therapy in combination with thiopurines.",
"affiliations": "Department of Internal Medicine, Kyung Hee University, Seoul, South Korea Department of Medicine, Graduate School, Kyung Hee University, Seoul, South Korea.;Department of Internal Medicine, Kyung Hee University, Seoul, South Korea.;Department of Internal Medicine, Kyung Hee University, Seoul, South Korea.;Department of Internal Medicine, Kyung Hee University, Seoul, South Korea.;Department of Internal Medicine, Kyung Hee University, Seoul, South Korea.;Department of Laboratory Medicine, School of Medicine, Kyung Hee University, Seoul, South Korea.;Department of Internal Medicine, Kyung Hee University, Seoul, South Korea.;Department of Internal Medicine, Kyung Hee University, Seoul, South Korea.;Department of Internal Medicine, Kyung Hee University, Seoul, South Korea.",
"authors": "Byun|Ja Min|JM|;Baek|Sun Kyung|SK|;Yoon|Hwi-Joong|HJ|;Kim|Si-Young|SY|;Maeng|Chi Hoon|CH|;Park|Tae Sung|TS|;Kim|Hyo-Jong|HJ|;Choi|Yun Young|YY|;Um|Yu Jin|YJ|",
"chemical_list": "D000069285:Infliximab",
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"keywords": "Crohn disease; acute leukemia; infliximab; mercaptopurine; papillary thyroid carcinoma; thiopurine",
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"title": "Thyroid cancer and T lymphoblastic leukemia in Crohn disease: a case report and literature review.",
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"abstract": "The combination of personalized therapy with immunotherapy might lead to rapid complete remission in patients who are too sick to be eligible for clinical trials. We report 2 such extraordinary responders. A discussion on the use and purpose of clinical trials in this new era of very active anticancer drug discovery concludes that a paradigm shift is urgently needed.",
"affiliations": "University of Vermont Cancer Center, Burlington, Vt., USA.",
"authors": "Verschraegen|Claire F|CF|;Rehman|Hibba|H|;Pulluri|Bhargavi|B|;DeKay|James|J|;Barry|Maura|M|;Folefac|Edmund|E|;Dittus|Kim|K|;Holmes|Chris|C|;Sprague|Julian|J|;Ades|Steve|S|;Gibson|Pam C|PC|",
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"mesh_terms": "D000368:Aged; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D057285:Precision Medicine; D012878:Skin Neoplasms; D065646:Thyroid Carcinoma, Anaplastic",
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"title": "When Clinical Trial Participation Is Not an Option in the Era of Personalized Medicine: The Case of Two Patients.",
"title_normalized": "when clinical trial participation is not an option in the era of personalized medicine the case of two patients"
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"abstract": "Central diabetes insipidus (CDI) may occur in the setting of intracranial abnormalities that affect the hypothalamus-pituitary system. It occurs rarely in neonates, especially in the premature population, and represents a challenging disease process to treat pharmacologically. Little is known regarding the treatment options in premature infants, including dose and route of administration of intravenous desmopressin (DDAVP). We present a case of a late premature male infant with gastroschisis and septo-optic dysplasia who developed transient CDI. He was treated with intravenous DDAVP but required frequent laboratory monitoring and a multidisciplinary approach, and ultimately his CDI resolved. Although there are minimal guidelines regarding the appropriate formulation and dosage of DDAVP for management of CDI in infants, we initiated the lowest dose available and titrated the medication based on close monitoring of urine output and serum sodium levels in order to successfully treat his transient CDI.",
"affiliations": "Department of Pediatrics, Division of Neonatology, Columbia University Medical Center/NewYork-Presbyterian Morgan Stanley Children's Hospital of New York, New York City, NY, USA.;Department of Pediatrics, Division of Neonatology, Columbia University Medical Center/NewYork-Presbyterian Morgan Stanley Children's Hospital of New York, New York City, NY, USA.",
"authors": "Kim|Faith|F|;Towers|Helen M|HM|",
"chemical_list": "D003894:Deamino Arginine Vasopressin",
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"issue": "14(2)",
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"keywords": "Diabetes insipidus; desmopressin; gastroschisis; prematurity; septo-optic dysplasia",
"medline_ta": "J Neonatal Perinatal Med",
"mesh_terms": "D003894:Deamino Arginine Vasopressin; D020790:Diabetes Insipidus, Neurogenic; D006801:Humans; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D008297:Male; D025962:Septo-Optic Dysplasia",
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"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Management of transient central diabetes insipidus with intravenous desmopressin in a premature infant with gastroschisis and septo-optic dysplasia: A case report.",
"title_normalized": "management of transient central diabetes insipidus with intravenous desmopressin in a premature infant with gastroschisis and septo optic dysplasia a case report"
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"abstract": "Background: Infection of Chlamydia psittaci (C. psittaci) could lead to serious clinical manifestations in humans, including severe pneumonia with rapid progression, adult respiratory distress syndrome (ARDS), sepsis, multiple organ dysfunction syndromes (MODS), and probably death. Implementation of extracorporeal membrane oxygenation (ECMO) in the patient with severe ARDS gives a promising new method for recovery. Case Presentation: We report our successful use of venovenous (VV) ECMO in a 48-year-old man who manifested with severe respiratory distress syndrome, acute kidney injury, and septic shock caused by a diagnosis of pneumonia. After the combination of therapy including anti-infection, mechanical ventilation, and continuous renal replacement therapy (CRRT), acute inflammatory syndrome developed. However, his respiratory status rapidly deteriorated. Then, venoarterial (VA)-ECMO support was placed on the patient as suddenly slowing of the heart rate. Harlequin (North-South) syndrome occurred after ECMO initiation. A series of the process could not relieve hypoxia in the upper body. At last, transition to VV-ECMO improved hypoxia. The duration of VV-ECMO was 7 days and the mechanical ventilation was weaned on the next day. On the day of ECMO weaning, nanopore targeted sequencing (NTS) of bronchoalveolar lavage fluid (BALF) reported the presence of C. psittaci. After 19 days of critical systemic rehabilitation and combination therapy, the patient fully recovered from C. psittaci. Conclusion: This is the first reported case of the patient receiving ECMO for C. psittaci pneumonia. ECMO puts the lungs on temporary rest, promotes the recovery of pulmonary function, and also wins time for finding the pathogens, which is crucial in the treatment of rare pathogens.",
"affiliations": "Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China.;Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China.;Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China.;Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China.;Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China.",
"authors": "Wang|Lu|L|;Shi|Zhaokun|Z|;Chen|Wei|W|;Du|Xianjin|X|;Zhan|Liying|L|",
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"country": "Switzerland",
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"doi": "10.3389/fmed.2021.731047",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.731047\nMedicine\nCase Report\nExtracorporeal Membrane Oxygenation in Severe Acute Respiratory Distress Syndrome Caused by Chlamydia psittaci: A Case Report and Review of the Literature\nWang Lu † ‡\n\nShi Zhaokun † ‡\nChen Wei † ‡\nDu Xianjin * †\n\nZhan Liying * †\n\nDepartment of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China\nEdited by: Luo Zhe, Fudan University, China\n\nReviewed by: Tommaso Mauri, University of Milan, Italy; Antonella Cotoia, University of Foggia, Italy\n\n*Correspondence: Liying Zhan 2582062108@qq.com\nXianjin Du duxianjin@whu.edu.cn\nThis article was submitted to Intensive Care Medicine and Anesthesiology, a section of the journal Frontiers in Medicine\n\n†These authors have contributed equally to this work\n\n‡These authors share first authorship\n\n15 10 2021\n2021\n8 73104726 6 2021\n14 9 2021\nCopyright © 2021 Wang, Shi, Chen, Du and Zhan.\n2021\nWang, Shi, Chen, Du and Zhan\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground: Infection of Chlamydia psittaci (C. psittaci) could lead to serious clinical manifestations in humans, including severe pneumonia with rapid progression, adult respiratory distress syndrome (ARDS), sepsis, multiple organ dysfunction syndromes (MODS), and probably death. Implementation of extracorporeal membrane oxygenation (ECMO) in the patient with severe ARDS gives a promising new method for recovery.\n\nCase Presentation: We report our successful use of venovenous (VV) ECMO in a 48-year-old man who manifested with severe respiratory distress syndrome, acute kidney injury, and septic shock caused by a diagnosis of pneumonia. After the combination of therapy including anti-infection, mechanical ventilation, and continuous renal replacement therapy (CRRT), acute inflammatory syndrome developed. However, his respiratory status rapidly deteriorated. Then, venoarterial (VA)-ECMO support was placed on the patient as suddenly slowing of the heart rate. Harlequin (North-South) syndrome occurred after ECMO initiation. A series of the process could not relieve hypoxia in the upper body. At last, transition to VV-ECMO improved hypoxia. The duration of VV-ECMO was 7 days and the mechanical ventilation was weaned on the next day. On the day of ECMO weaning, nanopore targeted sequencing (NTS) of bronchoalveolar lavage fluid (BALF) reported the presence of C. psittaci. After 19 days of critical systemic rehabilitation and combination therapy, the patient fully recovered from C. psittaci.\n\nConclusion: This is the first reported case of the patient receiving ECMO for C. psittaci pneumonia. ECMO puts the lungs on temporary rest, promotes the recovery of pulmonary function, and also wins time for finding the pathogens, which is crucial in the treatment of rare pathogens.\n\nChlamydia psittaci (C. psittaci)\npneumonia\nextracorporeal membrane oxygenation (ECMO)\nnext-generation sequencing (NGS)\ninfection\n==== Body\npmcBackground\n\nChlamydia psittaci is a type of bacteria that often infects birds. The bacteria can also infect people exposed to the infected birds and cause a disease called psittacosis. Those who have contact with pet birds and poultry, including the people who work in bird-related occupations, are at an increased risk of infection. In 2018, a multistate psittacosis outbreak occurred among the poultry workers that had 13 laboratory confirmed cases (1). A study found that out of the 311 parrots examined in China, 35.37% were seropositive and species, gender, age, season, and geographical location were identified as the risk factors (2). The occurrence of C. psittaci genotype A in the droppings of the two pet parrots in China suggests potential environmental contamination with C. psittaci and may raise public health concerns (2). A few isolated cases or outbreaks of psittacosis have been reported, usually presenting with severe pneumonia.\n\nExtracorporeal membrane oxygenation (ECMO) is used to treat patients with severe, life-threatening conditions of the heart and lungs, but some diseases may lead to progressive organ dysfunction such as liver failure or severe neurologic injury. Then, these conditions with a poor prognosis may warrant a discussion about discontinuing ECMO support (3). An ECMO study in the United Kingdom found that 95% of the patients with severe respiratory failure had venovenous (VV) ECMO alone (4). The survival rate at ECMO intensive care unit (ICU) discharge was 74% including 71% for the patients with respiratory failure (4). VV-ECMO support is an established treatment of acute respiratory distress syndrome (ARDS) and enables to minimize ventilator-induced lung injury (VILI) as rescue therapy in ARDS patients (5, 6). But, the successful use of ECMO to treat patients with psittacosis has not been published yet.\n\nTherefore, the use of ECMO in patients with psittacosis needs further study and discussion. However, the timing of ECMO initiation, ECMO model [VV, venoarterial (VA) or the other types], and length of ECMO also need to be studied.\n\nCase Presentation\n\nThis was a case of a 48-year-old community inspector with a history of possible hemorrhoids (hematochezia) for 2 months, gastric ulcer, cervical spondylosis, and penicillin allergy, who presented in January 2021 with fever, diarrhea, chest pain, fatigue, and syncope. The patient, who lived in a central urban area of Wuhan, China, had dizziness for 3 days and fell three times before being admitted to the hospital. Fever, diarrhea, and chest pain appeared 1 day before with chest pain subsided 5 min later. Physical examination: Temperature was 39.6°C, heart rate was 126 beats/min, breath rate was 20 breaths/min, blood pressure was 148/77 mm Hg, oxygen saturation (SpO2) was 98%, and lung auscultation was clear. Other physical examinations were negative. CT scan of the chest showed left upper zone consolidation (Figure 1). Blood tests indicated a white blood cell count 2,910/mm3, neutrophil count 2,630/mm3, lymphocyte count 100/mm3, hemoglobin 82 g/l, platelet count 7,300/mm3, C-reactive protein 193.9 mg/l (normal value <10 mg/l), serum amyloid A (SAA) protein > 300 mg/l (normal value <10 mg/l), and procalcitonin (PCT) 6.51 ng/ml. Galactomannan enzyme immunoassay (GM-EIA) shows 0.12 (normal value 0–0.49) and fungus (1 → 3)-β-D-glucan test shows <37.50 pg/ml (normal value <70 pg/ml). Blood and sputum culture were performed. The patient was diagnosed with community-acquired pneumonia and empirical intravenous antibiotic therapy was started with ceftazidime. 1 day later, he fainted suddenly with SpO2 80–90%, partial pressure of oxygen (pO2) 71 mm Hg, and then transferred to the ICU due to deterioration of respiratory status, severe desaturation, and delirium. At the same time, wet and dry rales could be heard in both the lungs, and the Acute Physiology and Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) scores were 18 and 8, respectively (Table 1). Tracheal intubation and mechanical ventilation were performed with positive end-expiratory pressure (PEEP) 10 mm Hg and a fraction of inspired oxygen (FiO2) 100%. Flexible bronchoscopy was performed and showed pulmonary edema without the other abnormalities. To get more information on etiology, bronchoalveolar lavage fluid (BALF) samples were obtained for nanopore targeted sequencing (NTS) and sputum culture. The results of echocardiography showed the size of the ventricles and atria were normal, the thickness and amplitude of movement of the ventricular septum and the free wall of the left ventricle, the morphology and activity of the valves, and the opening and closing of the valves were normal. Simultaneously, antibiotic therapy was changed to meropenem and ganciclovir. In the following days, he presented with progressive worsening of the bilateral pulmonary infiltrates, high ventilatory parameters, and increasing serum PCT and creatinine levels with the signs of septic shock. Ultrafiltration was required for oligoanuria and severe fluid was overload. On the fourth day after intubation, pO2/FiO2 was reduced to 59 and bronchoscopy showed severe airway mucosal edema. Then, ECMO was commenced on day 5 in the ICU. VV-ECMO was planned originally; VA-ECMO with the initial flow set at 4 L/min was finally performed as the heart rate of the patient sharply dropped before the inserting tubes. Then, the patient experienced intermittent episodes of significant hypoxemia with SpO2 ranging from 41 to 81% corresponding to right radial artery partial pressure of arterial oxygen (PaO2) ranging from 49 to 58 mm Hg. To find out the reason for hypoxemia, we raised the flow rate of ECMO from 4.0 to 4.5 L/min. This adjustment could not eliminate hypoxemia. The PaO2 of the right radial artery was 60 mm Hg, while the PaO2 of the right dorsal foot artery was 400 mm Hg. A severe North-South syndrome was presented as differential cyanosis. This cannot be eliminated by venoarterial venous (VAV)-ECMO with the presence of an internal jugular venous shunt of 18 Fr arterial cannulas. After the confirmation of ultrasound, the function of the heart was normal and at last, we converted to VV-ECMO. On day 2 (day 6) of ECMO, nucleic acid screening of the pharyngeal swab showed chlamydia. Antibiotic therapy with azithromycin was administered. Methylprednisolone pulses and respiratory physiotherapy were implemented. Improvement of pulmonary infiltrates was observed in the following days. After 7 days, ECMO support was discontinued (day 12) and ventilation was converted to high flow humidification oxygen therapy on the next day (day 13). On the 13th day after admission, the NTS results from the third sample of BALF showed the presence of C. psittaci and the readings of the sequences were 96. Therefore, the antibiotics were changed to meropenem and doxycycline accordingly. Signs of infection were improved after combined dialysis, nutrition, and other treatments. X-ray and CT scan of the chest demonstrated improved diffuse ground-glass infiltrates. Multiple cultures of blood and BALF were negative. The patient was weaned off the ventilator on the 17th day after the admission. Throughout the course of treatment, the indicators of infection and renal function tended to improve (Table 2). He regained some kind of consciousness, but could not give the exact answer and the vasoactive drugs were significantly downregulated.\n\nFigure 1 CT scan of the patient (A–C show CT scans on the 0th day after admission).\n\nTable 1 Characteristics of the patient and the methods of treatment.\n\n\tFeature\t\nAge, yr\t48\t\nSex\tMale\t\nClinical features\tFever, diarrhea, chest pain, fatigue, and syncope\t\nSmoke\tNo\t\nDrink\tNo\t\nSurgery\tNo\t\nHormone/immunosuppressive therapy\tNo\t\nChronic diseases\t\nHypertension\tNo\t\nDiabetes\tNo\t\nKidney failure\tNo\t\nChronic bronchitis\tNo\t\nTreatment\t\nVasoactive drugs\tYes\t\nArterial puncture\tYes\t\nECMO\tYes\t\nTracheotomy\tYes\t\nCVC\tYes\t\nNasogastric tube\tYes\t\nUrinary catheters\tYes\t\nCRRT\tYes\t\nSARS score\t56\t\nAPACHE II\t18\t\nSOFA\t8\t\nMechanical ventilation duration(days)\t16\t\nCVC, central venous catheter; ECMO, extracorporeal membrane oxygenation; CRRT, continuous renal replacement therapy.\n\nTable 2 Ventilator and the ECMO parameters, indicators of infection, and renal function.\n\n\tD1\tD2\tD3\tD5\tD7\tD8\tD9\tD12\tD17\t\nFiO2\t100%\t60%\t60%\t100%\t100%\t40%\t40%\t35%\t35%\t\nPEEP (cmH2O)\t10–8\t8\t8–5\t8–10\t8–10\t5\t5\t5\t3–5\t\nPplat\t18\t15\t16\t18\t18\t15\t14\t12\t8\t\nCL (ml/mmHg)\t35\t38\t42\t33\t38\t41\t49\t56\t65\t\nVt (ml)\t300–400\t400–450\t400–450\t300\t300–400\t300–400\t400–45–\t400–500\t400–500\t\nPCO2 (mmHg)\t30\t32\t42\t42\t42\t55\t36\t38\t34\t\nPO2 (mmHg)\t71\t97\t167\t59\t439\t96\t102\t71\t80\t\nP/F ratio (mmHg)\t71\t161\t228\t59\t439\t192\t240\t177.5\t228.6\t\nECMOration rate (revolutions/min)\t–\t–\t–\t3,000\t3,200\t3,200\t3,200\t2,200\t–\t\nECMO flux (3 L/min)\t–\t–\t–\t3.3\t3.3\t3.3\t3.3\t1.4\t–\t\nECMO FiO2\t–\t–\t–\t100%\t100%\t100%\t100%\t40%\t–\t\nDosage of vasoactive drugs\tNE 20 ug/min\tNE 15 ug/min\tNE 15 ug/min\tNE 30 ug/min pavee DFA 55 ug/min\tNE 15 ug/min pavee DFA 30 ug/min\tNE 15 ug/min pavee DFA 30 ug/min\tNE 15 ug/min pavee DFA 30 ug/min\t–\t–\t\nAntibiotics\tMeropenem and ganciclovir\tMeropenem and ganciclovir\tMeropenem and ganciclovir\tMeropenem and ganciclovir\tMeropenem, ganciclovir and azithromycin\tMeropenem, ganciclovir and azithromycin\tMeropenem, ganciclovir and azithromycin\tMeropenem and doxycycline\tDoxycycline\t\nW.B.C (mm3)\t3,830\t6,090\t10,950\t13,290\t6,270\t7,820\t7,650\t5,760\t2,770\t\nPCT (ng/ml)\t6.51\t60.1\t58.7\t35.9\t16\t9.23\t5.2\t1.38\t0.84\t\nCr (umol/L)\t178\t243\t180\t242\t180\t139\t199\t171\t209\t\nUrine volume (ml)\t1,450\t2,060\t1,400\t300\t70\t50\t30\t40\t1,700\t\nFiO2, fraction of inspired oxygen; PEEP, positive end-expiratory pressure; VT, tidal volume; Pplat, platform pressure; CL, lung compliance; pCO2, partial pressure of carbon dioxide; pO2, partial pressure of oxygen; WBC, white blood cell; PCT, procalcitonin.\n\nDiscussion\n\nChlamydia psittaci is a gram-negative, obligate intracellular parasite that is mainly transmitted to humans through contact with the infected birds (such as parrots and poultry), inhalation of aerosols, feces, or feather dust from the nasal secretions of the infected birds. The disease caused by C. psittaci infection is called psittacosis, which is considered a rare cause of pneumonia. A meta-analysis of an observational study found that about 1% of the community-acquired pneumonia was caused by C. psittaci (7). Probably due to the lack of routine detection of C. psittaci and the sensitivity and specificity of the common diagnostic methods, it is difficult to determine the accurate incidence and prevalence of C. psittaci (8, 9). Contact with the birds or poultry is the main risk factor for psittacosis. It has been reported that among 1,136 patients, 72% of the patients had pets or had contact with birds or poultry in a domestic environment and 6% had exposure to wild birds, 12% are poultry workers, and only 10% have no relevant contact history (10, 11). In addition to the parrots, poultry is also an important source of infection of C. psittaci. A study found that the seropositivity rates of C. psittaci in the chickens, ducks, and pigeons sold in Northwest China were 13.3, 38.9, and 31.1%, respectively (12).\n\nIn this case study, a positive environmental link has been identified. During the same period, the Chinese news outlets reported psittacosis cases in Changsha, Hunan province, and Zhongshan, Guangdong province. Although this case lived in an urban area, there were large forests and birds in the community. Therefore, the patients with a history of exposure to the birds or poultry should be alert to the possibility of atypical infection of the pathogen, especially C. psittaci. The incubation period ranges between 5 and 14 days. In a study of 135 patients, all the patients had a fever as the main manifestation and 61% of patients were accompanied by chills. Although 82% of the patients complained of cough, it often appeared later (13). Its typical clinical manifestations are fever, chills, headache, cough without sputum, and gastrointestinal symptoms. In severe cases, severe pneumonia, endocarditis, jaundice, and neurological complications may be developed. Since C. psittaci is difficult and dangerous to culture and is highly infectious, serological examination is usually used for the diagnosis. Among them, the most sensitive and specific is a microimmunofluorescence assay showing antibody titers at least 4-fold higher than the upper limit of normal in the duplicate serum samples or the titer of the IgM antibody is ≥1:16. The development of the PCR has greatly simplified DNA analysis and shortened the laboratory time to detect C. psittaci. This method can quickly and specifically identify the pathogens and perform genotyping at the same time, but many authors described the assays that were less sensitive and detected only when the high loads were observed during the acute phase of the disease. Nowadays, the microbiology laboratories do not routinely screen the above tests, but only in the specialized laboratories, so it is difficult for clinicians to diagnose psittacosis. Through the development of the second-generation metagenomic intervention technology [metagenomic next-generation sequencing (mNGS)], a variety of the pathogens in the different specimens can be quickly and accurately identified including atypical pathogens, viruses, and fungi that are difficult to cultivate. Thus, mNGS, also known as deep sequencing, is widely favored because of its rapid detection. This technology is based on collecting the human genes followed by the amplification and sequencing of pathogen nucleic acids and then high-throughput sequencing, machine-learning algorithms, and bioinformatics pipelines were performed. Its versatile detection has an advantage for the diagnosis of rare pathogenic bacteria in difficult cases. mNGS technology was done to diagnose Chlamydia pneumoniae by the BALF samples when the situation deteriorated in our procedure. With rapid analysis, this approach can quickly detect most of the pathogens and overcoming conventional culture-independent evaluation of the little clinical samples (microliter volumes) or prior antibiotic exposure. mNGS also provides additional data including bacterial DNA burden and community diversity that may help to identify pathogenic bacteria. New technology for performing targeted screening of NTS is a type of mNGS (14); therefore, it was developed to detect C. psittaci. Studies have shown that NTS is sensitive for detecting respiratory viruses (15), but its use in the detection of C. psittaci is less reported, so its rapid detection could be very beneficial for the early diagnosis and treatment of patients with parrot fever. In this case study, three BALF samples were sent to analyze by NTS technology. Only the last one reported C. psittaci. Nevertheless, we only found C. psittaci in the third test of NTS after we deeply discussed this case with the laboratory staff and the readings of the sequences were extremely low that is easy to ignore. In consistent with previously reported (16), the difference between blood and BALF may be due to the fewer effective cells in the BALF. Therefore, to obtain a meaningful diagnosis, the doctors need to consider the analysis of NTS combined with the clinical manifestations. NTS also has other disadvantages that limit its public application such as without drug sensitivity, the cost, and unavailable in mostly small hospitals, which increases the possibility of missed or misdiagnosis of the rare pathogenic bacteria in difficult cases.\n\nChlamydia psittaci belongs to the Chlamydia family (13) and tetracyclines, macrolides, and quinolones which suppress DNA and protein synthesis could be the appropriate antibacterial drugs (17). The first-line medication is tetracycline drugs for at least 3 weeks in order to avoid recurrence. If tetracyclines are restricted in some patients, such as children, pregnant women, or allergies, macrolides can be selected as an alternative treatment. In some cases, quinolones are effective but are less effective compared to tetracyclines and macrolides (18). The patient was presented in this study had used azithromycin and meropenem according to the nucleic acid test of pharyngeal swab that showed Chlamydia, but the patient still had fever with pulmonary function deterioration, which means poor efficacy or insufficient treatment. These two drugs are supposed to be second-line treatment and in effect (19, 20), but, at first, the condition of the patient progresses too fast and the disease is too severe. After NTS of BALF reported C. psittaci, timely adjustment of the antibacterial treatment based on doxycycline minimized the prognosis time and disease process. At the same time, NTS testing did not report other pathogens, thereby reduced the use of the unnecessary antibacterial drugs, effectively reduced the hospitalization costs, and avoided the emergence of the drug-resistant bacteria.\n\nIn the case of ventilator treatment, the condition of the patient deteriorated on the 5th day and the adjustment of ventilator parameters could not meet the needs of the patient, so ECMO treatment was given. In ECMO, blood is pumped outside of the body to a heart-lung machine, which removes carbon dioxide and fills oxygen into the blood back to the tissues in the body, which could be an effective technology to improve organ oxygenation when positive-pressure ventilation and prone position are inadequate to improve the blood oxygen saturation. There are two types of ECMO. The VA-ECMO is connected to both a vein and an artery and is used when there are problems with both the heart and lungs. In most cases of ECMO for severe acute respiratory failure, VV-ECMO is selected from which blood is pumped and returned to a central vein. ECMO allowed further reduction in ventilation-induced lung damage and the search of a diagnostic procession that included culture and mNGS making the patient to the definitive diagnosis, specific antibiotics, immunosuppressive treatment, and recovery. In the present case study, we first described the patient with psittacosis complicated by refractory respiratory failure and rescued with VV-ECMO. In this case study, VA-ECMO cannulation was selected because of the risk of hemodynamic collapse after a sharp reduction of heart rate. This choice leads to the North-South syndrome soon afterward, which is a form of Harlequin syndrome. North-South syndrome occurs in 38% of ECMO operations (21). Some scientists argue that draining from the superior vena cava (SVC) via a multistage cannula inserted in the right internal jugular vein is neutralized (22), but drainage of the internal jugular vein (also called VAV-ECMO) seems do not solve the problem in this case. In the VAV-ECMO circuit, with drainage from a cannula inserted in the femoral artery and then return of a cannula inserted in the internal jugular vein (tip in the SVC next to the right atrium) and the femoral vein (tip in the inferior vena cava), the blood volume of the upper body reduced with insufficient supply of oxygen and low blood pressure. It is also indicated that the patient had a severe pulmonary infection and poor oxygenation (Figure 2).\n\nFigure 2 North–South syndrome.\n\nConclusion\n\nIn summary, this is the first case of pulmonary infection with ECMO occurring in a patient in China suggesting that ECMO plays an increasing role as an opportunistic pathogen in immunocompromised patients. With the consent of the patient (supply figure), this case provides a reminder that the clinicians should expect the unexpected in terms of the infectious agents and emphasizes the importance of the microbiological diagnostic procedures.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n==== Refs\nReferences\n\n1. Shaw KA Szablewski CM Kellner S Kornegay L Bair P Brennan S . Psittacosis outbreak among workers at chicken slaughter plants, Virginia and Georgia, USA, 2018. Emerg Infect Dis. (2019) 25 :2143–5. 10.3201/eid2511.190703 31625859\n2. Zhang NZ Zhang XX Zhou DH Huang S-Y Tian W-P Yang Y-C . Seroprevalence and genotype of Chlamydia in pet parrots in China. Epidemiol Infect. (2015) 143 :55–61. 10.1017/S0950268814000363 24588856\n3. Hadaya J Benharash P . Extracorporeal membrane oxygenation. JAMA. (2020) 323 :2536. 10.1001/jama.2020.9148 32463441\n4. Warren A Chiu YD Villar SS Fowles J-A Symes N Barker J . Outcomes of the NHS England National Extracorporeal Membrane Oxygenation Service for adults with respiratory failure: a multicentre observational cohort study. Br J Anaesth. (2020) 125 :259–66. 10.1016/j.bja.2020.05.065 32736826\n5. Patroniti N Bonatti G Senussi T Robba C . Mechanical ventilation and respiratory monitoring during extracorporeal membrane oxygenation for respiratory support. Ann Transl Med. (2018) 6 :386. 10.21037/atm.2018.10.11 30460260\n6. Combes A Hajage D Capellier G Demoule A Lavoué S Guervilly C . Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med. (2018) 378 :1965–75. 10.1056/NEJMoa1800385 29791822\n7. Hogerwerf L De Gier B Baan B Van Der Hoek W . Chlamydia psittaci (psittacosis) as a cause of community-acquired pneumonia: a systematic review and meta-analysis. Epidemiol Infect. (2017) 145 :3096–105. 10.1017/S0950268817002060 28946931\n8. Rybarczyk J Versteele C Lernout T Vanrompay D . Human psittacosis: a review with emphasis on surveillance in Belgium. Acta Clin Belg. (2020) 75 :42–8. 10.1080/17843286.2019.1590889 30882289\n9. Rane V Khailin K Williams J Francis M Kotsanas D Korman TM . Underdiagnosis of Chlamydia trachomatis and Chlamydia psittaci revealed by introduction of respiratory multiplex PCR assay with Chlamydiaceae family primers. Diagn Microbiol Infect Dis. (2018) 90 :163–6. 10.1016/j.diagmicrobio.2017.11.013 29258707\n10. Hulin V Bernard P Vorimore F Aaziz R Cléva D Robineau J . Assessment of Chlamydia psittaci shedding and environmental contamination as potential sources of worker exposure throughout the mule duck breeding process. Appl Environ Microbiol. (2015) 82 :1504–18. 10.1128/AEM.03179-15 26712548\n11. Burnard D Polkinghorne A . Chlamydial infections in wildlife-conservation threats and/or reservoirs of ‘spill-over’ infections? Vet Microbiol. (2016) 196 :78–84. 10.1016/j.vetmic.2016.10.018 27939160\n12. Cong W Huang SY Zhang XY Zhou DH Xu MJ Zhao Q . Seroprevalence of Chlamydia psittaci infection in market-sold adult chickens, ducks and pigeons in north-western China. J Med Microbiol. (2013) 62 (Pt 8 ):1211–14. 10.1099/jmm.0.059287-0 23699067\n13. Stidham RA Richmond-Haygood M . Case report: possible psittacosis in a military family member-clinical and public health management issues in military settings. MSMR. (2019) 26 :2–7.31347370\n14. Kovaka S Fan Y Ni B Timp W Schatz MC . Targeted nanopore sequencing by real-time mapping of raw electrical signal with UNCALLED. Nat Biotechnol. (2021) 39 :431–41. 10.1038/s41587-020-0731-9 33257863\n15. Wang M Fu A Hu B Tong Y Liu R Gu J . Nanopore targeted sequencing for the accurate and comprehensive detection of SARS-CoV-2 and other respiratory viruses. Small. (2020) 16 :e2002169. 10.1002/smll.202002169 32578378\n16. Zhang H Zhan D Chen D Huang W Yu M Li Q . Next-generation sequencing diagnosis of severe pneumonia from fulminant psittacosis with multiple organ failure: a case report and literature review. Ann Transl Med. (2020) 8 :401. 10.21037/atm.2020.03.17 32355845\n17. Kohlhoff SA Hammerschlag MR . Treatment of Chlamydial infections: 2014 update. Expert Opin Pharmacother. (2015) 16 :205–12. 10.1517/14656566.2015.999041 25579069\n18. Scottish survey exposes low staffing levels and fears about speaking out. Nurs Stand. (2015) 30 :8. 10.7748/ns.30.16.8.s4 26669367\n19. Dukers-Muijrers N Wolffs PFG De Vries H Götz HM Heijman T Bruisten S . Treatment effectiveness of azithromycin and doxycycline in uncomplicated rectal and vaginal Chlamydia trachomatis infections in women: a multicenter observational study (FemCure). Clin Infect Dis. (2019) 69 :1946–54. 10.1093/cid/ciz050 30689759\n20. Yuan Y Zhang X Gui C . Detection of Chlamydia psittaci in both blood and bronchoalveolar lavage fluid using metagenomic next-generation sequencing: a case report. Medicine. (2021) 100 :e26514. 10.1097/MD.0000000000026514 34232184\n21. Werner NL Coughlin M Cooley E Haft JW Hirschl RB Bartlett RH . The University of Michigan experience with veno-venoarterial hybrid mode of extracorporeal membrane oxygenation. ASAIO J. (2016) 62 :578–83. 10.1097/MAT.0000000000000405 27347710\n22. Frenckner B Broman M Broome M . Position of draining venous cannula in extracorporeal membrane oxygenation for respiratory and respiratory/circulatory support in adult patients. Crit Care. (2018) 22 :163. 10.1186/s13054-018-2083-0 29907121\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-858X",
"issue": "8()",
"journal": "Frontiers in medicine",
"keywords": "Chlamydia psittaci (C. psittaci); extracorporeal membrane oxygenation (ECMO); infection; next-generation sequencing (NGS); pneumonia",
"medline_ta": "Front Med (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101648047",
"other_id": null,
"pages": "731047",
"pmc": null,
"pmid": "34722571",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "31625859;30689759;29258707;26669367;31347370;28946931;34232184;30460260;32463441;29907121;24588856;32736826;32578378;25579069;32355845;33257863;30882289;27347710;29791822;26712548;23699067;27939160",
"title": "Extracorporeal Membrane Oxygenation in Severe Acute Respiratory Distress Syndrome Caused by Chlamydia psittaci: A Case Report and Review of the Literature.",
"title_normalized": "extracorporeal membrane oxygenation in severe acute respiratory distress syndrome caused by chlamydia psittaci a case report and review of the literature"
} | [
{
"companynumb": "CN-SLATE RUN PHARMACEUTICALS-22CN001109",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN"
},
"drugadditiona... |
{
"abstract": "The incidence of perinatal and neonatal Listeriosis is underestimated due undiagnosed stillbirths, misdiagnosis of NL and underreporting of single case reports. Recent outbreaks reinforce the need for better surveillance and targeted health education in certain population groups especially during pregnancy.",
"affiliations": null,
"authors": "Kylat|R I|RI|;Bartholomew|A|A|;Cramer|N|N|;Bader|M Y|MY|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000667:Ampicillin",
"country": "Netherlands",
"delete": false,
"doi": "10.3233/NPM-16915121",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-4429",
"issue": "9(3)",
"journal": "Journal of neonatal-perinatal medicine",
"keywords": "Neonatal listeriosis; granulomatosis infantisepticum; listeria monocytogenes",
"medline_ta": "J Neonatal Perinatal Med",
"mesh_terms": "D000328:Adult; D000667:Ampicillin; D000900:Anti-Bacterial Agents; D002611:Cheese; D005260:Female; D005517:Foodborne Diseases; D007722:Health Knowledge, Attitudes, Practice; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D008088:Listeriosis; D011159:Population Surveillance; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D012307:Risk Factors; D014481:United States",
"nlm_unique_id": "101468335",
"other_id": null,
"pages": "313-6",
"pmc": null,
"pmid": "27589546",
"pubdate": "2016-09-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neonatal listeriosis: Uncommon or misdiagnosed?",
"title_normalized": "neonatal listeriosis uncommon or misdiagnosed"
} | [
{
"companynumb": "PHHY2017US156618",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPICILLIN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Sofosbuvir is a direct-acting antiviral drug used to treat chronic hepatitis C infection. In 2015, Gilead Sciences, the manufacturer of sofosbuvir, warned that bradycardia could occur when sofosbuvir is administered in combination with amiodarone. Interestingly, among the reported cases of patients with sofosbuvir and amiodarone related bradycardia, some of them were also treated with propranolol.\n\n\n\nWe herein report a case of ventricular extrasystoles within three hours after the coadministration of sofosbuvir-containing regimen with propranolol. This patient had never been treated with amiodarone. After the sofosbuvir-containing regimen was stopped, ventricular extrasystoles disappeared within 24 hours. This observation suggests that the association of sofosbuvir with propranolol may have a role in the emergence of cardiac arrhythmia.\n\n\n\nPatients treated with amiodarone and/or propranolol should be continuously monitored within the early hours following the initiation of sofosbuvir.",
"affiliations": "Department of Internal Medicine, University Hospital Center Touhami Benflis, Batna 05000, Algeria and Department of Medicine, University Batna 2, Batna 05000. Algeria.;Department of Internal Medicine, University Hospital Center Touhami Benflis, Batna 05000. Algeria.;Department of Internal Medicine, University Hospital Center Touhami Benflis, Batna 05000. Algeria.;Department of Internal Medicine, University Hospital Center Touhami Benflis, Batna 05000. Algeria.;Department of Internal Medicine, University Hospital Center Touhami Benflis, Batna 05000. Algeria.;Department of Medicine, University Batna 2, Batna 05000. Algeria.;Sadelaoud Laboratory of Medical Biology, La verdure, Batna, 05000. Algeria.;Department of Medicine, University Batna 2, Batna 05000. Algeria.;Weill Cornell Medicine-Qatar, Cornell University, Doha. Qatar.",
"authors": "Rouabhia|Samir|S|;Baghazza|Sabah|S|;Sadouki|Hamza|H|;Djezzar|Sihem|S|;Bencherif|Rafik|R|;Guehimeche|Rofia|R|;Sadelaoud|Mourad|M|;Mallem|Djamel|D|;Chaabna|Karima|K|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000998:Antiviral Agents; D011433:Propranolol; D000638:Amiodarone; D000069474:Sofosbuvir",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574887112666170725132044",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8871",
"issue": "12(3)",
"journal": "Reviews on recent clinical trials",
"keywords": "Cardiac arrhythmia; Hepatitis C; drug interaction; extrasystole; propranolol; sofosbuvir",
"medline_ta": "Rev Recent Clin Trials",
"mesh_terms": "D000368:Aged; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D000998:Antiviral Agents; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D004562:Electrocardiography; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D011433:Propranolol; D000069474:Sofosbuvir; D018879:Ventricular Premature Complexes",
"nlm_unique_id": "101270873",
"other_id": null,
"pages": "159-161",
"pmc": null,
"pmid": "28745218",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ventricular Extrasystoles after First Dose of Sofosbuvir in a Patient Treated with Propranolol but not with Amiodarone: A Case Report.",
"title_normalized": "ventricular extrasystoles after first dose of sofosbuvir in a patient treated with propranolol but not with amiodarone a case report"
} | [
{
"companynumb": "DZ-IMPAX LABORATORIES, INC-2017-IPXL-03841",
"fulfillexpeditecriteria": "1",
"occurcountry": "DZ",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditiona... |
{
"abstract": "Background Argentina is considered a region of low seroprevalence of hepatitis E virus (HEV), however; no studies have evaluated its burden among acute hepatitis cases.\n\n\n\nWe aimed to estimate the proportion of acute HEV and outcome in a cohort of patients with acute hepatitis from 6 liver units in the Metropolitan area of Buenos Aires (MABA).\n\n\n\nWe performed a prospective cohort study including patients ≥18 years with acute hepatitis (increase in transaminases x 5 ULN) fromJuly 2016 to May 2018. Severe hepatitis was defined as acute hepatitis + INR> 1.5 and acute liver failure as severe hepatitis + encephalopathy. In patients in whom other etiologies were excluded, HEV tests were performed: anti-HEV IgM/G and HEV-RNA in serum and feces.\n\n\n\nOverall, 268 patients with acute hepatitis were included in the study. The most frequent etiologies of acute hepatitis were hepatitis B (67patients, 25 %), hepatotoxicity (65, 24 %) and autoimmune hepatitis (26, 10 %). Acute HEV infection was confirmed in 8 (2.98 %; 95 %CI 1.25-5.63) patients who tested positive for anti-HEV IgM. A total of 63 (23.5 %) patients were hospitalized and 9 (3.3 %) patients died. Overall, 48 (18 %) patients developed severe hepatitis, 6 (2.2 %) have acute liver failure, 6 (1.9 %) underwent liver transplantation and 9 (3.4 %) patients died.\n\n\n\nthe proportion of acute HEV in MABA was low during the period studied. We believe our findings will aid physicians prioritize other etiologies of acute hepatitis over HEV in order to optimize diagnostic resources and offer better care to their patients.",
"affiliations": "Unidad de Hígado y Trasplante Hepático, Hospital Universitario Austral, Pilar, Argentina; Latin American Liver Research, Educational and Awareness Network (LALREAN). Electronic address: mmendiza@cas.austral.edu.ar.;Sección Hepatología, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.;Sección Hepatología, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; Departamento de Investigación, Hospital Italiano de Buenos Aires, Argentina.;Unidad de Hígado y Trasplante Hepático, Hospital Alemán, Buenos Aires, Argentina.;Unidad de Hígado, Hospital Británico, Buenos Aires, Argentina.;Hospital Italiano de La Plata, Buenos Aires, Argentina.;Unidad de Hígado y Trasplante Hepático, Hospital Universitario Austral, Pilar, Argentina; Latin American Liver Research, Educational and Awareness Network (LALREAN); Sección Hepatología, Centro de Educación Médica e Investigaciones Clínicas \"CEMIC\", Buenos Aires, Argentina.;Sección Hepatología, Centro de Educación Médica e Investigaciones Clínicas \"CEMIC\", Buenos Aires, Argentina.;Latin American Liver Research, Educational and Awareness Network (LALREAN); Unidad de Hígado, Hospital Británico, Buenos Aires, Argentina.;Latin American Liver Research, Educational and Awareness Network (LALREAN); Unidad de Hígado y Trasplante Hepático, Fundación Favaloro, Buenos Aires, Argentina.;Latin American Liver Research, Educational and Awareness Network (LALREAN); Unidad de Hígado y Trasplante Hepático, Hospital Alemán, Buenos Aires, Argentina.;Sección Hepatología, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; Departamento de Investigación, Hospital Italiano de Buenos Aires, Argentina.;Laboratorio de Virología, Centro de Educación Médica e Investigaciones Clínicas \"CEMIC\", Buenos Aires, Argentina.;Unidad de Hígado y Trasplante Hepático, Hospital Universitario Austral, Pilar, Argentina; Latin American Liver Research, Educational and Awareness Network (LALREAN).",
"authors": "Mendizabal|Manuel|M|;Haddad|Leila|L|;Marciano|Sebastián|S|;Ganem|Federico Orozco|FO|;Paz|Silvina|S|;Gruz|Fernando|F|;Ridruejo|Ezequiel|E|;Lurbet|María Fernanda|MF|;Fernandez|Nora|N|;Descalzi|Valeria|V|;Anders|Margarita|M|;Gadano|Adrián|A|;Martínez|Alfredo|A|;Silva|Y Marcelo|YM|",
"chemical_list": "D006508:Hepatitis Antibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D012367:RNA, Viral",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jcv.2020.104309",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6532",
"issue": "126()",
"journal": "Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology",
"keywords": "Acute hepatitis; Hepatitis E; Outcome",
"medline_ta": "J Clin Virol",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D001118:Argentina; D002947:Cities; D005260:Female; D005838:Genotype; D006508:Hepatitis Antibodies; D016751:Hepatitis E; D016752:Hepatitis E virus; D006525:Hepatitis, Viral, Human; D006801:Humans; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D017114:Liver Failure, Acute; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012367:RNA, Viral; D016036:Seroepidemiologic Studies",
"nlm_unique_id": "9815671",
"other_id": null,
"pages": "104309",
"pmc": null,
"pmid": "32155452",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Hepatitis E infection is an infrequent cause of acute hepatitis in the metropolitan area of Buenos Aires.",
"title_normalized": "hepatitis e infection is an infrequent cause of acute hepatitis in the metropolitan area of buenos aires"
} | [
{
"companynumb": "NVSC2020AR099805",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
"dr... |
{
"abstract": "OBJECTIVE\nPhysiologic uptake of 18F-fluorodeoxyglucose (FDG) in brown adipose tissue (adipose tissue) of cancer patients may confound interpretation of positron emission tomography (PET) scans. Uptake in adipose tissue occurs in up to half of pediatric oncology patients undergoing PET scans, and is especially common in adolescents. adipose tissue is innervated by the sympathetic nervous system, and beta blockers such as propranolol have shown efficacy in reducing adipose tissue uptake on PET scans done in older adult oncology patients.\n\n\nMETHODS\nBecause propranolol may cause hypoglycemia or other side effects in fasting patients, we prospectively assessed the safety of a single dose of 20 mg propranolol in adolescent and young adult oncology patients undergoing FDG-PET imaging.\n\n\nMETHODS\nTen patients (median age 18 years, range 14-24) received propranolol premedication prior to FDG-PET.\n\n\nRESULTS\nNo adverse effects or clinically significant changes in serum glucose, heart rate, or blood pressure were observed. Five of the 10 patients had adipose tissue identified on previous PET scans. However, following propranolol administration only, one patient had persistent uptake in adipose tissue.\n\n\nCONCLUSIONS\nPropranolol was convenient and safe in fasting adolescent and young adult oncology patients undergoing PET scans. Larger studies are warranted to better define the effectiveness of this approach.",
"affiliations": "a Department of Pediatrics , University of Kentucky , Lexington , Kentucky , USA.;b Department of Radiology , University of Kentucky , Lexington , Kentucky , USA.;b Department of Radiology , University of Kentucky , Lexington , Kentucky , USA.;a Department of Pediatrics , University of Kentucky , Lexington , Kentucky , USA.;c Department of Biostatistics , University of Kentucky , Lexington , Kentucky , USA.;a Department of Pediatrics , University of Kentucky , Lexington , Kentucky , USA.",
"authors": "George|Anil|A|;Sinha|Partha|P|;Conrad|Gary|G|;Memon|Aum A|AA|;Dressler|Emily V|EV|;Wagner|Lars M|LM|",
"chemical_list": "D001786:Blood Glucose; D019788:Fluorodeoxyglucose F18; D011433:Propranolol",
"country": "England",
"delete": false,
"doi": "10.1080/08880018.2017.1338806",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0888-0018",
"issue": "34(3)",
"journal": "Pediatric hematology and oncology",
"keywords": "Adolescent and young adult; PET; brown adipose tissue; lymphoma; propranolol sarcoma",
"medline_ta": "Pediatr Hematol Oncol",
"mesh_terms": "D002001:Adipose Tissue, Brown; D000293:Adolescent; D000328:Adult; D001786:Blood Glucose; D001794:Blood Pressure; D005260:Female; D019788:Fluorodeoxyglucose F18; D006339:Heart Rate; D006801:Humans; D008297:Male; D009369:Neoplasms; D010865:Pilot Projects; D049268:Positron-Emission Tomography; D011433:Propranolol; D011446:Prospective Studies; D055815:Young Adult",
"nlm_unique_id": "8700164",
"other_id": null,
"pages": "149-156",
"pmc": null,
"pmid": "28727480",
"pubdate": "2017-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "22048045;22129321;787953;17225118;12571205;14602861;21839465;10353945;25572088;15235065;15988582;17452860;19188245",
"title": "Pilot study of propranolol premedication to reduce FDG uptake in brown adipose tissue on PET scans of adolescent and young adult oncology patients.",
"title_normalized": "pilot study of propranolol premedication to reduce fdg uptake in brown adipose tissue on pet scans of adolescent and young adult oncology patients"
} | [
{
"companynumb": "US-PFM-2020-22790",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nIdentifying specific endotypes within the broad picture of chronic rhinosinusitis with nasal polyps (CRSwNP), by using biomarkers for instance, remains a challenge. The prognostic role of the neutrophil-to-lymphocyte ratio (NLR) and the eosinophil-to-lymphocyte ratio (ELR) as potential markers of inflammation has already been discussed.\n\n\nOBJECTIVE\nThe aim of the present study was to compare NLR and ELR before and after endoscopic sinus surgery (ESS) and nasal mometasone furoate for CRSwNP by stratifying patients by their clinical and histologic features.\n\n\nMETHODS\nThe study included 115 consecutive patients with CRSwNP treated with ESS and nasal mometasone furoate, with a postoperative follow-up of >12 months. Eosinophilic-type CRSwNP was histopathologically defined after hematoxylin and eosin tissue staining.\n\n\nRESULTS\nIn the subcohort of patients with an histologic diagnosis of eosinophilic-type CRSwNP, the mean ± standard deviation ELR significantly decreased after surgery (0.22 ± 0.16 versus 0.18 ± 0.12; p = 0.04), whereas, among patients with a histologic diagnosis of noneosinophilic-type CRSwNP, the mean NLR significantly decreased after surgery (1.98 ± 0.98 versus 1.90 ± 0.90; p = 0.04).\n\n\nCONCLUSIONS\nDifferent CRSwNP endotypes are characterized by different biohumoral patterns. It is reasonable to assume that surgery enables clearance of the polyps and polypoid mucosa, which reduces the load of antigens that triggers the inflammation. Consistent with the above-mentioned biologic mechanism, ESS could correspond to a reduction in blood ELR values and eosinophil count in eosinophilic-type CRSwNP. Analysis of the data did not demonstrate an added value of measuring pre- versus postoperative ELR compared with measuring the blood eosinophil count. When used after ESS, topical corticosteroids also had more significant anti-inflammatory effects. As for the subcohort of patients with noneosinophilic CRSwNP, the fact that the mean NLR dropped significantly after surgery was definitely an original finding. Unlike eosinophilic inflammation, the inflammatory patterns seen in noneosinophilic CRSwNP are still poorly understood.",
"affiliations": null,
"authors": "Brescia|Giuseppe|G|;Barion|Umberto|U|;Zanotti|Claudia|C|;Parrino|Daniela|D|;Marioni|Gino|G|",
"chemical_list": "D015415:Biomarkers",
"country": "United States",
"delete": false,
"doi": "10.2500/aap.2017.38.4068",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1088-5412",
"issue": "38(5)",
"journal": "Allergy and asthma proceedings",
"keywords": null,
"medline_ta": "Allergy Asthma Proc",
"mesh_terms": "D000328:Adult; D000368:Aged; D015415:Biomarkers; D001706:Biopsy; D002908:Chronic Disease; D004724:Endoscopy; D004804:Eosinophils; D006801:Humans; D007958:Leukocyte Count; D018655:Lymphocyte Count; D008875:Middle Aged; D009298:Nasal Polyps; D009504:Neutrophils; D011184:Postoperative Period; D057234:Preoperative Period; D012189:Retrospective Studies; D012220:Rhinitis; D012852:Sinusitis",
"nlm_unique_id": "9603640",
"other_id": null,
"pages": "64-69",
"pmc": null,
"pmid": "28814353",
"pubdate": "2017-09-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pre- and postoperative blood neutrophil-to-lymphocyte and eosinophil-to-lymphocyte ratios in patients with sinonasal polyps: A preliminary investigation.",
"title_normalized": "pre and postoperative blood neutrophil to lymphocyte and eosinophil to lymphocyte ratios in patients with sinonasal polyps a preliminary investigation"
} | [
{
"companynumb": "IT-009507513-1709ITA004598",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3"... |
{
"abstract": "Refractory hypotension is a known entity in liver transplantation. Catecholamine and vasopressin infusions are first-line therapies. There has been recent interest in angiotensin II (Ang-2) as an alternative vasopressor; however, liver failure patients were excluded from the original trials. Ang-2 has potential in this patient population. This case discusses a patient who received an infusion of Ang-2 during a liver transplant for combined liver failure-induced distributive shock and septic shock. It is the first known successful use of intraoperative Ang-2 in this situation, and it shows that Ang-2 may be safe in liver transplantation when traditional therapies fail.",
"affiliations": "From the Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia.",
"authors": "Running|Kati|K|;Weinberg|Devin|D|;Trudo|William|W|;Sullivan|Cinnamon L|CL|;Patel|Gaurav P|GP|",
"chemical_list": "D014662:Vasoconstrictor Agents; D000804:Angiotensin II",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000001402",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "15(2)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000804:Angiotensin II; D006801:Humans; D007022:Hypotension; D016031:Liver Transplantation; D012769:Shock; D014662:Vasoconstrictor Agents",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "e01402",
"pmc": null,
"pmid": "33577171",
"pubdate": "2021-02-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intraoperative Use of Angiotensin II for Severe Vasodilatory Shock During Liver Transplantation: A Case Report.",
"title_normalized": "intraoperative use of angiotensin ii for severe vasodilatory shock during liver transplantation a case report"
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{
"companynumb": "US-TEVA-2021-US-1944753",
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"activesubstancename": "NOREPINEPHRINE"
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"abstract": "Pegylated liposomal doxorubicin (PLD) is an anthracycline anticancer agent used in ovarian cancer and a form of doxorubicin enclosed in pegylated liposomes. There are only a few reports on intertrigo-like eruptions caused by PLD. We describe the first case of severe bullous erythema, including intertrigo-like eruptions with angioedema, induced by PLD in Japan. We present the case of a 53-year-old woman who was diagnosed with stage IIIC ovarian cancer. After receiving three cycles of PLD, the patient developed swelling of the upper lip and painful erythema with blisters and erosions on the axilla, upper back, flank and wrists. The patient was diagnosed with angioedema and severe skin lesions, including intertrigo-like eruptions induced by PLD. Although treatment with oral prednisolone and topical steroids was effective against these eruptions, the administration of PLD was discontinued because of its ineffectiveness against the primary disease. Several risk factors, such as obesity, perspiration and racial differences, may contribute toward a severe manifestation such as that seen in our patient. Moreover, our case was the first accompanied by angioedema. The mechanism of coexistence of intertrigo-like eruptions and angioedema is not clear; further studies are required to clarify the pathological mechanism of intertrigo-like eruptions.",
"affiliations": "Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Gynecology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.",
"authors": "Totsuka|Michiru|M|https://orcid.org/0000-0002-1478-2897;Watanabe|Yuko|Y|;Asai|Chika|C|https://orcid.org/0000-0002-2714-5248;Takahashi|Saki|S|;Ishikawa|Hideyuki|H|https://orcid.org/0000-0002-6767-1242;Takamura|Naoko|N|;Hagiwara|Mayumi|M|;Aihara|Michiko|M|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.14895",
"fulltext": null,
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"issn_linking": "0385-2407",
"issue": "46(6)",
"journal": "The Journal of dermatology",
"keywords": "angioedema; bullous skin diseases; intertrigo; ovarian neoplasms; pegylated liposomal doxorubicin",
"medline_ta": "J Dermatol",
"mesh_terms": "D000284:Administration, Oral; D000799:Angioedema; D000903:Antibiotics, Antineoplastic; D001768:Blister; D004317:Doxorubicin; D003875:Drug Eruptions; D004890:Erythema; D005260:Female; D006801:Humans; D007402:Intertrigo; D008875:Middle Aged; D010051:Ovarian Neoplasms; D011092:Polyethylene Glycols; D011239:Prednisolone; D012867:Skin; D016896:Treatment Outcome",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "535-539",
"pmc": null,
"pmid": "31021010",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case of severe bullous erythema including intertrigo-like eruptions with angioedema induced by pegylated liposomal doxorubicin.",
"title_normalized": "case of severe bullous erythema including intertrigo like eruptions with angioedema induced by pegylated liposomal doxorubicin"
} | [
{
"companynumb": "JP-PFIZER INC-2019209228",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
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"abstract": "BACKGROUND\nWe evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA).\n\n\nMETHODS\nNeonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2-6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy.\n\n\nRESULTS\nTwenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P < 0.01), but required >1 µmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P < 0.05).\n\n\nCONCLUSIONS\nThe clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro.",
"affiliations": "Department of Pediatrics, The Rotunda Hospital, Dublin, Ireland.;Department of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada.;Department of Pediatrics, The Rotunda Hospital, Dublin, Ireland.;Department of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada.;Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.;Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.;Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.;Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.;Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.;Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.;1] Department of Neonatology, The Hospital for Sick Children, Toronto, Ontario, Canada [2] Department of Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.",
"authors": "El-Khuffash|Afif|A|;Jain|Amish|A|;Corcoran|David|D|;Shah|Prakesh S|PS|;Hooper|Christopher W|CW|;Brown|Naoko|N|;Poole|Stanley D|SD|;Shelton|Elaine L|EL|;Milne|Ginger L|GL|;Reese|Jeff|J|;McNamara|Patrick J|PJ|",
"chemical_list": "D016861:Cyclooxygenase Inhibitors; D011448:Prostaglandin Antagonists; D014662:Vasoconstrictor Agents; D000082:Acetaminophen; D007213:Indomethacin",
"country": "United States",
"delete": false,
"doi": "10.1038/pr.2014.82",
"fulltext": null,
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"issn_linking": "0031-3998",
"issue": "76(3)",
"journal": "Pediatric research",
"keywords": null,
"medline_ta": "Pediatr Res",
"mesh_terms": "D000082:Acetaminophen; D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure; D016861:Cyclooxygenase Inhibitors; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004373:Ductus Arteriosus; D004374:Ductus Arteriosus, Patent; D006801:Humans; D007213:Indomethacin; D007231:Infant, Newborn; D008026:Ligation; D011448:Prostaglandin Antagonists; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents",
"nlm_unique_id": "0100714",
"other_id": null,
"pages": "238-44",
"pmc": null,
"pmid": "24941212",
"pubdate": "2014-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "2140240;23205872;23485965;23548678;22611117;9855607;8498410;9919502;20646976;22802632;22065264;19049898;24359938;9290437;15846626;10473046;23606713;16445149;23942783;23921567;22847176;23258386;11339668;23921529;22414883",
"title": "Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies.",
"title_normalized": "efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent evidence from human and murine studies"
} | [
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"actiondrug": "5",
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"activesubstancename": "ACETAMINOPHEN"
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{
"abstract": "Valproate-induced hypothyroidism is a rare condition and has been considered asymptomatic. Here, we report a case of bipolar I disorder who developed symptomatic valproate-induced hypothyroidism.\nA 44-year-old woman with bipolar I disorder complained of severe fatigue after starting valproate. She showed a hormonal pattern of central hypothyroidism. Thyroid autoantibodies were negative, and no pituitary abnormality was seen on magnetic resonance imaging. After stopping valproate, her severe fatigue rapidly improved with normalizing thyroid function.\nOur case suggests that valproate-induced hypothyroidism should be considered when patients complain of excessive fatigue under treatment with valproate.",
"affiliations": "Department of Psychiatry, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610 Japan.;Department of Psychiatry, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610 Japan.;Department of Psychiatry, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610 Japan.;Department of Psychiatry, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610 Japan.;Department of Psychiatry, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610 Japan.;Department of Psychiatry, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610 Japan.",
"authors": "Kanamori|Tadashi|T|;Suzuki|Masahiro|M|;Kaneko|Yoshiyuki|Y|;Yamada|Kouju|K|;Kubo|Hideyuki|H|;Uchiyama|Makoto|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12991-020-00299-y",
"fulltext": "\n==== Front\nAnn Gen Psychiatry\nAnn Gen Psychiatry\nAnnals of General Psychiatry\n1744-859X BioMed Central London \n\n299\n10.1186/s12991-020-00299-y\nCase Report\nSevere fatigue due to valproate-induced hypothyroidism in a case of bipolar disorder\nKanamori Tadashi 12 Suzuki Masahiro suzuki.masahiro94@nihon-u.ac.jp 1 Kaneko Yoshiyuki 1 Yamada Kouju 12 Kubo Hideyuki 1 Uchiyama Makoto 13 1 grid.260969.20000 0001 2149 8846Department of Psychiatry, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610 Japan \n2 Kunpukai Yamada Hospital, Tokyo, Japan \n3 Tokyoadachi Hospital, Tokyo, Japan \n5 9 2020 \n5 9 2020 \n2020 \n19 4930 5 2020 27 8 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nValproate-induced hypothyroidism is a rare condition and has been considered asymptomatic. Here, we report a case of bipolar I disorder who developed symptomatic valproate-induced hypothyroidism.\n\nCase presentation\nA 44-year-old woman with bipolar I disorder complained of severe fatigue after starting valproate. She showed a hormonal pattern of central hypothyroidism. Thyroid autoantibodies were negative, and no pituitary abnormality was seen on magnetic resonance imaging. After stopping valproate, her severe fatigue rapidly improved with normalizing thyroid function.\n\nConclusions\nOur case suggests that valproate-induced hypothyroidism should be considered when patients complain of excessive fatigue under treatment with valproate.\n\nKeywords\nBipolar disorderHypothyroidismSymptomaticValproateissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nValproate, which is recognized to be much safer than lithium, the archetypal mood stabilizer, in terms of effects on thyroid function, is widely used in the treatment of bipolar disorder [1]. However, previous reports have suggested that valproate can also cause hypothyroidism [2, 3]. Here, we report a case of bipolar disorder showing severe fatigue due to valproate-induced hypothyroidism.\n\nCase presentation\nA 44-year-old woman with bipolar disorder was referred to our outpatient clinic 2 months after her first manic episode. She developed bipolar disorder with depressive episodes when she was 42 years old. Her first depressive episode was ameliorated with 3 months’ treatment with sertraline. She had no previous episodes of hypomania or mixed states, and no history of thyroid disease. When she presented at our clinic, she had been treated with quetiapine for 1 month, but still had elevated mood, irritability, and mood-congruent delusions. According to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, we diagnosed her as having bipolar I disorder, and added 200 mg of valproate on 100 mg of quetiapine. Valproate was later increased to 400 mg, after which, her manic symptoms ameliorated.\n\nDespite her mood being well controlled, she developed severe fatigue 30 days after starting valproate. She had no depression-related symptoms other than fatigue, and no findings suggesting sedation with valproate such as somnolence or impaired attention. Her blood concentration of valproate was 24.2 μg/mL, which was not at the toxic level (normal range 50–100 μg/mL). She had never had a similar reaction to previously used psychotropics. A physical examination and laboratory test found no abnormalities except for low values of free thyroxine 0.50 ng/dL (F-T4; normal range 0.8–1.5 ng/dL) and free triiodothyronine 1.85 pg/mL (F-T3; normal range 2.0–3.8 pg/mL). Although F-T4 was decreased, thyroid-stimulating hormone 2.97 μU/mL (TSH; normal range 0.34–3.8 μU/mL) was within the normal range, suggesting central hypothyroidism. Since other fatigue-causing medical conditions and medications were ruled out by systematic evaluations, we considered that the severe fatigue was associated with hypothyroidism. Thyroid autoantibodies were negative, and gadolinium-enhanced magnetic resonance imaging of the pituitary gland showed no evidence of a pituitary lesion. Considering that her F-T4 levels progressively decreased with increasing doses of valproate (F-T4 0.70 ng/dL under 200 mg and F-T4 0.50 ng/dL under 400 mg), we suspected that her hypothyroidism was caused by valproate. Therefore, we stopped valproate 33 days after its introduction. Her severe fatigue then improved, completely disappearing in about 20 days. A laboratory test 35 days after stopping valproate confirmed that her thyroid function had normalized (TSH 2.17 μU/mL, F-T3 2.99 pg/mL, F-T4 1.10 ng/dL). For the next 12 months, she had no recurrence of mood episodes, hypothyroidism, or fatigue under maintenance treatment with risperidone and carbamazepine.\n\nDiscussion\nIn this case, severe fatigue was relieved by discontinuation of valproate with normalizing thyroid function. In addition, her severe fatigue and hypothyroidism were clearly exacerbated depending on the dose of valproate. Therefore, we determined that the use of valproate was associated with her hypothyroidism and severe fatigue. Furthermore, we assessed the causal relationship between the use of valproate and the observed reactions using the Adverse Drug Reaction Probability Scale developed in 1981 by Naranjo and coworkers (i.e., the Naranjo Scale) [4]. This scale has been widely used to assess causality for adverse drug reactions. The Naranjo Scale is composed of 10 questions that are answered as either “Yes”, “No”, or “Do not know”. The total score ranges from –4 to 13, and a reaction is considered definite when the score is ≥ 9, probable if 5–8, possible if 1–4, and doubtful if ≤ 0. In this case, the causality of the association between valproate and hypothyroidism was estimated as being “Probable” based on the total score of 8. We did not re-administer valproate or perform a placebo challenge; therefore, we answered “Do not know” for two of the 10 questions. Our case showed fatigue, but no other symptoms of hypothyroidism, such as weight gain or myxedema; this may have been due to the mild decline in thyroid hormone levels.\n\nValproate-induced hypothyroidism has been considered to be asymptomatic, even if it occurs [2, 3]. To our knowledge, this is the second report of a case of symptomatic valproate-induced hypothyroidism. Similar to our case, Rao et al. reported a case of bipolar disorder who presented with excessive fatigue under treatment with valproate [5]. While their report noted that symptomatic hypothyroidism can be caused by valproate, whether this can be improved by discontinuation of valproate has remained unclear, because their report did not include a description about the treatment for hypothyroidism. Our case firstly demonstrates that valproate-induced hypothyroidism can be rapidly improved by discontinuation of valproate, even if it is symptomatic.\n\nClinical manifestations of hypothyroidism such as fatigue and psychomotor retardation are similar to those of depression. Therefore, hypothyroidism that develops during the course of treatment for depression is often overlooked. In such cases, patients can be considered as having treatment-resistant depression [6]. In patients with bipolar disorder who develop treatment-resistant depressive episodes, mood stabilizers such as valproate and lithium are continued, and patients are often supplemented with other treatments. Thyroid function is regularly screened for lithium, but is less likely to be tracked in patients using valproate [7]. Although the incidence of hypothyroidism due to valproate is speculated to be low, our case suggests that valproate-induced hypothyroidism should be considered when patients complain of excessive fatigue under treatment with valproate.\n\nThe mechanism of valproate-induced hypothyroidism is unclear. In our case, F-T4 was decreased, but TSH did not increase in reactivity, suggesting central hypothyroidism. Central hypothyroidism is caused by a malfunction of the hypothalamic–pituitary–thyroid (HPT) axis. Previous studies have suggested that γ-aminobutyric acid (GABA), whose action is enhanced by valproate, affects the HPT axis [8]. Given this finding, the central hypothyroidism in the present case might have been caused by the enhancing effect of valproate on the action of GABA. On the other hand, another mechanism in children using valproate has also been previously reported. Secondary deficiency of zinc and selenium due to valproate may decrease the synthesis of thyroid hormone and cause hypothyroidism with elevated TSH [9, 10]. However, in adults with bipolar disorder, the mechanism of valproate-induced hypothyroidism has been poorly studied. The effects of valproate on thyroid function have important implications for the treatment of bipolar disorder, so the elucidation of this mechanism is needed in future studies.\n\nConclusion\nWe reported the second case of symptomatic valproate-induced hypothyroidism. Our case suggests that valproate-induced hypothyroidism can be rapidly improved by discontinuation of valproate, even if it is symptomatic. Valproate-induced hypothyroidism should be considered when patients complain of excessive fatigue under treatment with valproate.\n\nAbbreviations\nF-T4Free thyroxine\n\nF-T3Free triiodothyronine\n\nTSHThyroid-stimulating hormone\n\nHPTHypothalamic–pituitary–thyroid\n\nGABAγ-Aminobutyric acid\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable\n\nAuthors’ contributions\nTK and HK were involved in patient care and treatment. TK and TS both mainly wrote the manuscript. YK, KY, and MU interpreted the patient data and were involved in revisions to the manuscript. All authors read and approved the final mauscript.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWe have obtained written consent from the patient for the publication of this case report.\n\nCompeting interests\nAll authors report no conflicts of interest or financial disclosures related to this manuscript.\n==== Refs\nReferences\n1. Rej S Herrmann N Gruneir A Jandoc R McArthur E Dixon S Blood lithium monitoring practices in a population-based sample of older adults J Clin Psychiatry 2018 10.4088/JCP.17m12095 30549481 \n2. Olcay G Ahmet KÖ Fatih T The effect of antiepileptic drugs on thyroid hormonal function: valproic acid and phenobarbital Acta Neurol Belg. 2020 120 615 619 10.1007/s13760-018-0908-x 29508221 \n3. Mikati MA Tarabay H Khalil A Rahi AC El Banna D Najjar S Risk factors for development of subclinical hypothyroidism during valproic acid therapy J Pediatr 2007 151 178 181 10.1016/j.jpeds.2007.02.046 17643774 \n4. 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 \n5. Pallavi R Shanker MN Madhu MG Bashir A Valproate-induced subclinical hypothyroidism J Neuropsychiatry Clin Neurosci. 2008 20 111 112 10.1176/jnp.2008.20.1.111 18305299 \n6. Bruce MC Barbara RS Alexander V Antidepressant-resistant depression in patients with comorbid subclinical hypothyroidism or high-normal TSH levels Am J Psychiatry. 2018 175 598 604 10.1176/appi.ajp.2017.17080949 29961367 \n7. Joseph FH Louise M Kate W John RG Michael K David PJO Adverse renal, endocrine, hepatic, and metabolic events during maintenance mood stabilizer treatment for bipolar disorder: a population-based cohort study PLoS Med. 2016 13 e1002058 10.1371/journal.pmed.1002058 27483368 \n8. Elias AN Valenta LJ Szekeres AV Grossman M Effect of di-N-propylacetic Acid (Valproic Acid) on the TSH Response to TRH–a presumptive role for gamma aminobutyric acid Metabolism 1981 30 1021 1023 10.1016/0026-0495(81)90104-9 6792461 \n9. Bucci I Napolitano G Giuliani C Lio S Minnucci A Di Giacomo F Zinc sulfate supplementation improves thyroid function in hypozincemic down children Biol Trace Elem Res 1999 67 257 268 10.1007/BF02784425 10201332 \n10. Pizzulli A Ranjbar A Selenium deficiency and hypothyroidism: a new etiology in the differential diagnosis of hypothyroidism in children Biol Trace Elem Res 2000 77 199 208 10.1385/BTER:77:3:199 11204462\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1744-859X",
"issue": "19()",
"journal": "Annals of general psychiatry",
"keywords": "Bipolar disorder; Hypothyroidism; Symptomatic; Valproate",
"medline_ta": "Ann Gen Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101236515",
"other_id": null,
"pages": "49",
"pmc": null,
"pmid": "32944056",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "11204462;29961367;18305299;7249508;17643774;6792461;10201332;29508221;27483368;30549481",
"title": "Severe fatigue due to valproate-induced hypothyroidism in a case of bipolar disorder.",
"title_normalized": "severe fatigue due to valproate induced hypothyroidism in a case of bipolar disorder"
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"activesubstancename": "VALPROIC ACID"
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"abstract": "Baclofen (BLF) has been prescribed in the UK since 1972 for the alleviation of spasticity. However, evidence suggests BLF is also recreationally misused. It has been associated with ethanol, gamma-hydroxybutyric acid (GHB), pregabalin (PGL) and gabapentin (GBP) use/abuse, and deaths have been reported. With current postmortem (PM) toxicological screening approaches, BLF is not routinely included in the general drugs screen and is only screened for if specifically mentioned in the case documents. The extent of BLF misuse is thus unclear. This study was carried out to determine the prevalence and concentrations of BLF in Coroners' toxicology, to investigate whether BLF misuse with ethanol, GHB, PGL and GBP is causing death and to determine the potential extent of the underreporting of BLF-associated deaths. Between 1 January 2016 and 31 December 2017, 3,750 PM femoral vein bloods were screened for BLF; all positive cases were quantified. Only 0.56% of samples screened positive for BLF, with concentration ranging from 0.08 to 102.00 µg/mL (median = 0.28). It was determined that if routine analysis without additional screening of BLF had been performed, 43% of BLF positives cases would have been missed. However, given the low incidence of detection, this only represents 0.25% of the cohort. Likely illicit use of BLF with GHB was seen in one case only. Death from the recreational use of BLF with PGL and GBP was not observed. Only two cases positive for BLF had an ethanol concentration of ≥50 mg%. Two cases of presumed intentional overdose of BLF were observed. This study highlights that although BLF abuse may be occurring, deaths are rare. It is therefore not cost- or time-effective to screen for BLF in all PM cases. With BLF currently being investigated for the treatment of alcoholism and withdrawal symptoms of illicit drug use, BLF-related deaths may rise in the future.",
"affiliations": "Toxicology Unit, Imperial College London, Toxicology Unit, London, W6 8RP, UK.;Section of Endocrinology and Investigative Medicine, Imperial College London, Endocrinology and Metabolism, London, W12 0NN, UK.;Toxicology Unit, Imperial College London, Toxicology Unit, London, W6 8RP, UK.",
"authors": "Nahar|Limon Khatun|LK|;Murphy|Kevin G|KG|;Paterson|Sue|S|",
"chemical_list": "D000069583:Pregabalin; D000077206:Gabapentin; D001418:Baclofen",
"country": "England",
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"issue": "45(6)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D001344:Autopsy; D001418:Baclofen; D000077206:Gabapentin; D006801:Humans; D000069583:Pregabalin; D019966:Substance-Related Disorders",
"nlm_unique_id": "7705085",
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"references": null,
"title": "Baclofen: To Screen or Not to Screen in Postmortem Blood?",
"title_normalized": "baclofen to screen or not to screen in postmortem blood"
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugadditional": ... |
{
"abstract": "We describe a 64-year-old male of Indian descent with a history of atrial fibrillation who was started on warfarin after hospital admission for acute stroke. He received genotype-guided warfarin dosing as per the standard-of-care at our hospital, with daily dose recommendations provided by the pharmacogenetics service. Genotyping revealed the rare CYP2C9*1/*14 genotype and warfarin insensitive VKORC1 -1639GG and CYP4F2 433Met/Met genotypes. The patient received an initial warfarin loading dose of 4 mg for 2 days, followed by 2-3 mg/day for the following 11 days. He reached a therapeutic international normalized ratio on day 5, which was maintained over the following week. This report adds to the limited data of the effects of the CYP2C9*14 allele on warfarin dose requirements.",
"affiliations": "Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL 60612-7230, USA.",
"authors": "Lee|Yee Ming|YM|;Eggen|Jessica|J|;Soni|Vinay|V|;Drozda|Katarzyna|K|;Nutescu|Edith A|EA|;Cavallari|Larisa H|LH|",
"chemical_list": "D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9",
"country": "England",
"delete": false,
"doi": "10.2217/pgs.14.47",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-2416",
"issue": "15(7)",
"journal": "Pharmacogenomics",
"keywords": "CYP2C9*14; VKORC1; anticoagulation; pharmacogenetics; warfarin",
"medline_ta": "Pharmacogenomics",
"mesh_terms": "D000483:Alleles; D001281:Atrial Fibrillation; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020521:Stroke; D014859:Warfarin",
"nlm_unique_id": "100897350",
"other_id": null,
"pages": "909-14",
"pmc": null,
"pmid": "24956244",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "15094935;12968085;18523153;21451434;23864527;24251361;18535201;19077919;15900281;18305455;20072124;18250228;19578179;22315259;12496751;23752738;15371982;24251363;15970795;18574025;17515465;16099926;21270790;15930419;21900891;24322786;19297519;11455026;22378156",
"title": "Warfarin dose requirements in a patient with the CYP2C9*14 allele.",
"title_normalized": "warfarin dose requirements in a patient with the cyp2c9 14 allele"
} | [
{
"companynumb": "US-ROXANE LABORATORIES, INC.-2014-BI-55472GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugad... |
{
"abstract": "Optimal conditioning regimens for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplant are not known. Likewise, the role of dose intensity is not clear. We conducted a nonrandomized, prospective, phase II trial using low-dose, later escalated to high-dose (myeloablative conditioning), busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to age 74 years. The first 15 patients received i.v. busulfan 130 mg/m2/day on days -3 and -2 (\"low dose\"); 31 patients received high-dose conditioning, either 100 mg/m2/day (days -5 to -2; n = 4) or pharmacokinetic-guided area under the curve of 4000 μmol/min (days -5 to -2; n = 27). The primary endpoint was day 100 nonrelapse mortality (NRM). Median age was 58 years (interquartile range [IQR], 53-63). Dynamic international prognostic scoring system-plus was intermediate (n = 28) or high (n = 18). Donors were related (n = 19) or unrelated (n = 27). Cumulative incidence of NRM was 9.7% (95% confidence interval [CI], 0-20.3) at day 100 and at 3 years in the high-dose group and 0% in the low-dose group at day 100, which increased to 20% (95% CI, 0-41.9) at 3 years. With a median follow-up of 5.1 years (IQR, 3.8-6), 3-year relapse was 32.3% (95% CI, 15.4-49.1) in high dose versus 53.3% (95% CI, 26.6-80.1) in low dose. Event-free survival was 58% (95% CI, 43-78) versus 27% (95% CI, 12-62), and overall survival was 74% (95% CI, 60-91) versus 60% (95% CI, 40-91). In multivariate analysis, high-dose busulfan had a trend toward lower relapse (hazard ratio, .44; 95% CI, .18-1.07; P = .07), with no impact on NRM. Intensifying the Bu-Flu regimen using pharmacokinetic-monitoring appears to be promising in reducing relapse without increasing NRM.",
"affiliations": "Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas. Electronic address: upopat@mdanderson.org.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas; Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Bangkok, Thailand.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.",
"authors": "Popat|Uday|U|;Mehta|Rohtesh S|RS|;Bassett|Roland|R|;Kongtim|Piyanuch|P|;Chen|Julianne|J|;Alousi|Amin M|AM|;Anderlini|Paolo|P|;Ciurea|Stefan|S|;Hosing|Chitra|C|;Jones|Roy|R|;Kebriaei|Partow|P|;Khouri|Issa|I|;Lindsay|Richard|R|;Nieto|Yago|Y|;Olson|Amanda|A|;Oran|Betul|B|;Qazilbash|Muzaffar H|MH|;Rondon|Gabriela|G|;Shpall|Elizabeth J|EJ|;Verstovsek|Srdan|S|;Andersson|Borje S|BS|;Champlin|Richard E|RE|",
"chemical_list": "D014740:Vidarabine; D002066:Busulfan",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2020.03.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "26(8)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Myelofibrosis; myeloablative; reduced intensity; stem cell transplant",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000368:Aged; D002066:Busulfan; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D055728:Primary Myelofibrosis; D011446:Prospective Studies; D019172:Transplantation Conditioning; D014740:Vidarabine",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1439-1445",
"pmc": null,
"pmid": "32438043",
"pubdate": "2020-08",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "21133885;19879949;17317589;22234678;12815476;7581076;12920019;24963042;15994282;21552298;31284069;26456259;27061824;15725091;8704209;16338616;26970380;30930192;10204198;10216077;27025789;24161923;30760453;24978138;21149668;15073038;30615982;15671439;31288096;7746977;18728030;30625392;30826464;19812383;30579966;22280409;27991894",
"title": "Optimizing the Conditioning Regimen for Hematopoietic Cell Transplant in Myelofibrosis: Long-Term Results of a Prospective Phase II Clinical Trial.",
"title_normalized": "optimizing the conditioning regimen for hematopoietic cell transplant in myelofibrosis long term results of a prospective phase ii clinical trial"
} | [
{
"companynumb": "NVSC2020US177629",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nBecause of relatively small treatment numbers together with low adverse drug reaction (ADR) reporting rates the timely identification of ADRs affecting children and young people is problematic. The primary objective of this study was to assess the utility of unplanned medication discontinuation as a signal for possible ADRs in children and young people.\n\n\nMETHODS\nUsing orlistat as an exemplar, all orlistat prescriptions issued to patients up to 18 years of age together with patient characteristics, prescription duration, co-prescribed medicines and recorded clinical (Read) codes were identified from the Primary Care Informatics Unit database between 1st Jan 2006-30th Nov 2009. Binary logistic regression was used to assess association between characteristics and discontinuation.\n\n\nRESULTS\nDuring the study period, 79 patients were prescribed orlistat (81% female, median age 17 years). Unplanned medication discontinuation rates for orlistat were 52% and 77% at 1 and 3-months. Almost 20% of patients were co-prescribed an anti-depressant. One month unplanned medication discontinuation was significantly lower in the least deprived group (SIMD 1-2 compared to SIMD 9-10 OR 0.09 (95% CI0.01 - 0.83)) and those co-prescribed at least one other medication. At 3 months, discontinuation was higher in young people (≥17 yr versus, OR 3.07 (95% CI1.03 - 9.14)). Read codes were recorded for digestive, respiratory and urinary symptoms around the time of discontinuation for 24% of patients. Urinary retention was reported for 7.6% of patients.\n\n\nCONCLUSIONS\nIdentification of unplanned medication discontinuation using large primary care datasets may be a useful tool for pharmacovigilance signal generation and detection of potential ADRs in children and young people.",
"affiliations": "Division of Applied Health Sciences, University of Aberdeen, King's College, Aberdeen AB24 3FX, UK. j.mclay@abdn.ac.uk.",
"authors": "Sun|Angela Peichen|AP|;Kirby|Bradley|B|;Black|Corri|C|;Helms|Peter John|PJ|;Bennie|Marion|M|;McLay|James Stuart|JS|",
"chemical_list": "D019440:Anti-Obesity Agents; D007783:Lactones; D000077403:Orlistat",
"country": "England",
"delete": false,
"doi": "10.1186/2050-6511-15-11",
"fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central 2050-6511-15-112459437410.1186/2050-6511-15-11Research ArticleUnplanned medication discontinuation as a potential pharmacovigilance signal: a nested young person cohort study Sun Angela Peichen 1peichen.sun@abdn.ac.ukKirby Bradley 1bradley.kirby@nhs.netBlack Corri 1corri.black@abdn.ac.ukHelms Peter John 1p.j.helms@abdn.ac.ukBennie Marion 2m.bennie@nhs.netMcLay James Stuart 13j.mclay@abdn.ac.uk1 Division of Applied Health Sciences, University of Aberdeen, King's College, Aberdeen AB24 3FX, UK2 National Medicines Utilisation Unit, Information Services Division, NHS National Services Scotland, Edinburgh, Scotland3 Department of Child Health, Royal Aberdeen Children’s Hospital, Westburn Road, Aberdeen, Scotland AB25 2ZG, UK2014 4 3 2014 15 11 11 3 8 2013 20 2 2014 Copyright © 2014 Sun et al.; licensee BioMed Central Ltd.2014Sun et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background\nBecause of relatively small treatment numbers together with low adverse drug reaction (ADR) reporting rates the timely identification of ADRs affecting children and young people is problematic. The primary objective of this study was to assess the utility of unplanned medication discontinuation as a signal for possible ADRs in children and young people.\n\nMethods\nUsing orlistat as an exemplar, all orlistat prescriptions issued to patients up to 18 years of age together with patient characteristics, prescription duration, co-prescribed medicines and recorded clinical (Read) codes were identified from the Primary Care Informatics Unit database between 1st Jan 2006-30th Nov 2009. Binary logistic regression was used to assess association between characteristics and discontinuation.\n\nResults\nDuring the study period, 79 patients were prescribed orlistat (81% female, median age 17 years). Unplanned medication discontinuation rates for orlistat were 52% and 77% at 1 and 3-months. Almost 20% of patients were co-prescribed an anti-depressant. One month unplanned medication discontinuation was significantly lower in the least deprived group (SIMD 1–2 compared to SIMD 9–10 OR 0.09 (95% CI0.01 – 0.83)) and those co-prescribed at least one other medication. At 3 months, discontinuation was higher in young people (≥17 yr versus, OR 3.07 (95% CI1.03 – 9.14)). Read codes were recorded for digestive, respiratory and urinary symptoms around the time of discontinuation for 24% of patients. Urinary retention was reported for 7.6% of patients.\n\nConclusions\nIdentification of unplanned medication discontinuation using large primary care datasets may be a useful tool for pharmacovigilance signal generation and detection of potential ADRs in children and young people.\n\nPharmacovigilancePharmacoepidemiologyObesityChildOrlistatAdverse drug reactionMedical records systemsComputerizedYoung people\n==== Body\nBackground\nAlthough adverse drug reactions (ADR) represent a major source of morbidity and mortality in adults, the nature and frequency of ADRs affecting children and young people remains poorly defined. Published data suggest that ADRs account for 1.5-2.1% of paediatric hospital admissions and affect 2.6-9.3% of paediatric inpatients and 1.5-11.1% of paediatric outpatients [1-10].\n\nIn the past children and young people have frequently been excluded from clinical trials and where trials are undertaken, they are often insufficiently powered to detect even relatively common ADRs. This means that children and young people are often prescribed medication with limited information about a treatment’s ADR profile, at doses which are not evidence based, and “off–label”; a practice which itself is associated with increased risk of ADRs [2].\n\nPost marketing surveillance is an essential tool in enabling the detection of potentially serious ADRs; however, to detect an ADR with a frequency of 1:10,000, at least 30,000 individuals need to be treated with the drug for at least 1 case to be identified. Therefore, post-marketing surveillance requires the monitoring of large patient cohorts exposed to a medication to detect ADRs. Currently, pharmacovigilance systems rely primarily on spontaneous reporting of ADRs. However under-reporting of ADRs is a significant issue affecting all European ADR monitoring systems. It is widely accepted that only 10% of UK and European healthcare professionals take part in the process of ADR reporting and that only 6-9% of ADRs affecting adults, which should be reported, are actually reported to the regulatory authorities [11-15]. Despite extending spontaneous ADR reporting in the UK to the public, and a wider group of healthcare professionals, public reporting rates still remain low, and significantly lower for children and young people than adults [16].\n\nA growing area of medical concern and drug treatment is that of obesity [17,18]. Obese adolescents tend to be become obese adults, and it is well recognised that obesity in adults is associated with increased morbidity and mortality [19,20].\n\nIn the UK, orlistat, is currently the only anti-obesity drug licensed for use in severely obese (Body Mass Index, BMI ≥30 kg/m2) adult patients or obese patients with comorbidities. Use in adults is associated with a 30% discontinuation within 3 months due to intolerable ADRs [21-24]. In pediatric/adolescent clinical trials, orlistat use has also been associated with a high level of ADRs (97-100%) and medication discontinuation (3.4-30%). However the majority of these orlistat studies have included less than 30 subjects so the ADR profile in children and young people is poorly understood [25-27].\n\nIn the UK, the majority of children and young people who require medical intervention for obesity, even when assessed in secondary care, are routinely reviewed and prescribed their medication in primary care. Primary Care electronic administrative data provide a record of relevant clinical information, service contacts and prescribing information and can, therefore, be used to assess the effectiveness of medications and potentially to generate pharmacovigilance signals. Such datasets which have been previously used for pharmacoepidemiology t have not been widely used for pharmacovigilance and have the potential to offer a complementary approach to routine pharmacovigilance methodologies.\n\nUnplanned medication discontinuation (UMD), as a signal for the identification of possible ADRs, has been previously assessed in the adult population using Primary Care electronic administrative data. This approach is based on the recognition of an early, unplanned discontinuation of the prescription for a medication, possibly accompanied by switching to alternative medication. A close agreement has been previously reported between the UMD rate and ADR rates reported in the literature for a variety of adult medications [28].\n\nThe primary objective of this study was to assess the utility of UMD as a signal for possible ADRs in children and young people. Using a large Primary Care electronic administrative dataset and orlistat as an exemplar, we assessed prescribing pattern, medicine use and the potential to generate pharmacovigilance signals for medicines prescribed with low frequency to special populations such as children and young people.\n\nMethods\nData source\nThe Primary Care Clinical Informatics Unit (PCCIU) research database is a large administrative dataset covering, in 2006, 179 Primary Care practices across Scotland [29]; representing approximately 20% of the Scottish population (1 million patients).\n\nThe PCCIU database, contains demographic data including gender, date of birth and socioeconomic status based on the practice post code (the Scottish Index of Multiple Deprivation (SIMD) 2006 quintiles) [30]: clinical information including diagnoses, procedures and practice encounter data, all recorded as Read codes, and prescribing data. Read codes are a national coding system used in primary care to code and record relevant information arising from a patient encounter in a standardised format. Read codes permit codification of a patient’s history, symptoms, examination findings, physical signs, diagnostic procedures, therapeutic and administrative procedures, drugs, appliances, occupation and social information [31]. PCCIU contains validated clinical data on a large representative proportion of the Scottish population [30,32,33].\n\nStudy population\nThe study population included a closed cohort, all children and young people aged 0–16 years of age registered with a General Practice on the 1st January 2006. This cohort was then followed until they reached their 19th birthday or 30th November 2009.\n\nExposure\nAll children and young people newly prescribed orlistat (British National Formulary code 4.5) were identified and tracked through the study period.\n\nFor this study, a “new prescription” was defined as the first prescription for orlistat during the study period with no previous prescription in the preceding 3 months.\n\nPrimary outcome\nThe primary outcome of interest was identification of a potential pharmacovigilance signal, defined as the discontinuation of orlistat for at least 3 months without a subsequent prescription. Unplanned medication discontinuations were categorised based on duration of treatment as: <1 month, 1–3 months, 4–6 months or >6 months. Duration was calculated from the date of the first prescription to the date of the last prescription. If prescriptions were ongoing at the end of the study, the child was categorised as continuing treatment.\n\nBecause the majority of patient records identified in the PCCIU dataset did not contain a specific reason for drug discontinuation, clinical symptoms, diagnoses, investigations and procedures recorded as Read codes around the time of medication discontinuation were examined. All Read codes occurring after starting orlistat were identified. Potential signal associations were limited to codes recorded during the 3 months before and 3 months after the last prescription. Read codes were reported and summarised according to the International Classification of Diseases (ICD)-10 top level categories.\n\nOther covariates\nAll co-prescriptions were extracted from the date of the first orlistat prescription up to 3 months after the last orlistat prescription date and classified into their respective British National Formulary (BNF) therapeutic drug classes [33]. The number of therapeutic drug classes prescribed for each patient was then determined and classified into 3 groups: no co-prescriptions issued, 1–4 therapeutic drug classes prescribed and >4 drug classes prescribed.\n\nAs national guidelines recommend that the BMI be calculated for the purposes of diagnosis, monitoring and initiation of pharmacological treatment, the date of the last recorded weight and height was also noted, and if assessed more than 1 year before start of orlistat was treated as missing.\n\nTo allow comparison between gender and developmental stages, the BMI standard deviation score (BMI SDS) was calculated based on Cole’s LMS method [34].\n\nIndividuals with a BMI SDS between 2.5 – 3.49 were classified as overweight to obese, those with a BMI SDS over 3.5 classified as severely obese and those over 4 as very severely obese.\n\nStatistical analysis\nDescriptive statistics (percentages, mean (SD), median (IQR)) were used to report the characteristics of the cohort. The incidence rate for orlistat prescription was calculated for 2006.\n\nDiscontinuations were summarised as percentages and reported graphically.\n\nTo explore factors that might influence the discontinuation of orlistat treatment, we compared those who discontinued orlistat treatment at one and three months with those continuing treatment. We used binary logistic regression to calculate unadjusted odds ratios (OR) and 95% confidence intervals (CI). The factors considered included: gender, age, socioeconomic status, co-prescribing of antidepressants, and number of co-prescriptions. Analysis was performed using SPSS for windows 19.0 (SPSS Inc, Chicago, Illinois, USA).\n\nEthics and approvals\nData were anonymised and no personally identifiable information was sought. Approval for the study was granted by the Primary Care Clinical Informatics Unit research steering committee in accordance with their research governance process.\n\nResults\nFrom the study population of 166,726 children and young people (49% female) aged 0–16 years and registered with a participating primary care practice in Jan 2006, a cohort of 79 young people newly prescribed orlistat during the study period were identified. In 2006, at cohort inception, the incidence of orlistat was 0.06/1000/year for children aged 0–16 years.\n\nCharacteristics of the individuals prescribed orlisat\nThe median age at first orlistat prescription was 17 years (IQR 16 – 18), 81% were female and 55% were from General Practices situated in the most deprived socioeconomic areas (SIMD deciles 7–10) (Table 1). Of the 79 children and young people prescribed orlistat, only 54 (68.3%) had a BMI recorded, of which 42 (53.2%) had a BMI measured within 1 year, and 28 (35.4%) within one month of orlistat initiation. For the 42 individuals in whom BMI was measured within a year of orlistat initiation, the median time between BMI measurement and the index orlistat prescription was 0.3 months (IQR 0.0 – 2.2 months). The mean BMI SDS was 3.31 (SD0.9) with only 16 (20.3%) of all patients prescribed orlistat having a recorded BMI SDS greater than 3.5. The demographic characteristics of individuals prescribed orlistat is described in Table 1.\n\nTable 1 Patient characteristics at time of first orlistat prescription during the follow up period (1st Jan 2006 -30th Nov 2009)\n\n \tOrlistat population\tMale\tFemale\t\n(N = 79)\t(N = 15)\t(N = 64)\t\n \t(19% of total)\t(81% of total)\t\nAge n (%)\t\nChildren (under 17 years)\t24 (30.5%)\t4 (26.7%)\t20 (31.3%)\t\nYoung people (17 – 18 years)\t55 (69.6%)\t11 (73.3%)\t44 (68.7%)\t\nMedian (IQR)\t17 (16–18)\t\nBMI SDS n (%)\t\n<2.5\t12 (15.2%)\t0\t12 (18.8%)\t\n2.5 – 3.49\t24 (30.4%)\t6 (40%)\t18 (28.1%)\t\n>3.5\t18 (22.8%)\t6 (40%)\t12 (18.8%)\t\nMissing\t25 (31.6%)\t3 (20%)\t22 (34.4%)\t\nMean (SD)\t3.13 (1.0)\t\nDeprivation SIMD (2006) n (%)\t\n1-2 (least deprived)\t8 (10.1%)\t1 (6.7%)\t7 (10.9%)\t\n3-4\t7 (8.9%)\t2 (13.3%)\t5 (7.8%)\t\n5-6\t20 (25.3%)\t3 (20.0%)\t17 (26.6%)\t\n7-8\t18 (22.8%)\t7 (46.7%)\t11 (17.2%)\t\n9-10 (most deprived)\t26 (32.9%)*\t2 (13.3%)\t24 (37.5%)\t\nCo-prescribed drug classes n (%)\t\n0\t24 (30.4%)\t7 (46.7%)\t17 (26.6%)\t\n1-4\t52 (65.8%)\t8 (53.3%)\t44 (68.8%)\t\n>4\t3 (3.8%)\t0 (0.0%)\t3 (4.7%)\t\nMedian (IQR)\t1 (0–2)\t\nAll percentage calculated from column total. *Chi squared test for trend p = 0.03.\n\nSIMD: Scottish Index of Multiple Deprivation, IQR: Inter-quartile range, BMI SDS: Body mass index standard deviation score.\n\nTwo thirds (65.8%) of patients were co-prescribed between 1–4 drug classes/items. The medicines most commonly co-prescribed were antibiotics (17.4% of all prescriptions), topical skin treatments (12.4%), analgesics (10.7%), oral contraceptives (9.9%), asthma medications (7.4%) and antidepressants (4.1%). Four (5%) patients prescribed orlistat were also prescribed metformin. For three of these, metformin was initiated immediately following cessation of the orlistat prescription.\n\nOrlistat discontinuation\nFifty-two percent of patients (41) discontinued orlistat medication within 1 month of the index prescription and 77% (61) within 3 months.\n\nDiscontinuation within 1 month was not affected by age or gender but was significantly less likely if the patient had received any co-prescription (OR 0.12 (95% CI 0.03 – 0.41) or was in the least deprived group (OR 0.09 (95% CI 0.01 – 0.84) (SIMD 1–2) though there was no obvious trend by deprivation category.\n\nGender, co-prescription and socio-economic status, were not significantly related to 3-month discontinuation, however young people over 17 years of age were three times more likely to discontinue their prescription at 3-months when compared with those under 17 years of age (OR 3.07; 95%Cl 1.03 – 9.14) (Table 2).\n\nTable 2 Crude odds ratios for 1 month and 3 month discontinuation for factors such as: gender, age, deprivation score, prescription of anti-depressants and co-prescription of other therapeutic drug classes\n\n \tDuration of treatment\t \t \tDuration of treatment\t \t \t\n \t<1 month\t≥1 month\tOR\t95% CI\t<3 month\t≥3 month\tOR\t95% CI\t\n \tN = 41\tN = 38\t \t \tN = 61\tN = 18\t \t \t\nGendern (%)\t \t \t \t \t \t \t \t \t\nFemale\t33 (80.5%)\t31 (81.6%)\tRef\t \t48 (78.7%)\t16 (88.9%)\tRef\t \t\nMale\t8 (19.5%)\t7 (18.4%)\t1.07\t0.35–3.31\t13 (21.3%)\t2 (11.1%)\t2.17\t0.44– 10.65\t\nAge bandsn (%)\t \t \t \t \t \t \t \t \t\nChildren (under 17 years)\t9 (22.0%)\t15 (39.5%)\tRef\t \t15 (24.6%)\t9 (50.0%)\tRef\t \t\nYoung people (17-18 years)\t32 (78.0%)\t23 (60.5%)\t2.32\t0.87–6.21\t46 (75.4%)\t9 (50.0%)\t3.07\t1.03– 9.14\t\nDeprivation SIMD 2006n (%)\t \t \t \t \t \t \t \t \t\n1-2\t1 (2.4%)\t7 (18.4%)\t0.09\t0.01–0.84\t5 (8.2%)\t3 (16.7%)\t0.23\t0.03-1.41\t\n3-4\t3 (7.3%)\t4 (10.5%)\t0.47\t0.09–2.55\t6 (9.8%)\t1 (0.6%)\t0.78\t0.07– 8.93\t\n5-6\t12 (29.3%)\t8 (21.1%)\t0.94\t0.28–3.09\t15 (24.6%)\t5 (27.8%)\t0.39\t0.08– 1.89\t\n7-8\t9 (22.0%)\t9 (23.7%)\t0.63\t0.19–2.11\t12 (19.7%)\t6 (33.3%)\t0.26\t0.06– 1.23\t\n9-10\t16 (39.0%)\t10 (26.3%)\tRef\t \t23 (37.7%)\t3 (16.7%)\tRef\t \t\nAntidepressantsn (%)\t \t \t \t \t \t \t \t \t\nYes\t37 (90.2%)\t28 (73.7%)\tRef\t \t51 (83.6%)\t14 (77.8%)\tRef\t \t\nNo\t4 (9.8%)\t10 (26.3%)\t0.30\t0.09–1.07\t10 (16.4%)\t4 (22.2%)\t0.69\t0.19– 2.52\t\nCo-prescriptions issuedn (%)\t \t \t \t \t \t \t \t \t\nYes\t20 (48.8%)\t4 (10.5%)\tRef\t \t22 (36.1%)\t2 (11.1%)\tRef\t \t\nNo\t21 (51.2%)\t34 (89.5%)\t0.12\t0.03–0.41\t39 (63.9%)\t16 (88.9%)\t0.22\t0.05– 1.06\t\nCI; Confidence Interval. OR; Odds Ratio.\n\nAll percentage calculated from column total. SIMD: Scottish Index of Multiple Deprivation.\n\nRead codes and possible adverse events\nIn total, 404 Read codes were recorded from the start of orlistat treatment to 3 months after the last orlistat prescription for 77.2% (61) of the study population. The median number of Read codes per individual was 5; IQR 1–6 (range 0–51), and 20.3% (82) of these Read codes related specifically to symptoms or treatments. Eight (10.1%) patients had a Read Code recorded for: the respiratory, seven (8.9%) for the genitourinary, six (7.6%) for skin, six (7.6%) for endocrine, four (5.1%) for obstetric and gynaecological, four (5.1%) for gastrointestinal, four (5.1%) for musculoskeletal, 3 (3.8%) for mental health and behavioural and 3 (3.8%) for the CNS systems. (Symptoms and diagnoses are listed in Table 3).\n\nTable 3 Actual Symptoms and diagnoses recorded as Read codes by the treating primary care physician within 3 months of orlistat discontinuation (n = 79)\n\nSystem\tNumber of patients (%)\tSymptoms\tFrequency\t\nRespiratory\t8 (10.1%)\tInfluenza\t3\t\nAcute tonsillitis\t3\t\nAcute bronchitis and bronchiolitis\t2\t\nAsthma\t1\t\nChest infection\t1\t\nAcute laryngitis and tracheitis\t1\t\nUpper respiratory infection\t1\t\nCough\t1\t\nRespiratory symptom\t1\t\nGenitourinary\t7 (8.9%)\tTreatment via bladder catheter\t5\t\nRetention of urine\t1\t\nUrinary tract infection (UTI)\t1\t\nSuspected UTI\t2\t\nCystitis\t1\t\nDermatology\t6 (7.6%)\tRash and other non-specific skin eruption\t1\t\nDermatitis\t1\t\nSkin cyst\t1\t\nChalazion (meibomian cyst)\t1\t\nAcne vulgaris\t1\t\nUnilateral mastalgia\t1\t\nLump in breast\t1\t\nPsoriasis and similar disorders\t1\t\nEndocrine\t6 (7.6%)\tObesity\t4\t\nAcquired hypothyroidism\t2\t\nGynaecomastia\t3\t\nObstetrics & Gynaecology\t4 (5.1%)\tMenorrhagia\t1\t\nDysmenorrhoea\t1\t\nSpontaneous abortion\t1\t\nCodes related to spontaneous abortion\t6\t\nPolycystic ovarian syndrome\t1\t\nGastrointestinal\t4 (5.1%)\tNon-infective gastritis\t1\t\nGastritis\t1\t\nAbdominal pain\t3\t\nAbdominal discomfort\t1\t\nIrritable bowel syndrome\t1\t\nMusculoskeletal\t4 (5.1%)\tBackache\t1\t\nPain in lumbar spine\t1\t\nClosed fracture of radius\t1\t\nTemporomandibular joint disorder\t1\t\nArthralgia of knee\t1\t\nMental health and behavioural\t3 (3.8%)\tSocial phobias\t4\t\nLoss of confidence\t1\t\nAnxiety state\t1\t\nDepressed mood\t4\t\nAt risk of deliberate self harm\t1\t\nCentral nervous system\t3 (3.8%)\tIn-coordination\t1\t\nTiredness\t1\t\nMigraine\t1\t\nHeadache\t1\t\nInfantile autism\t1\t\nInfection\t3 (3.8%)\tViral infection\t3\t\nOf note 8.9% (7, all female) of all patients prescribed orlistat had a Read code recorded within three months of orlistat discontinuation for the genitourinary system, of whom five were recorded as having urinary catheterisation and one urinary retention. None of these individuals were prescribed any medication or items during the three year study period to suggest neurological, bowel, bladder or malignant disease, which might explain the need for urinary catheterisation.\n\nDiscussion\nWe demonstrate that using UMD as a surrogate for possible adverse events, routinely collected primary care datasets may be used for pharmacovigilance signal generation, although validation of generated signals and confirmation of potential ADRs will require appropriately designed prospective studies. We believe that this approach will be complementary to the spontaneous reporting systems currently in use and enhance the capability of these systems to widen the breadth of ADRs detected while reducing cost and time to ADR detection. Furthermore such an approach permits assessment of prescribing appropriateness together with real life prescribing patterns. In this study, one in every two patients prescribed orlistat discontinued within a month, and more than three quarters discontinued within three months, of starting treatment.\n\nFor medicines such as orlistat, continued use is likely to reflect patient acceptability and perceived effectiveness. In this context it is likely that early discontinuation reflects the appearance of unwanted poorly tolerated ADRs, while later discontinuation represents a perceived lack of response [35]. The levels of UMD in this study are similar to those reported by Viner at al, who noted orlistat discontinuations of 45% at one month, 75% at 3 months and 90% at 6 months [36].\n\nDiscontinuation at three months was significantly more frequent in the young people aged 17 years and over, possibly reflecting the effects of emerging autonomy and loss of parental influence [37-39]. One month discontinuation was significantly associated with social class and the presence of other co-prescribed medication, with patients from the most affluent social groups and those co-prescribed other medications less likely to discontinue orlistat therapy. While the association between social deprivation and poor adherence is well recognised the observation that medication discontinuation was less likely in those co-prescribed other medications runs counter to the perceived wisdom that higher levels of non-adherence are observed among adolescents and young adults prescribed multiple medicines [40,41].\n\nIn this study orlistat was prescribed predominantly to adolescents females, and those from the most socially deprived areas. Although the relationship between obesity and social deprivation is well recognised, this is the first study to report a link between social deprivation and orlistat prescribing [42-46].\n\nSeventy percent of the cohort prescribed orlistat was co-prescribed medications including antibiotics, topical treatments for skin conditions and analgesia. Five percent of patients were also prescribed metformin, licensed for use in individuals aged 10 years and older for type II diabetes mellitus, but which is being increasingly used for the treatment of obesity and insulin resistance [46-51].\n\nIn the present study, one fifth of all patients (predominantly female) prescribed orlistat were also prescribed antidepressants at some point during the study period. In the general adolescent population antidepressants are reportedly prescribed to 1-5/1000 individuals per year [52-54], therefore the high level of use observed in our study suggests a significantly greater prevalence of depression in the obese t population a finding consistent with studies in both young people and adults [54-56].\n\nRead code, describing clinical symptoms and treatments, were recorded by a primary care physician for approximately a fifth of patients around the time of orlistat discontinuation. Respiratory, genitourinary, endocrine, skin, gynaecological and gastrointestinal symptoms were reported to occur in 10%, 8.9%, 7.6%, 7.6%, 5.1% and 5.1% of patients respectively. Data from pediatric/young person orlistat trials suggest that adverse effects, primarily diarrhoea, affect 97-100% of individuals, leading to a discontinuation rate of 2% - 30% [26,27,57]. In this study a Read code for gastrointestinal symptoms (all of which were abdominal pain) was only recorded for 5.1% of patients. The reasons for this apparent difference between our data and that from clinical trials may be that patients were pre-warned about possible gastrointestinal symptoms and therefore did not report the ADR, or that gastrointestinal side effects were so common that primary care physicians did not record them as a reason for discontinuation.\n\nAn unexpected finding was the number of individuals for whom urological system Read codes, urinary catheterisation and urinary retention, were recorded. The reasons for this finding are not clear. While urinary retention is frequently associated with neurological disorders and or constipation, assessment of co-prescribed medicines and items for these individuals, identified only one subject prescribed laxatives and none prescribed medicines or items commonly used for the treatment of neurological, bowel, bladder, malignant or infective conditions during the study period. Although orlistat use has been associated with nephrolithiasis and acute renal injury [58,59], there are currently no data in the literature linking orlistat with urinary retention. However as of November 2013 (current reporting period), the Medicines and Healthcare products Regulatory Agency, the UK government medicine regulatory agency, had received two “Yellow Card” reports for urinary retention possibly associated with orlistat use [60], raising the possibility that the association between orlistat use and urological symptoms observed in this study may be real. Although the approach used in this study doesn’t allow us to attribute causality, it is reassuring to observe that the symptoms and diagnoses recorded by primary care physicians around the time of orlistat discontinuation, such as influenza infection, upper respiratory infection, headache and menstrual irregularities are in close agreement with those reported for adults in the real world [61].\n\nCurrent clinical guidelines make it clear that prior to the initiation of orlistat therapy, height and weight should be recorded. In our study, 70% of the study cohort had this information recorded, and of these only a third had measurements recorded within a month of their initial prescription. The failure to undertake appropriate BMI assessment prior to orlistat initiation means that it is not possible to determine for the majority of patients whether orlistat was prescribed appropriately, according to the UK guidelines.\n\nWe have previously reported that electronic prescribing databases can be used to identify UMD in adult patients, and that such UMD rates can be used as a surrogate for ADR/AE rates [28,35]. However, the use of UMD does not identify the reasons for discontinuation or the nature of possible ADRs/AEs. The UMD and ADR results we obtained for orlistat are in close agreement with previously published UMD and ADR rates obtained using more traditional methods of ascertainment, indicating that UMD obtained from routinely collected data may represent a surrogate marker for ADR/ADE occurrence. Using this approach together with more traditional spontaneous reporting systems [62], may reveal potential pharmacovigilance signals at an earlier stage following introduction of a medicine and permit a more accurate assessment of ADR incidence than is currently possible.\n\nThe use of large primary care electronic datasets enables the linkage of whole population prescription information with recorded clinical symptoms, diagnoses and encounters. As we have demonstrated, this approach permits the assessment of prescribing trends and identification of individuals who discontinue their medication at an early stage before clinical effectiveness might be expected. Assessment of clinical symptoms and diagnosis recorded around the time of orlistat discontinuation identified unexpected findings which might indicate, although not prove, the occurrence of an ADR to the study medication.\n\nThere were several limitations to our study. It is possible that the small number of patients prescribed orlistat in this study may reduce the generalisability of the orlistat specific findings; however it does not alter the overall conclusion that the linkage of UMD with medical Read codes identifies possible pharmacovigilance signals of interest. Moreover, the PCCIU-R database, like most other prescribing/dispensing databases, only reflects primary care prescribing and does not provide information on secondary care prescribing or over the counter purchase of orlistat. It is therefore possible that patients for whom an initial prescription was issued in secondary care or who purchased their medication OTC may have been missed. However this is unlikely to be a major issue in the Western world, where primary care remains the major source of medication prescriptions. A further limitation is the lack of a specific recorded reason for orlistat discontinuation in the PCCIU-R database, and this is the reason why all Read codes at or about the time of discontinuation were identified and examined.\n\nConclusions\nUsing orlistat as the exemplar, we have demonstrated that when unplanned medication discontinuation are linked to clinical codes for events occurring at the time of discontinuation, it is possible to generate both predictable and unpredicted pharmacovigilance signals. These findings support the use of this approach together with traditional pharmacovigilance methodologies to identify possible signals and plan more specific and focused pharmacovigilance studies with the aim of validating suspected ADRs.\n\nPatient consent\nAs all data analyzed was fully anonymised and non attributable the approval for the study was granted by the Primary Care Clinical Informatics Unit research steering committee in accordance with their research governance process and individual patient consent was not necessary.\n\nAbbreviations\nADR: Adverse drug reaction; BMI: Body mass index; BMISDS: Body mass index standard deviation score; BNF: British National Formulary; ICD: International Classification of Diseases; MHRA: Medicines and healthcare products regulatory agency; PCCIUR: Primary care clinical informatics unit research; NICE: National institute for health and clinical excellence; SIMD: Scottish index of multiple deprivation; SIGN: Scottish intercollegiate guidelines network.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nAS: assisted in conceptualization, design and analysis of the study, drafted the initial manuscript, and approved the final manuscript as submitted. BK: assisted in conceptualization, design and analysis of the study and approved the final manuscript as submitted. PH: assisted in conceptualization, design and analysis of the study and approved the final manuscript as submitted. CB: assisted in conceptualization, design and analysis of the study and approved final manuscript as submitted. MB: assisted in conceptualization, design and analysis of the study and approved the final manuscript as submitted. JM: conceptualized and designed the study, assisted with analysis and interpretation of results, and approved the final manuscript as submitted. JM acts as study guarantor. All authors read and approved the final manuscript.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\nhttp://www.biomedcentral.com/2050-6511/15/11/prepub\n\nAcknowledgement\nThe authors wish to acknowledge that the data contained herein were provided by the Primary Care Clinical Informatics Unit (PCCIU) at the University of Aberdeen. The views in this publication are not necessarily the views of the University of Aberdeen, it’s agents, or employees. The authors also wish to acknowledge the Chief Scientists Office, Scotland who funded this study and the Scottish Children’s Research Network (ScotCRN).\n\nFunding source\nAll phases of this study were supported by a Scottish Government, Chief Scientist Office project grant. 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ISD Scotland July 2000 https://www.google.co.uk/search?q=Read+Code+User+Guide+Dr.+Lesley+Graham,+Ann+Ward,+Gerry+Mulvenna.+599+ISD+Scotland+July+2000.&ie=utf-8&oe=utf-8&rls=org.mozilla:en-US:official&client=firefox-a&channel=sb&gws_rd=cr&ei=SakZU8iFLaWS7AaIiYA4 Accessed 23/07/2013) \nDatabase review by PCCIU http://www.abdn.ac.uk/iahs/uploads/files/PCI.pdf. Accessed 25 06 2013 \nWhitelaw FG Nevin SL Milne RM Taylor RJ Taylor MW Watt AH Completeness and accuracy of morbidity and repeat prescribing records held on general practice computers in Scotland B J G P 1996 46 404 181 186 \nCole TJ Freeman JV Preece MA Body mass index reference curves for the UK, 1990 Arch Dis Child 1995 73 1 25 29 10.1136/adc.73.1.25 7639544 \nBritish National Formulary, Volume No 64 2012 BMJ and Pharmaceutical Press \nMohamed IN Helms PJ Simpson CR McLay JS Using routinely collected prescribing data to determine drug persistence for the purpose of pharmacovigilance J Clin Pharmacol 2011 51 2 279 284 10.1177/0091270010366444 20400648 \nViner RM Hsia Y Neubert A Wong ICK Rise in antiobesity drug prescribing for children and adolescents in the UK: a population-based study Br J Clin Pharmacol 2009 68 6 844 851 10.1111/j.1365-2125.2009.03528.x 20002078 \nTebbi CK Treatment compliance in childhood and adolescence Cancer 1993 71 10 Suppl 3441 3449 8490895 \nFriedman IM Litt IF Adolescents’ compliance with therapeutic regimens. Psychological and social aspects and intervention J Adolescent Health Care 1987 8 1 52 67 10.1016/0197-0070(87)90246-4 \nTebbi CK Cummings KM Zevon MA Compliance of pediatric and adolescent cancer patients Cancer 1986 58 5 1179 1184 10.1002/1097-0142(19860901)58:5<1179::AID-CNCR2820580534>3.0.CO;2-E 3731045 \nTucker CM Fennell RS Pedersen T Higley BP Wallack CE Peterson S Associations with medication adherence among ethnically different pediatric patients with renal transplants Pediatr Nephrol 2002 17 4 251 256 10.1007/s00467-001-0806-x 11956876 \nClaxton AJ Cramer J Pierce C A systematic review of the associations between dose regimens and medication compliance Clin Ther 2001 23 8 1296 1310 10.1016/S0149-2918(01)80109-0 11558866 \nKinra S Nelder RP Lewendon GJ Deprivation and childhood obesity: a cross sectional study of 20,973 children in Plymouth, United Kingdom J Epidemiol Community Health 2000 54 6 456 460 10.1136/jech.54.6.456 10818122 \nStrauss RS Knight J Influence of the home environment on the development of obesity in children Pediatr 1999 103 6 e85 10.1542/peds.103.6.e85 \nGoldblatt PB Moore ME Stunkard AJ Social factors in obesity JAMA 1965 192 1039 1044 10.1001/jama.1965.03080250017004 14293500 \nSobal J Stunkard AJ Socioeconomic status and obesity: a review of the literature Psychol Bull 1989 105 2 260 275 2648443 \nYanovski JA Krakoff J Salaita CG McDuffie JR Kozlosky M Sebring NG Reynolds JC Brady SM Calis KA Effects of metformin on body weight and body composition in obese insulin-resistant children: a randomized clinical trial Diabetes 2011 60 2 477 485 10.2337/db10-1185 21228310 \nBurgert TS Duran EJ Goldberg-Gell R Dziura J Yeckel CW Katz S Tamborlane WV Caprio S Short-term metabolic and cardiovascular effects of metformin in markedly obese adolescents with normal glucose tolerance Pediatr Diabetes 2008 9 6 567 576 10.1111/j.1399-5448.2008.00434.x 18761646 \nAtabek ME Pirgon O Use of metformin in obese adolescents with hyperinsulinemia: a 6-month, randomized, double-blind, placebo-controlled clinical trial J Pediatr Endocrinol 2008 21 4 339 348 \nSrinivasan S Ambler GR Baur LA Garnett SP Tepsa M Yap F Ward GM Cowell CT Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin J Clinl Endocrinol Metab 2006 91 6 2074 2080 10.1210/jc.2006-0241 \nFreemark M Bursey D The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes Pediatr 2001 107 4 E55 10.1542/peds.107.4.e55 \nLove-Osborne K Sheeder J Zeitler P Addition of metformin to a lifestyle modification program in adolescents with insulin resistance J Pediatr 2008 152 6 817 822 10.1016/j.jpeds.2008.01.018 18492523 \nMurray ML de Vries CS Wong IC A drug utilisation study of antidepressants in children and adolescents using the General Practice Research Database Arch Dis Child 2004 89 12 1098 1102 10.1136/adc.2004.064956 15557040 \nZito JM Safer DJ Sai D Gardner JF Thomas D Coombes P Dubowski M Mendez-Lewis M Psychotropic medication patterns among youth in foster care Pediatr 2008 121 1 e157 63 10.1542/peds.2007-0212 \nMustillo S Worthman C Erkanli A Keeler G Angold A Costello EJ Obesity and psychiatric disorder: developmental trajectories Pediatr 2003 111 4 Pt 1 851 859 \nAtlantis E Baker M Obesity effects on depression: systematic review of epidemiological studies Int J Obes 2008 32 6 881 891 10.1038/ijo.2008.54 \nRevah-Levy A Speranza M Barry C Hassler C Gasquet I Moro MR Falissard B Association between Body Mass Index and depression: the “fat and jolly” hypothesis for adolescents girls BMC Public Health 2011 11 649 10.1186/1471-2458-11-649 21846386 \nChanoine J Hampl S Jensen C Boldrin M Hauptman J Effect of orlistat on weight and body composition in obese adolescents: a randomized controlled trial JAMA 2005 293 23 2873 83 10.1001/jama.293.23.2873 15956632 \nSingh A Sarkar SR Gaber LW Perazella MA Acute oxalate nephropathy associated with orlistat, a gastrointestinal lipase inhibitor Am J Kidney Dis 2007 49 1 153 157 10.1053/j.ajkd.2006.10.004 17185156 \nWeir MA Beyea MM Gomes T Juurlink DN Mamdani M Blake PG Wald R Amit MPH Garg X Orlistat and acute kidney injury: an analysis of 953 patients Arch Intern Med 2011 171 7 703 4 21482850 \nMHRA orlistat drug analysis print http://www.mhra.gov.uk/Safetyinformation/Howwemonitorthesafetyofproducts/Medicines/TheYellowCardScheme/YellowCarddata/Druganalysisprints/index.htm?secLevelIndexChar=Oq%20-%20Ou#retainDisplay Accessed 22.01.2014 \nHighlights of prescribing information-Xenical http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020766s029lbl.pdf Accessed 19/06/2013) \nThe World Health Organisation Pharmacovigilance toolkit. pharmacovigilance methods http://www.pvtoolkit.org/index.php?option=com_content&view=article&id=6&Itemid=10 Accessed 20. 07 2013\n\n",
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"mesh_terms": "D000293:Adolescent; D019440:Anti-Obesity Agents; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016208:Databases, Factual; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007783:Lactones; D008297:Male; D055118:Medication Adherence; D000077403:Orlistat; D060735:Pharmacovigilance; D010818:Practice Patterns, Physicians'; D011320:Primary Health Care",
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"title": "Unplanned medication discontinuation as a potential pharmacovigilance signal: a nested young person cohort study.",
"title_normalized": "unplanned medication discontinuation as a potential pharmacovigilance signal a nested young person cohort study"
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"abstract": "Association of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary team management of these patients should be provided.",
"affiliations": "Maxillo-facial and ENT Surgery Unit INT - IRCCS \"Fondazione G. Pascale\" Naples Italy.;Head & Neck/Thyroid Medical Oncology Unit INT - IRCCS \"Fondazione G. Pascale\" Naples Italy.;Maxillo-facial and ENT Surgery Unit INT - IRCCS \"Fondazione G. Pascale\" Naples Italy.;Melanoma, Oncological Immunotherapy and Innovative Therapies Department INT - IRCCS \"Fondazione G. Pascale\" Naples Italy.;Melanoma, Oncological Immunotherapy and Innovative Therapies Department INT - IRCCS \"Fondazione G. Pascale\" Naples Italy.",
"authors": "Guida|Agostino|A|https://orcid.org/0000-0003-0177-1301;Perri|Francesco|F|https://orcid.org/0000-0001-8158-7509;Ionna|Franco|F|;Ascierto|Paolo A|PA|;Grimaldi|Antonio M|AM|",
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"doi": "10.1002/ccr3.3418",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3418\nCCR33418\nCase Report\nCase Reports\nNew‐generation anticancer drugs and medication‐related osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy\nGUIDA et al.Guida Agostino https://orcid.org/0000-0003-0177-1301\n1\n Perri Francesco https://orcid.org/0000-0001-8158-7509\n2\nf.perri@istitutotumori.na.it Ionna Franco \n1\n Ascierto Paolo A. \n3\n Grimaldi Antonio M. \n3\n \n1 \nMaxillo‐facial and ENT Surgery Unit\nINT – IRCCS “Fondazione G. Pascale”\nNaples\nItaly\n\n\n2 \nHead & Neck/Thyroid Medical Oncology Unit\nINT – IRCCS “Fondazione G. Pascale”\nNaples\nItaly\n\n\n3 \nMelanoma, Oncological Immunotherapy and Innovative Therapies Department\nINT – IRCCS “Fondazione G. Pascale”\nNaples\nItaly\n\n* Correspondence\n\nFrancesco Perri, Head & Neck/Thyroid Medical Oncology Unit, INT – IRCCS “Fondazione G. Pascale,” via M. Semmola 53, 80131 Naples, Italy.\n\nEmail: f.perri@istitutotumori.na.it\n\n02 12 2020 \n1 2021 \n9 1 10.1002/ccr3.v9.161 66\n14 7 2020 28 9 2020 04 10 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nAssociation of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary team management of these patients should be provided.\n\nAssociation of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary team management of these patients should be provided.\n\n\nbisphosphonate‐associated osteonecrosisipilimumabmedically compromised patientsmedication‐related osteonecrosis of the jawtarget therapy source-schema-version-number2.0cover-dateJanuary 2021details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:18.01.2021\n\n\nGuida \nA \n, \nPerri \nF \n, \nIonna \nF \n, \nAscierto \nPA \n, \nGrimaldi \nAM \n. New‐generation anticancer drugs and medication‐related osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy\n. Clin Case Rep .2021 ;9 :61 –66\n. 10.1002/ccr3.3418\n==== Body\n1 INTRODUCTION\nThe number of medication which may cause osteonecrosis of the jaws is increasing. Up until now, Ipilimumab has been associated with MRONJ only two times in literature. A woman underwent endovenous chemotherapy with ipilimumab in 2015 for metastatic melanoma. In 2018, while she was undergoing target therapy (vemurafenib + cobimetinib), after wisdom tooth extraction, she developed MRONJ. She was successfully treated with medical therapy alone. Ongoing target therapy may have played a role in MRONJ late onset. Caution and vigilance in dental management of patients treated with novel MRONJ‐related chemotherapy are needed. A multidisciplinary evaluation is advised.\n\nFirst reported cases of nonhealing‐exposed bone in the maxillofacial region were recognized by oral and maxillofacial surgeons in patients treated with intravenous (IV) bisphosphonates (BP).\n1\n During 2004, Novartis, manufacturer of pamidronate (Aredia) and zoledronic acid (Zometa)—two IV BPs—labeled this product as at risk for osteonecrosis of the jaws (ONJ).\n2\n Consequently, the subsequent year a warning followed for all BP drug class to be at risk for ONJ, which was renamed as bisphosphonate‐related ONJ (BRONJ).\n3\n\n\n\nSince then, other BPs and medications from other classes have been related to the development of ONJ, including denosumab (humanized monoclonal antibody blocking the activation of receptors for nuclear factor κβ ligand), bevacizumab (humanized monoclonal antibody), and antiangiogenic medications—sunitinib (tyrosine kinase inhibitor).\n4\n, \n5\n, \n6\n, \n7\n, \n8\n, \n9\n, \n10\n Additionally, case reports have indicated possible association between ONJ and azacitidine, imatinib, everolimus, ziv‐aflibercept, ipilimumab, and tocilizumab.\n11\n, \n12\n, \n13\n, \n14\n, \n15\n, \n16\n, \n17\n, \n18\n With the advent of these new classes of medications, the condition is now more aptly known as medication‐related osteonecrosis of the jaw (MRONJ).\n1\n Both pathogenesis and associated risk factors not fully comprehended. This majorly reflects on its therapy as indications for surgery (sequestrectomy/curettage with possible reconstruction) vs antibiotic medical therapy (3 g amoxicillin + 1.5 metronidazole per os per day for at least 2 weeks) are still unclear and so great effort is also put in studying and developing complementary treatments, including application of platelet concentrates, ozone therapy, and laser treatment, in order both to prevent MRONJ and to improve healing after surgical treatment of such lesions.\n19\n\n\n\nUncertainty increases both for diagnosis and treatment especially for non‐BP drugs related to ONJ, which may have very few cases reported in literature, such as ipilimumab.\n\nIpilimumab is a monoclonal antibody directed against the CTLA4 receptor, present on activated T lymphocytes. The resulting binding causes an increase of lymphocyte T activity directed against melanoma cells, which are therefore destructed. The antibody is administered intravenously at a dose of 3 mg/kg every 3 weeks, for 4 cycles. Approval of ipilimumab was based on a randomized three‐arm phase III study which compared ipilimumab with a vaccine therapy (gp100) and with their combination,\n20\n showing improved overall survival in patients undergoing Ipilimumab. Ipilimumab is associated with the risk of immune‐related side effects; sixty percent of immune‐related adverse events were recorded in the study population. Approximately 15% of patients experienced grade 3 or 4 adverse events. Dermatitis was the most frequent immune‐related event, and diarrhea, the most dangerous (perforation risk if not promptly treated); severe cases should be treated with high‐dose corticosteroids.\n\nIn present scientific literature, there are two reported cases of MRONJ onset in patients treated with ipilimumab alone and 1 in a patient treated with concomitant denosumab + ipilimumab.\n12\n, \n17\n MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion of it.\n\nIn this case report, we describe MRONJ occurred 3 years after the conclusion of treatment with ipilimumab.\n\n2 CASE PRESENTATION\nIn November 2018, a 58 year‐old‐woman with BRAF‐mutated metastatic melanoma, treated at the immunotherapy unit of our institute, was referred to our oral pathology outpatient clinic. During a regular follow‐up visit, the patient reported that she was experiencing severe pain in the oral cavity for 4 months due to a nonhealing alveolus, after the extraction of the lower right third molar. During this time, the patient had been treated by her dentist for an alveolar osteitis (AO, dry sockets) with 1‐week cycle of amoxicillin + clavulanic acid (2.25 + 0.75 g/d per os) and chlorhexidine 0.2% mouthwash daily socket irrigation. She referred that she had repeated this therapy three times during those months, continuing chlorhexidine 0.2% mouthwash daily socket irrigation among the antibiotic cycles. She referred that, occasionally, she also underwent application of zinc oxide eugenol in her alveolus. Furthermore, the patient had used chlorhexidine 0.2% mouth rinse since day before the extraction. Every treatment tried up until now had been unsuccessful. She had no extra‐oral sign of swelling nor of ongoing abscess. Intraorally, clinical inspection confirmed the presence of a nonhealed alveolar socket; the bottom and the walls of the alveolus were clearly visible, made of nonvascularized nonsuppurated bone, surrounded by swollen mucosa (Figure 1).\n\nFIGURE 1 Intraoral inspection revealed the nonhealing alveolus\n\nShe exhibited a 3‐day‐old orthopantomography (OPT), which showed radiographic sign of a nonhealed alveolus (Figure 2).\n\nFIGURE 2 Orthopantomography (OPT) exhibited from the patient during the first visit, revealing the nonhealing alveolus 4 mo after tooth extraction\n\nHer anamnesis was carefully harvested. The patient underwent a surgical resection of a cutaneous melanoma in 2009. Then, in 2015, for lung progression of disease, she was treated with ipilimumab (3 mg/kg mg iv, every 3 weeks for 4 cycles) with complete remission of the disease. During the follow‐up, in 2017 the patient had hepatic progression, and so, due to the presence of the BRAF mutation, she started the treatment with dabrafenib + trametinib (300 + 2 mg per os/die). Due to the G. 3 toxicity (fever) experienced by the patient, the treatment was stopped and was replaced with vemurafenib + cobimetinib (vemurafenib: 1920 per os/die for 3 months, then 1440 mg per os/die; cobimetinib: 60 mg per os/die for 3 weeks then 1‐week pause), still ongoing. She was then taking 1440 mg vemurafenib + 60 mg cobimetinib per os/die at the moment of her tooth extraction. She had no history of smoking nor head and neck radiotherapy. Among all the medications she had undergone, ipilimumab was the only one that has been related to MRONJ.\n12\n, \n17\n Staging of the MRONJ was thus performed; it was evaluated to be a “stage 2 MRONJ” according to the AAOMS classification, showing “Exposed and necrotic bone(…) with evidence of infection, (…) symptomatic.”\n1\n She was thus treated accordingly, starting a treatment with amoxicillin + metronidazole (3 + 1.5 g per os/die) and chlorhexidine 0.2% mouth rinse twice a day; paracetamol (1 g per os) was prescribed for pain control. During the 2‐week follow‐up visit, the patient showed clinical improvement. She referred the ejection of a 10 × 5 mm bone sequestrum after 6 days of therapy and that her symptoms had therefore disappeared. The clinical examination still highlighted an incomplete alveolar healing. Two additional weeks of therapy were prescribed and, after that, the patient obtained a complete healing of the defect (Figure 3). Treatment for the MRONJ was stopped, and the patient was regularly followed up monthly. After 6 months, a new OPT showed complete healing of the alveolus (Figure 4).\n\nFIGURE 3 Complete clinical resolution after 4 wks of antibiotic/disinfectant therapy (amoxicillin + metronidazole −3 + 1.5 g per os/die‐ and chlorhexidine 0.2% mouth rinse)\n\nFIGURE 4 Radiographic appearance at OPT after 6 mo of follow‐up, showing complete bone healing\n\n3 DISCUSSION\nSeveral new medications have been added to the potential cause of MRONJ drug list. Among these, ipilimumab has been reported in three published clinical cases as a possible cause of MRONJ, two as single therapy and one in association with denosumab.\n12\n, \n20\n As far as literature reports, MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion. Our patient suspended the treatment with ipilimumab 3 years before. Dabrafenib, trametinib, vemurafenib, and cobimetinib—the other chemotherapy drugs taken by the patient—have never been reported as possible cause of MRONJ.\n\nTherefore, diagnosis was the first issue we encountered in the management of this case. For the symptoms and the clinical presentation, the differential diagnosis was between alveolar osteitis (dry socket, AO), MRONJ, and osteoradionecrosis (ORN). ORN was the first possibility to be discarded as the patients had no history of head and neck radiotherapy. AO was carefully taken into account prior to start any therapy. The clinical and radiographic appearance was indeed compatible with such disease which is defined as “postoperative pain in and around the extraction site, which increases in severity at any time between one and 3 days after the extraction, associated with a partially or totally disintegrated blood clot within the alveolar socket, with or without halitosis.”\n21\n Still, as a matter of fact, most recent meta‐analyses show that AO therapy should be more symptomatic\n21\n, \n22\n rather than therapeutic, as there is no full comprehension of its pathogenesis and, above all, it is considered as a “self‐limiting” disease. The antibiotic therapy prescribed by the dentist of the patient resulted useless, and no improvement was observed after 4 months even with topic injection of chlorhexidine and zinc oxide eugenol, which are reported between the most successful treatment for AO.\n21\n, \n22\n As reported in literature, after the diagnosis, AO, regardless of the therapy, tends to remit in a period of days or weeks, most commonly,\n22\n while there is no report in scientific literature of AO persisting for several months. AO was thus discarded in the differential diagnosis process.\n\nFurthermore, the presence of a bone sequestrum related to a nonhealing postextraction socket, not visible at the first inspection but ejected during antibiotic therapy, is an event more compatible with MRONJ rather than AO. About the therapy administered, it must be underlined that no guideline exists yet. Consensus conferences\n1\n advise to begin with antibiotic therapy and then, in case of partial/no response, re‐evaluate the patient for surgery. In our case, antibiotic therapy was administered as first choice and we reached complete healing. Yet, literature\n23\n warns that partial/no response to antibiotic therapy is a common event, and so is the necessity to complete the therapeutic pathway with surgical approach in order to reach complete healing. Patients must be thus followed up carefully.\n\nAs reported before, among the various anticancer therapy agents administered to the patient, ipilimumab was the only drug that could be related to MRONJ. Ipilimumab was approved by the US Food and Drug Administration in March 2011 as an immunotherapy for the management of advanced (unresectable or metastatic) melanoma patients.\n12\n Ipilimumab is a humanized monoclonal antibody against cytotoxic T lymphocyte–associated antigen‐4 (CTLA‐4). CTLA‐4 is expressed both in activated T cells and in suppressor T‐regulatory cells, binding to antigen‐presenting cells and therefore diminishing T‐cell responses. The block of the CTLA‐4 is able to improve the antitumor responses of activated T cells. The result is a significant incremented survival in patients with metastatic melanoma undergoing ipilimumab.\n18\n, \n24\n The immune response induced by ipilimumab with only 4 cycles of treatment (about 2 months of therapy) can persist for many years, inducing a kind of vaccination against metastatic melanoma. In literature, there are reported cases of ipilimumab‐related ONJ occurred during or shortly after the end of the systemic therapy. The authors suggested that that Ipilimumab may have been involved in the process of bone necrosis by empowering the number of systemic activated T‐cell presence. CTLA4‐deficient activated T cells have been shown to be associated with osteonecrosis, as activated T cells may ignite osteoclastogenesis via osteoprotegerin ligand, resulting in bone loss.\n25\n Trauma from regular oral activity or oral surgery (eg, tooth extraction) could increase the demand for this vulnerable bone to mend itself, resulting in localized bone necrosis.\n12\n\n\n\nIpilimumab is known to have a 14.7‐day blood half‐life\n26\n while the patient described in our case had completed Ipilimumab treatment 3 years before. As we have seen, the real advantage of the drug is in the long‐term efficacy with about 20% of patients alive at 5, 7, and 10 years after treatment completion. This long‐term efficacy is due to the immune responses induced by checkpoint inhibitors. Still, just like the anticancer effects, side effects can last for many years.\n12\n It is conceivable that, similarly to pruritus, diarrhea, vitiligo, hepatitis, and endocrinopathies, MRONJ may be also a late side effect under certain circumstances. We suggest that the MRONJ onset may have been co‐caused by the ongoing target therapy (vemurafenib + cobimetinib) of the patient. The effect of BRAF and MEK inhibitors in BRAF‐mutant melanoma can lead to an immune‐stimulating microenvironment by enhancing expression of immune‐stimulating molecules and cytokines, reducing immunosuppressive cell populations, and decreasing immunosuppressive cytokines. The cell damage to the tumor by the target therapy may have induced a tumor‐antigen spreading, restimulating T‐cell activity whose response had been increased and modulated by the effect of ipilimumab. Moreover, it has been demonstrated that anti‐BRAF therapy enhances the reactivity and cytotoxicity of T cells.\n27\n, \n28\n The re‐activation of such empowered T‐cell clones may have lead the patient into a window of time in which she was at risk for MRONJ, similarly to when the patient was on treatment with ipilimumab.\n\n4 CONCLUSIONS\nIn addition to well‐known medications, MRONJ may be a major adverse reaction to several new‐generation anticancer drugs. These drugs may have unexpected mechanisms, being their pharmacodynamic not fully comprehended up until now. Even if this paper reports of a single event—in addition to the few other cases reported in literature of ipilimumab MRONJ, the authors recommend caution and strict vigilance in the dental management of patients treated with novel chemotherapy drugs, reported to be at risk for MRONJ. Multidisciplinary evaluation is thus strongly advised; cooperation between the oncologist and the dentist/oral and maxillofacial surgeon may help in taking the best decision in the patient's interest, ensuring the best possible result in the management of relatively recent drugs, which may cause unpredictable side effects. The administration of the prophylactic antibiotic protocol (amoxicillin + metronidazole; 3 + 1.5 g per os/die) may be arranged in accordance between the surgeon and the oncologist, with the best possible evaluation of both oral and systemic conditions. Such cooperation may reduce the occurrence of adverse events which, as we have shown in our paper, may result in patient's discomfort and pain. Further studies are needed on a large number of cases, in order to fully understand the relation between ipilimumab and MRONJ, and the possible interference of target therapy.\n\n5 ETHICS APPROVAL AND CONSENT TO PARTICIPATE\nNot applicable.\n\n6 CONSENT FOR PUBLICATION\nNot applicable.\n\nCONFLICT OF INTEREST\nThe authors declare that they have no competing interests.\n\nAUTHOR CONTRIBUTIONS\nAG and AMG: drafted the manuscript. FP: revised the manuscript. FI and PAA: performed scientific supervision.\n\nACKNOWLEDGMENTS\nNot applicable.\n\nDATA AVAILABILITY STATEMENT\nThe datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n1 \n\nRuggiero \nSL \n, \nDodson \nTB \n, \nFantasia \nJ \n, et al. American association of oral and maxillofacial surgeons position paper on medication‐related osteonecrosis of the jaw—2014 update\n. J Oral Maxillofac Surg . 2014 ;72 :1938 ‐1956\n.25234529 \n2 \n\nHohnecker \nJA \n. DearDoctor. Precautions Added to the Label of Aredia and Zometa . East Hanover, NJ : Novartis Oncology ; 2004 :2 .\n3 \nUnited States Food and Drug Administration, Office of Drug Safety: Postmarketing safety review \n. Bisphosphonates\n. http://www.fda.gov/ohrms/dockets/ac/05/briefing/20054095B2_03_04‐FDA‐Tab3.pdf. Accessed October 09, 2019.\n4 \n\nLipton \nA \n, \nSteger \nGG \n, \nFigueroa \nJ \n, et al. Randomized active controlled phase II study of denosumab efficacy and safety in patients with breast cancer‐related bone metastases\n. J Clin Oncol . 2007 ;25 :4431 ‐4437\n.17785705 \n5 \n\nStopeck \nAT \n, \nLipton \nA \n, \nBody \nJJ \n, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double‐blind study\n. J Clin Oncol . 2010 ;28 :5132 ‐5139\n.21060033 \n6 \n\nMalan \nJ \n, \nEttinger \nK \n, \nNaumann \nE \n, \nBeirne \nOR \n. The relationship of denosumab pharmacology and osteonecrosis of the jaws\n. Oral Surg Oral Med Oral Pathol Oral Radiol . 2012 ;114 :671 ‐676\n.23159111 \n7 \n\nOwosho \nAA \n, \nBlanchard \nA \n, \nLevi \nL \n, et al. Osteonecrosis of the jaw in patients treated with denosumab for metastatic tumors to the bone: a series of thirteen patients\n. J Craniomaxillofac Surg . 2016 ;44 (3 ):265 ‐270\n.26782845 \n8 \n\nFleissig \nY \n, \nRegev \nE \n, \nLehman \nH \n. Sunitinib related osteonecrosis of jaw: a case report\n. Oral Surg Oral Med Oral Pathol Oral Radiol . 2012 ;113 :e1 ‐e3\n.\n9 \n\nEstilo \nCL \n, \nFornier \nM \n, \nFarooki \nA \n, et al. Osteonecrosis of the jaw related to bevacizumab\n. J Clin Oncol . 2008 ;26 :4037 ‐4038\n.18711196 \n10 \n\nNicolatou‐Galitis \nO \n, \nMigkou \nM \n, \nPsyrri \nA \n, et al. Gingival bleeding and jaw bone necrosis in patients with metastatic renal cell carcinoma receiving sunitinib: report of 2 cases with clinical implications\n. Oral Surg Oral Med Oral Pathol Oral Radiol . 2012 ;113 :234 ‐238\n.22669112 \n11 \n\nKim \nDW \n, \nJung \nYS \n, \nPark \nHS \n, \nJung \nHD \n. Osteonecrosis of the jaw related to everolimus: a case report\n. Br J Oral Maxillofac Surg . 2013 ;51 :e302 ‐e304\n.24094895 \n12 \n\nOwosho \nAA \n, \nScordo \nM \n, \nYom \nSK \n, et al. Osteonecrosis of the jaw a new complication related to Ipilimumab\n. Oral Oncol . 2015 ;51 :e100 ‐e101\n.26421864 \n13 \n\nPonzetti \nA \n, \nPinta \nF \n, \nSpadi \nR \n, et al. Jaw osteonecrosis associated with aflibercept, irinotecan and fluorouracil: attention to oral district\n. Tumori . 2016 ;102 (suppl.2 ).\n14 \n\nMawardi \nH \n, \nEnzinger \nP \n, \nMcCleary \nN \n, et al. Osteonecrosis of the jaw associated with ziv‐aflibercept\n. J Gastrointest Oncol . 2016 ;7 :E81 ‐E87\n.28078129 \n15 \n\nNicolatou‐Galitis \nO \n, \nGaliti \nD \n, \nMoschogianni \nM \n, et al. Osteonecrosis of the jaw in a patient with acute myeloid leukemia, who received azacitidine\n. J Cancer Metasta Treat . 2016 ;2 :220 ‐223\n.\n16 \n\nNicolatou‐Galitis \nO \n, \nRazis \nE \n, \nGaliti \nD \n, \nVardas \nE \n, \nTzerbos \nF \n, \nLabropoulos \nS \n. Osteonecrosis of the jaw in a patient with chronic myelogenous leukemia receiving imatinib: a case report with clinical implications\n. Forum Clin Oncol . 2013 ;4 :29 ‐33\n.\n17 \n\nOwosho \nAA \n, \nLiang \nSTY \n, \nSax \nAZ \n, et al. Medication‐related osteonecrosis of the jaw: An update on the memorial sloan kettering cancer center experience and the role of premedication dental evaluation in prevention\n. Oral Surg Oral Med Oral Pathol Oral Radiol . 2018 ;125 :440 ‐445\n.29580668 \n18 \n\nBennardo \nF \n, \nBuffone \nC \n, \nGiudice \nA \n. New therapeutic opportunities for COVID‐19 patients with Tocilizumab: possible correlation of interleukin‐6 receptor inhibitors with osteonecrosis of the jaws\n. Oral Oncol . 2020 ;106 :104659.32209313 \n19 \n\nFortunato \nL \n, \nBennardo \nF \n, \nBuffone \nC \n, \nGiudice \nA \n. Is the application of platelet concentrates effective in the prevention and treatment of medication‐related osteonecrosis of the jaw? A systematic review\n. J Craniomaxillofac Surg . 2020 ;48 (3 ):268 ‐285\n.32063481 \n20 \n\nHodi \nFS \n, \nO’Day \nSJ \n, \nMcDermott \nDF \n, et al. Improved survival with ipilimumab in patients with metastatic melanoma\n. N Engl J Med . 2010 ;363 :711 ‐723\n.20525992 \n21 \n\nKolokythas \nA \n, \nOlech \nE \n, \nMiloro \nM \n. Alveolar osteitis: a comprehensive review of concepts and controversies\n. Int J Dent . 2010 ;2010 :249073.20652078 \n22 \n\nTaberner‐Vallverdú \nM \n, \nNazir \nM \n, \nSánchez‐Garcés \nMÁ \n, et al. Efficacy of different methods used for dry socket management: a systematic review\n. Med Oral Patol Oral Cir Bucal . 2015 ;20 (5 ):e633 ‐e639\n.26116842 \n23 \n\nFavia \nG \n, \nTempesta \nA \n, \nLimongelli \nL \n, \nCrincoli \nV \n, \nMaiorano \nE \n. Medication‐related osteonecrosis of the jaw: Surgical or non‐surgical treatment?\n\nOral Dis . 2018 ;24 (1‐2 ):238 ‐242\n.29480596 \n24 \n\nPrieto \nPA \n, \nYang \nJC \n, \nSherry \nRM \n, et al. CTLA‐4 blockade with ipilimumab: long‐term follow‐up of 177 patients with metastatic melanoma\n. Clinical Cancer Res Off J Am Assoc Cancer Res . 2012 ;18 :2039 ‐2047\n.\n25 \n\nKong \nYY \n, \nFeige \nU \n, \nSarosi \nI \n, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand\n. Nature . 1999 ;402 :304 ‐309\n.10580503 \n26 \n\nBurki \nTK \n. Ipilimumab prolongs survival in advanced melanoma\n. Lancet Oncol . 2016 ;17 (11 ):e481.27746107 \n27 \n\nDonia \nM \n, \nFagone \nP \n, \nNicoletti \nF \n, et al. BRAF inhibition improves tumor recognition by the immune system: potential implications for combinatorial therapies against melanoma involving adoptive T‐cell transfer\n. Oncoimmunology . 2012 ;1 (9 ):1476 ‐1483\n.23264894 \n28 \n\nBoni \nA \n, \nCogdill \nAP \n, \nDang \nP \n, et al. Selective BRAFV600E inhibition enhances T‐cell recognition of melanoma without affecting lymphocyte function\n. Cancer Res . 2010 ;70 (13 ):5213 ‐5219\n.20551059\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "9(1)",
"journal": "Clinical case reports",
"keywords": "bisphosphonate‐associated osteonecrosis; ipilimumab; medically compromised patients; medication‐related osteonecrosis of the jaw; target therapy",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "61-66",
"pmc": null,
"pmid": "33489133",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports",
"references": "18711196;25234529;26350200;22676833;23159111;23264894;26782845;26421864;22669112;20525992;21060033;24094895;28078129;27746107;26116842;29580668;20652078;32063481;17785705;10580503;32209313;20551059;22271879;29480596",
"title": "New-generation anticancer drugs and medication-related osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy.",
"title_normalized": "new generation anticancer drugs and medication related osteonecrosis of the jaw mronj late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy"
} | [
{
"companynumb": "IT-ROCHE-2742974",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nTo observe the efficacy and safety of chemotherapy regimens oxaliplatin combined with capecitabine (CAPOX) or oxaliplatin combined with tegafur, gimeracil and oteracil potassium capsules (S-1)(SOX), and to investigate the value of expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) proteins in tumor tissue for predicting the efficacy of CAPOX and SOX regimens in advanced gastric cancer patients.\n\n\nMETHODS\nA total of 107 newly-diagnosed, stage Ⅲc/Ⅳ gastric cancer patients (no surgical indication, ECOG performance scores 0-2 and expected survival time ≥3 months) were recruited with 101 patients evaluated. The patients were randomly divided into two groups. One was study group in which the patients received CAPOX regimen. The other was control group received SOX regimen. Each patient received four cycles, at least two cycles chemotherapy every three weeks and followed up until death or lost. Tumor biopsies were obtained by gastroscopy for immunohistochemical examination of the expression of TP and DPD proteins before chemotherapy. Response rate (ORR), overall survival (OS) and time to tumor progression (TTP) of the patients were assessed.\n\n\nRESULTS\nThe objective response rate (ORR) of the study and control groups was 49.0% (5/51) vs. 46.0% (23/50), respectively (P>0.05). The overall survival (OS) was 357.36±24.69 days in the study group and 349.87±22.63 days in the control group, and the time-to-progression (TTP) was 216.75±19.32 days in the study group and 220.54±18.47 days in the control group (P>0.05 for both). Stratified analysis showed that the ORR of TP-positive patients in the study group was significantly higher than that in the control group (72.0 % vs. 41.7 %, P=0.032). There was no significant difference in ORR between the TP-negative patients in the study and control groups (26.9% vs. 50.0%, P=0.087), while the ORR of DPD-positive patients in the control group was significantly higher than that of the study group (51.9% vs. 34.6%, P=0.046). There was no significant difference in the ORR between DPD-negative patients in the study and control groups (64.0% vs. 39.1%, P=0.084). The follow-up showed that the OS (378.42±22.56 days) and TTP (271.77±24.92 days) in the TP-positive patients of the study group were significantly longer than those of the control group (OS: 326.57±19.84 days, and TTP: 229.13±22.68 days)( P<0.05). The OS was 371.25±23.97 days and TTP was 264.66±21.36 days in the DPD-positive patients of control group, significantly longer than those of the study group (OS: 334.73±21.47days, and TTP: 208.58±20.70 days) (P<0.05). But there was no significant difference in the OS and TTP between the TP- and DPD-negative patients in the two groups (P>0.05). In respect of adverse events, both the rates of hematological and non-hematological toxicities were low and similar between the two groups (P>0.05), and well-tolerated by the patients.\n\n\nCONCLUSIONS\nBoth CAPOX and SOX regimens are effective chemotherapeutic protocols in treatment of patients with advanced gastric cancer. The expression levels of TP and DPD in tumor tissue can be used as a predictive factor for the efficacy of capecitabine or tegafur, gimeracil and oteracil potassium capsules combined with oxaliplatin regimens. CAPOX chemotherapy regimen is more suitable for the TP-positive gastric cancer patients, and SOX regimen is more suitable for the DPS-positive gastric cancer patients.",
"affiliations": "Department of Medical Oncology, the First Hospital of Huai'an City Affiliated to Nanjing Medical University, Huai'an, Jiangsu Province 223300, China.;Department of Medical Oncology, the First Hospital of Huai'an City Affiliated to Nanjing Medical University, Huai'an, Jiangsu Province 223300, China.;Department of Medical Oncology, the First Hospital of Huai'an City Affiliated to Nanjing Medical University, Huai'an, Jiangsu Province 223300, China.;Department of Pathology, the First Hospital of Huai'an City Affiliated to Nanjing Medical University, Huai'an, Jiangsu Province 223300, China.;Department of Pathology, the First Hospital of Huai'an City Affiliated to Nanjing Medical University, Huai'an, Jiangsu Province 223300, China.",
"authors": "Wan|Yiyuan|Y|;Hui|Hongxia|H|;Wang|Xiaowei|X|;Wu|Jian|J|;Sun|Su'an|S|",
"chemical_list": "D000970:Antineoplastic Agents; D002214:Capsules; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D011725:Pyridines; D000077150:Oxaliplatin; D005641:Tegafur; C489337:potassium oxonate; D010094:Oxonic Acid; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D013939:Thymidine Phosphorylase; C104201:gimeracil",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.issn.0253-3766.2016.01.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0253-3766",
"issue": "38(1)",
"journal": "Zhonghua zhong liu za zhi [Chinese journal of oncology]",
"keywords": null,
"medline_ta": "Zhonghua Zhong Liu Za Zhi",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D002214:Capsules; D042943:Dihydrouracil Dehydrogenase (NADP); D018450:Disease Progression; D006801:Humans; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010094:Oxonic Acid; D011725:Pyridines; D013274:Stomach Neoplasms; D005641:Tegafur; D013939:Thymidine Phosphorylase",
"nlm_unique_id": "7910681",
"other_id": null,
"pages": "28-34",
"pmc": null,
"pmid": "26796803",
"pubdate": "2016-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Comparison of the efficacy and safety of capecitabine or tegafur, gimeracil and oteracil potassium capsules combined with oxaliplatin chemotherapy regimens in the treatment of advanced gastric cancer.",
"title_normalized": "comparison of the efficacy and safety of capecitabine or tegafur gimeracil and oteracil potassium capsules combined with oxaliplatin chemotherapy regimens in the treatment of advanced gastric cancer"
} | [
{
"companynumb": "CN-ROCHE-1713762",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nTo compare intravitreal ranibizumab and dexamethasone implant in patients with macular edema (ME) secondary to central retinal vein occlusion (CRVO).\n\n\nMETHODS\nParticipants were 42 treatment naive patients with ME due to CRVO, who received either intravitreal 0.5 mg ranibizumab (n = 25) or intravitreal 0.7 mg dexamethasone implant (n = 17). The main outcomes included the mean change in best corrected visual acuity (BCVA) and central subfield thickness (CST) at month 12 compared to baseline in the two groups.\n\n\nRESULTS\nAt month 12, there was no statistically significant difference in BCVA and CST change between the two groups. However, there was recurrence in ME at month 5 in the dexamethasone group.\n\n\nCONCLUSIONS\nBoth ranibizumab and dexamethasone implant were found to be safe and effective at the 12-month follow-up in patients with ME secondary to CRVO. Since there was a recurrence in ME at month 5 in the dexamethasone group, we suggested that intravitreal injection of dexamethasone implant should be potentially administered sooner than 6 months.",
"affiliations": "2nd Department of Ophthalmology, \"Attikon\" Hospital, National and Kapodistrian University of Athens, Athens, Greece. eirchat@yahoo.gr.;2nd Department of Ophthalmology, Henry Dunant Hospital, Athens, Greece.;Medical Retina Department, Korgialeneio Benakeio, Red Cross Hospital, Athens, Greece.;2nd Department of Ophthalmology, Ophthalmiatrion Athinon, Athens, Greece.;Medical Retina Department, Korgialeneio Benakeio, Red Cross Hospital, Athens, Greece.;2nd Department of Ophthalmology, Ophthalmiatrion Athinon, Athens, Greece.;2nd Department of Ophthalmology, \"Attikon\" Hospital, National and Kapodistrian University of Athens, Athens, Greece.",
"authors": "Chatziralli|Irini|I|;Theodossiadis|George|G|;Kabanarou|Stamatina A|SA|;Parikakis|Efstratios|E|;Xirou|Tina|T|;Mitropoulos|Panagiotis|P|;Theodossiadis|Panagiotis|P|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D004343:Drug Implants; D005938:Glucocorticoids; D003907:Dexamethasone; D000069579:Ranibizumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00417-017-3719-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0721-832X",
"issue": "255(10)",
"journal": "Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie",
"keywords": "Central retinal vein occlusion; Dexamethasone; Inflammation; Ranibizumab; Treatment",
"medline_ta": "Graefes Arch Clin Exp Ophthalmol",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D003907:Dexamethasone; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000069579:Ranibizumab; D012170:Retinal Vein Occlusion; D013997:Time Factors; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome",
"nlm_unique_id": "8205248",
"other_id": null,
"pages": "1899-1905",
"pmc": null,
"pmid": "28620704",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "20430446;20417567;21764136;21715011;26540281;25673251;27163237;23653882;19120547;24612095;19118700;23629796;26358547;20702826;25471901;26197958;23638803;24112944;22301066;20022117",
"title": "Ranibizumab versus dexamethasone implant for central retinal vein occlusion: the RANIDEX study.",
"title_normalized": "ranibizumab versus dexamethasone implant for central retinal vein occlusion the ranidex study"
} | [
{
"companynumb": "GR-ALLERGAN-1726329US",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nProgressive multifocal leukoencephalopathy results from lytic infection of the glia by the JC polyomavirus (JCV); JCV granule cell neuronopathy is caused by infection with a mutated form of JCV, leading to a shift in viral tropism from the glia to cerebellar granule cells. This shift results in a clinical syndrome dominated by progressive cerebellar dysfunction that might elude standard diagnostic workup strategies for ataxia.\n\n\nMETHODS\nWe present the case report of a patient receiving long-term rituximab therapy who developed progressive cerebellar ataxia and marked isolated cerebellar degeneration. This syndrome resulted from JCV granule cell neuronopathy associated with a novel JCV mutation.\n\n\nCONCLUSIONS\nNew onset or worsening of isolated cerebellar ataxia in patients being treated with rituximab or natalizumab warrants early assessment for JCV infection.",
"affiliations": "Department of Neurology, University of Michigan, Ann Arbor.;Division of Neurovirology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.;Division of Neurovirology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.;Department of Neurology, University of Michigan, Ann Arbor.",
"authors": "Dang|Louis|L|;Dang|Xin|X|;Koralnik|Igor J|IJ|;Todd|Peter K|PK|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1001/jamaneurol.2013.4668",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6149",
"issue": "71(4)",
"journal": "JAMA neurology",
"keywords": null,
"medline_ta": "JAMA Neurol",
"mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D002524:Cerebellar Ataxia; D003594:Cytoplasmic Granules; D020233:Gait Disorders, Neurologic; D006801:Humans; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal; D008297:Male; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "101589536",
"other_id": null,
"pages": "487-9",
"pmc": null,
"pmid": "24515530",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "14504320;20937629;21576685;21940415;15786466;20298967;16894191",
"title": "JC polyomavirus granule cell neuronopathy in a patient treated with rituximab.",
"title_normalized": "jc polyomavirus granule cell neuronopathy in a patient treated with rituximab"
} | [
{
"companynumb": "US-ROCHE-1351825",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "To estimate the incidence of pulmonary aspiration and other anesthesia-related adverse events in women undergoing dilation and evacuation (D&E) under intravenous deep sedation without tracheal intubation in an outpatient setting.\n\n\n\nWe reviewed all D&Es done under anesthesiologist-administered intravenous deep sedation without tracheal intubation between February 2009 and April 2013. The study's primary outcome was pulmonary aspiration; secondary outcomes included other anesthesia-related complications. We calculated the incidence of anesthesia-related adverse events as well as a 95% CI around the point estimate.\n\n\n\nDuring the 51-month study period, 4,481 second-trimester abortions were completed. Of these, 2,523 (56%) were done under deep sedation without tracheal intubation, 652 (26%) between 14 and 19 6/7 weeks of gestation, and 1,871 (74%) between 20 and 24 weeks of gestation. Seven cases of anesthesia-related complications were identified: two cases of pulmonary aspiration (0.08%, 95% CI 0.01-0.29%), four cases of upper airway obstruction (0.016%, 95% CI 0.04-0.41%), and one case of lingual nerve injury (0.04%, 95% CI 0.001-0.22%).\n\n\n\nDeep sedation without tracheal intubation for women undergoing D&E has a low incidence of anesthesia-related complications.",
"affiliations": "Department of Obstetrics & Gynecology and Women's Health, Montefiore Medical Center, Bronx, New York; and the Departments of Anesthesia and Perioperative Care, Obstetrics, Gynecology and Reproductive Sciences, Medicine, and Anesthesia and Perioperative Care, and the Women's Options Center of Zuckerberg San Francisco General, University of California, San Francisco, and the University of California, San Francisco School of Medicine, San Francisco, California.",
"authors": "Aksel|Sarp|S|;Lang|Laura|L|;Steinauer|Jody E|JE|;Drey|Eleanor A|EA|;Lederle|Lauren|L|;Sokoloff|Abby|A|;Carlisle|A Sue|AS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/AOG.0000000000002692",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-7844",
"issue": "132(1)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D000028:Abortion, Induced; D000328:Adult; D054810:Deep Sedation; D004106:Dilatation; D005260:Female; D005865:Gestational Age; D006801:Humans; D015994:Incidence; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D053120:Respiratory Aspiration; D012189:Retrospective Studies",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "171-178",
"pmc": null,
"pmid": "29889744",
"pubdate": "2018-07",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety of Deep Sedation Without Intubation for Second-Trimester Dilation and Evacuation.",
"title_normalized": "safety of deep sedation without intubation for second trimester dilation and evacuation"
} | [
{
"companynumb": "PHHY2019US117854",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Pyoderma gangrenosum is a rare, chronic, non infectious ulcerative skin disease. It is an inflammatory neutrophilic dermatosis. It is associated in 50% with a systemic disorder. Unfortunately, there are no randomized controlled studies concerning PG treatment. Immunosuppression is the mainstay of treatment and includes local and systemic measures, with high risk of potential side effects. Multidisciplinary care to patients with PG is essential for best management. We present a patient with pyoderma gangrenosum which was admitted in our Infectious Diseases Unit and first treated based on an infectious assumption. Collaboration between internists and dermatologists led to quick correct diagnosis, PG management, exclusion of an associated systemic disorder and management of further complications.",
"affiliations": "Départment de Médecine Interne, CHU Saint-Pierre, Bruxelles. charlotte.p.martin@gmail.com",
"authors": "Martin|C|C|;Neczyporenko|F|F|;De Wit|S|S|",
"chemical_list": "D005938:Glucocorticoids",
"country": "England",
"delete": false,
"doi": "10.1179/acb.2010.056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "65(4)",
"journal": "Acta clinica Belgica",
"keywords": null,
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D003937:Diagnosis, Differential; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D017511:Pyoderma Gangrenosum",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "265-8",
"pmc": null,
"pmid": "20954466",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A man with recurrent skin ulcerations.",
"title_normalized": "a man with recurrent skin ulcerations"
} | [
{
"companynumb": "BE-PFIZER INC-2020301925",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3",
... |
{
"abstract": "Background Nontuberculous mycobacterial (NTM) flexor tenosynovitis represents a rare but potentially devastating manifestation of upper extremity infection. We present a novel case of NTM flexor tenosynovitis in which Mycobacter iumimmunogenum was found to be the causative agent. Case Description The patient presented with pain and insidiously progressive swelling and required multiple operative interventions and a complex antimicrobial regimen based on susceptibility profiles. Specifically, our patient was managed with three debridements and empiric antimicrobial agents based on inherent macrolide sensitivity, with later conversion to a complex antimicrobial regimen tailored to sensitivity. Literature Review The diagnosis and management of NTM tenosynovitis arechallenging because of low suspicion, nonspecific presentation, and cumbersome laboratory identification techniques. M. immunogenum was only characterized in the past two decades, and, to our knowledge, this is the first reported case of the pathogen causing a musculoskeletal infection. Clinical Relevance We present this case primarily because of the novelty of the organism and to demonstrate the recalcitrant nature of the infection. Due to the extensive resistant patterns of M. immunogenum , management requires complex antimicrobial preparations and almost certainly needs multispecialty collaboration between orthopaedic surgery and infectious diseases.",
"affiliations": "Department of Orthopaedic Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.;Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia.;Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia.;Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia.",
"authors": "Aryee|Jomar N A|JNA|;Akinleye|Sheriff D|SD|;Freilich|Aaron M|AM|;Deal|D Nicole|DN|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1055/s-0040-1715803",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2163-3916",
"issue": "10(3)",
"journal": "Journal of wrist surgery",
"keywords": "Mycobacterium immunogenum; flexor tenosynovitis; nontuberculous mycobacterium; upper extremity infection",
"medline_ta": "J Wrist Surg",
"mesh_terms": null,
"nlm_unique_id": "101603430",
"other_id": null,
"pages": "241-244",
"pmc": null,
"pmid": "34109068",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": "21128921;25568437;30132250;29223631;22933682;16954248;8964035;25070033;16343388;12704068",
"title": "Mycobacterium Immunogenum Flexor Tenosynovitis: A Case Report.",
"title_normalized": "mycobacterium immunogenum flexor tenosynovitis a case report"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-325413",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN"
},
"dr... |
{
"abstract": "An immunocompetent adult received corticosteroids for chest pain, which later was clinically found to be herpes zoster (HZ). She developed severe disease and rapid viral dissemination that elicited an exceptionally strong varicella zoster virus-specific B-cell and CD8 T-cell response. Clinicians should consider atypical HZ presentation prior to corticosteroid administration.",
"affiliations": "Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia.;Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia.;Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia.;Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia.;Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Georgia.;Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Georgia.;Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia.",
"authors": "Sullivan|Nicole L|NL|;Eberhardt|Christiane S|CS|;Wieland|Andreas|A|;Akondy|Rama S|RS|;Yi|Jumi|J|;McElroy|Anita K|AK|;Ahmed|Rafi|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciy984",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "69(2)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "CD8 T cells; herpes zoster; plasmablasts; varicella zoster virus",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D056704:Adaptive Immunity; D001402:B-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D020804:Encephalitis, Varicella Zoster; D005260:Female; D014645:Herpesvirus 3, Human; D006801:Humans; D055815:Young Adult",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "348-351",
"pmc": null,
"pmid": "30668661",
"pubdate": "2019-07-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "23863052;28942398;25775592;28863472;22102814;26821966;26995703;18468462;26977081;24675761;28502771;20398732;26546419",
"title": "Characterization of Virus-specific Immune Response During Varicella Zoster Virus Encephalitis in a Young Adult.",
"title_normalized": "characterization of virus specific immune response during varicella zoster virus encephalitis in a young adult"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201910477",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACYCLOVIR SODIUM"
},
"drugadditional": "3... |
{
"abstract": "The programmed-death-1 inhibitors selectively block programmed-death-1 interaction with its receptor, which restores active T-cell response directed at tumor cells, inducing an anti-tumor effect. This nonspecific activation of the immune system can also lead to a wide spectrum of side effects. Nivolumab has been used effectively to prolong survival in patients with metastatic melanoma and is recommended as a category 1 agent for systemic therapy in metastatic or unresectable melanoma per the National Comprehensive Cancer Network guidelines. We present a case of a 64-year-old woman who began nivolumab therapy for metastatic melanoma. After six doses of nivolumab therapy, the patient experienced generalized hypopigmentation on her face, chest, back, arms, and lower extremities. Although vitiligo has been reported in as many as 10.7% of patients undergoing nivolumab therapy in some clinical trials, we believe this is the first case to describe the progression of nivolumab-induced vitiligo in a metastatic melanoma patient. This case provides significant insight into the onset, symptoms, development, and treatment options for patients experiencing vitiligo as a result of nivolumab therapy.",
"affiliations": "Seton Healthcare Family, Austin, TX, USA.;Seton Healthcare Family, Austin, TX, USA.;Seton Healthcare Family, Austin, TX, USA.",
"authors": "Edmondson|Lindsay A|LA|;Smith|Leticia V|LV|;Mallik|Alka|A|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1177/1078155216667636",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "23(8)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Immunotherapy; nivolumab; programmed-death-1 inhibitors; vitiligo",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D008545:Melanoma; D008875:Middle Aged; D000077594:Nivolumab; D012878:Skin Neoplasms; D014820:Vitiligo",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "629-634",
"pmc": null,
"pmid": "27609337",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nivolumab-induced vitiligo in a metastatic melanoma patient: A case report.",
"title_normalized": "nivolumab induced vitiligo in a metastatic melanoma patient a case report"
} | [
{
"companynumb": "US-SA-2017SA259045",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIFLUPREDNATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nEndoscopic endonasal approaches have been shown to be as effective as transcranial approaches for sinonasal malignancies involving the skull base. Although they are associated with less risk than an open cranial resection, cerebrospinal fluid (CSF) leaks remain a main concern. Some drugs can raise the intracranial pressure and exacerbate the risk of a postoperative CSF leak. In this case report, we present a 32-year-old woman who was treated via endoscopic endonasal approach for an olfactory neuroblastoma and later underwent fertility preservation treatment with leuprolide, which likely led to a delayed CSF leak.\n\n\nMETHODS\nA 32-year-old woman diagnosed with a large invasive olfactory neuroblastoma underwent resection via an endonasal transcribriform approach and repair of skull base defect using a pericranial flap. Forty-seven days post operation the patient returned, presenting with a clear nasal discharge. Magnetic resonance imaging raised concern for focal flap necrosis, while computed tomography cisternogram revealed a defect in the pericranial flap. The defect was debrided and repaired; a postoperative lumbar drain was placed and showed an opening pressure of 26 cm of water. Discussion with the patient revealed that she received fertility preservation treatment with leuprolide followed by oocyte retrieval 32 days before presentation of her delayed CSF leak.\n\n\nCONCLUSIONS\nLeuprolide or any drug that can potentially increase intracranial pressure should be held for 3 months after surgery or until after a skull base defect has fully healed.",
"affiliations": "University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.;Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.;Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.;Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.;Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.;Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address: gardpa@upmc.edu.",
"authors": "Jaman|Emade|E|;Goldschmidt|Ezequiel|E|;Algattas|Hanna|H|;Wang|Eric|E|;Snyderman|Carl H|CH|;Gardner|Paul A|PA|",
"chemical_list": "D005300:Fertility Agents, Female; D016729:Leuprolide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2019.05.134",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "128()",
"journal": "World neurosurgery",
"keywords": "CSF leak; Endonasal endoscopic approach; Intracranial hypertension; Leuprolide",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000328:Adult; D065634:Cerebrospinal Fluid Leak; D004724:Endoscopy; D018304:Esthesioneuroblastoma, Olfactory; D005260:Female; D005300:Fertility Agents, Female; D059247:Fertility Preservation; D006801:Humans; D016729:Leuprolide; D009296:Nasal Cavity; D059747:Nasal Surgical Procedures; D009669:Nose Neoplasms; D054315:Oocyte Retrieval; D011183:Postoperative Complications; D012307:Risk Factors",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "458-463",
"pmc": null,
"pmid": "31132487",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hormonal Fertility Therapy as Potential Risk Factor for Cerebrospinal Fluid Leak After Endoscopic Endonasal Surgery: Case Study and Literature Review.",
"title_normalized": "hormonal fertility therapy as potential risk factor for cerebrospinal fluid leak after endoscopic endonasal surgery case study and literature review"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-213388",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUPROLIDE"
},
"drug... |
{
"abstract": "OBJECTIVE\nSerotonin syndrome (SS) can occur when linezolid is combined with other serotonergic agents.\n\n\nMETHODS\nWe report a case of possible SS in an elderly patient receiving linezolid in combination with carbidopa-levodopa (CL).\n\n\nCONCLUSIONS\nAlthough certain classes of agents are commonly reported as causing SS among patients receiving linezolid, there are no specific case reports detailing this reaction with CL. Linezolid combined with CL should generally be avoided; however, if linezolid must be used, discontinuation of other agents with serotonergic activity is recommended with careful monitoring for signs and symptoms of SS.",
"affiliations": "Department of Pharmacy, University of Chicago Medicine, Chicago, IL, USA.;Department of Medicine, University of Chicago, Chicago, IL, USA.;Creighton University School of Medicine, Omaha, NE, USA.;Department of Medicine, University of Chicago, Chicago, IL, USA.;Department of Medicine, Section of Infectious Diseases and Global Health, University of Chicago, Chicago, IL, USA.;Department of Medicine, Section of Infectious Diseases and Global Health, University of Chicago, Chicago, IL, USA.",
"authors": "Pettit|N N|NN|http://orcid.org/0000-0002-8937-8039;Alonso|V|V|;Wojcik|E|E|;Anyanwu|E C|EC|;Ebara|L|L|;Benoit|J-L|JL|",
"chemical_list": "D000900:Anti-Bacterial Agents; D018491:Dopamine Agonists; D004338:Drug Combinations; D018490:Serotonin Agents; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D000069349:Linezolid; D002230:Carbidopa",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12352",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "41(1)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "carbidopa-levodopa; linezolid; serotonin syndrome",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D002230:Carbidopa; D018491:Dopamine Agonists; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007980:Levodopa; D000069349:Linezolid; D018490:Serotonin Agents; D020230:Serotonin Syndrome",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "101-3",
"pmc": null,
"pmid": "26813986",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Possible serotonin syndrome with carbidopa-levodopa and linezolid.",
"title_normalized": "possible serotonin syndrome with carbidopa levodopa and linezolid"
} | [
{
"companynumb": "US-IMPAX LABORATORIES, INC-2016-IPXL-00183",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditio... |
{
"abstract": "A 47-year-old live kidney-donor woman presented with headaches and blurred vision. Neuro-ophthalmological examination demonstrated papilledema and right eye inferior nasal defect. Brain MRV showed no sinus thrombosis but solitary right venous sinus draining the torcular Herophili to right jugular bulb. Lumbar puncture revealed elevated CSF opening pressure of 40 cm H2O with normal composition. She was diagnosed with idiopathic intracranial hypertension (IIH). She did not tolerate medical management and declined CSF diversion surgery. Cerebral angiography and venography showed venous outflow drainage from torcular Herophili through a solitary occipital sinus which has distal severe stenosis and pressure gradient of 10 mmHg. Balloon angioplasty and stenting of the occipital sinus were performed. Post-stenting, the stenosis and pressure gradient resolved. At 3-months follow-up, her symptoms and papilledema had resolved and CSF opening pressure was normal at 15 cm H2O. Aberrant cerebral venous anatomy may cause IIH and can be treatable with neuroendovascular techniques.",
"affiliations": "Department of Neurological Surgery, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY, USA.;Department of Ophthalmology, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY, USA.;Department of Neurological Surgery, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY, USA.",
"authors": "Al Balushi|Ali|A|https://orcid.org/0000-0002-8759-2576;Oliveira|Cristiano|C|;Patsalides|Athos|A|https://orcid.org/0000-0002-3035-4331",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1591019920949094",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1591-0199",
"issue": "26(5)",
"journal": "Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences",
"keywords": "Idiopathic intracranial hypertension; occipital sinus; pressure gradient; stenosis; stenting",
"medline_ta": "Interv Neuroradiol",
"mesh_terms": "D017130:Angioplasty; D002533:Cerebral Angiography; D003251:Constriction, Pathologic; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008875:Middle Aged; D011559:Pseudotumor Cerebri; D012851:Sinus Thrombosis, Intracranial; D013129:Spinal Puncture; D015607:Stents",
"nlm_unique_id": "9602695",
"other_id": null,
"pages": "664-667",
"pmc": null,
"pmid": "32757674",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23966248;12743224;30169466;24154635;28560487;29871989;30166333;27621945;27886896;28255904;31001030;27556959;29356857",
"title": "Idiopathic intracranial hypertension with stenosis of a solitary occipital venous sinus treated with stenting.",
"title_normalized": "idiopathic intracranial hypertension with stenosis of a solitary occipital venous sinus treated with stenting"
} | [
{
"companynumb": "US-TARO-2021TAR00162",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAZOLAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "This randomised, double-blind study compared pharmacokinetics, efficacy, safety and immunogenicity of PF-05280014 (potential trastuzumab biosimilar) and trastuzumab reference product (Herceptin) sourced from the European Union (trastuzumab-EU) as neoadjuvant treatment for operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer.\n\n\n\nPatients (N = 226), stratified by primary tumour size and hormone receptor status, were randomised 1:1 to PF-05280014 or trastuzumab-EU (8 mg/kg loading dose; 6 mg/kg thereafter), each with docetaxel and carboplatin, every 3 weeks for six treatment cycles. Primary endpoint was percentage of patients with trough plasma concentration (Ctrough) >20 μg/ml at Cycle 5 (Cycle 6 predose). Efficacy endpoints included pathological complete response and objective response rate. Non-inferiority of PF-05280014 to trastuzumab-EU was declared if the lower limit of the 95% confidence interval for the stratified difference between groups in the percentage of patients with Cycle 5 Ctrough >20 μg/ml was above the prespecified non-inferiority margin of - 12.5%.\n\n\n\nFor PF-05280014 vs trastuzumab-EU patients, respectively, 92.1% vs 93.3% had Cycle 5 Ctrough >20 μg/ml; the lower limit of the 95% confidence interval (- 8.02%, 6.49%) for the stratified difference between groups was above the non-inferiority margin (- 12.5%). Pathological complete response (47.0% vs 50.0%) and central radiology review-assessed objective response (88.1% vs 82.0%) rates were comparable. Incidence of all-causality, grade 3-4 treatment-emergent adverse events was 38.1% vs 45.5%; antidrug antibody rates were 0% vs 0.89%.\n\n\n\nPF-05280014 demonstrated non-inferior pharmacokinetics and comparable efficacy, safety and immunogenicity to trastuzumab-EU in patients with operable HER2-positive breast cancer receiving neoadjuvant chemotherapy.",
"affiliations": "Meharry Medical College, 1005 Dr. D.B. Todd Jr. Blvd, Nashville, TN, 37208-3501, USA.;Semmelweis University, Cancer Center, Tömő u. 25-29, Budapest, 1083, Hungary.;Catholic University of Rome, Largo Agostino Gemelli, 8, Rome, 00168, Italy.;Pfizer Inc., 500 Arcola Road, Collegeville, PA, 19426, USA.;Pfizer Inc., 450 Eastern Point Road, Groton, CT, 06340, USA.;Pfizer Inc., 235 and 219 East 42nd Street, New York, NY, 10017-5755, USA.;Pfizer Inc., 235 and 219 East 42nd Street, New York, NY, 10017-5755, USA. ira.jacobs@pfizer.com.",
"authors": "Lammers|Philip E|PE|;Dank|Magdolna|M|;Masetti|Riccardo|R|;Abbas|Richat|R|;Hilton|Fiona|F|;Coppola|Jennifer|J|;Jacobs|Ira|I|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D059451:Biosimilar Pharmaceuticals; C000598430:PF-05280014; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "England",
"delete": false,
"doi": "10.1038/s41416-018-0147-1",
"fulltext": "\n==== Front\nBr J Cancer\nBr J Cancer\nBritish Journal of Cancer\n0007-0920\n1532-1827\nNature Publishing Group UK London\n\n30002437\n147\n10.1038/s41416-018-0147-1\nArticle\nNeoadjuvant PF-05280014 (a potential trastuzumab biosimilar) versus trastuzumab for operable HER2+ breast cancer\nLammers Philip E. 1\nDank Magdolna 2\nMasetti Riccardo 3\nAbbas Richat 4\nHilton Fiona 5\nCoppola Jennifer 6\nJacobs Ira +212 733 0876 ira.jacobs@pfizer.com\n\n6\n1 0000 0001 0286 752X grid.259870.1 Meharry Medical College, 1005 Dr. D.B. Todd Jr. Blvd, Nashville, TN 37208-3501 USA\n2 0000 0001 0942 9821 grid.11804.3c Semmelweis University, Cancer Center, Tömő u. 25-29, Budapest, 1083 Hungary\n3 0000 0001 0941 3192 grid.8142.f Catholic University of Rome, Largo Agostino Gemelli, 8, Rome, 00168 Italy\n4 0000 0000 8800 7493 grid.410513.2 Pfizer Inc., 500 Arcola Road, Collegeville, PA 19426 USA\n5 0000 0000 8800 7493 grid.410513.2 Pfizer Inc., 450 Eastern Point Road, Groton, CT 06340 USA\n6 0000 0000 8800 7493 grid.410513.2 Pfizer Inc., 235 and 219 East 42nd Street, New York, NY 10017-5755 USA\n13 7 2018\n13 7 2018\n1 8 2018\n119 3 266273\n31 8 2017\n26 4 2018\n25 5 2018\n© The Author(s) 2018\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/.\nBackground\n\nThis randomised, double-blind study compared pharmacokinetics, efficacy, safety and immunogenicity of PF-05280014 (potential trastuzumab biosimilar) and trastuzumab reference product (Herceptin) sourced from the European Union (trastuzumab-EU) as neoadjuvant treatment for operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer.\n\nMethods\n\nPatients (N = 226), stratified by primary tumour size and hormone receptor status, were randomised 1:1 to PF-05280014 or trastuzumab-EU (8 mg/kg loading dose; 6 mg/kg thereafter), each with docetaxel and carboplatin, every 3 weeks for six treatment cycles. Primary endpoint was percentage of patients with trough plasma concentration (Ctrough) >20 μg/ml at Cycle 5 (Cycle 6 predose). Efficacy endpoints included pathological complete response and objective response rate. Non-inferiority of PF-05280014 to trastuzumab-EU was declared if the lower limit of the 95% confidence interval for the stratified difference between groups in the percentage of patients with Cycle 5 Ctrough >20 μg/ml was above the prespecified non-inferiority margin of – 12.5%.\n\nResults\n\nFor PF-05280014 vs trastuzumab-EU patients, respectively, 92.1% vs 93.3% had Cycle 5 Ctrough >20 μg/ml; the lower limit of the 95% confidence interval (− 8.02%, 6.49%) for the stratified difference between groups was above the non-inferiority margin (– 12.5%). Pathological complete response (47.0% vs 50.0%) and central radiology review-assessed objective response (88.1% vs 82.0%) rates were comparable. Incidence of all-causality, grade 3–4 treatment-emergent adverse events was 38.1% vs 45.5%; antidrug antibody rates were 0% vs 0.89%.\n\nConclusions\n\nPF-05280014 demonstrated non-inferior pharmacokinetics and comparable efficacy, safety and immunogenicity to trastuzumab-EU in patients with operable HER2-positive breast cancer receiving neoadjuvant chemotherapy.\n\nissue-copyright-statement© Cancer Research UK 2018\n==== Body\npmcIntroduction\n\nTrastuzumab is a recombinant humanised immunoglobulin G1 monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2) and is approved for the treatment of HER2-overexpressing breast and gastric cancers.1,2 HER2 overexpression occurs in 15–20% of invasive breast cancers; it is associated with more-aggressive biological behaviour and, in the absence of treatment with HER2-targeted therapy, worse clinical outcomes.3–6 The addition of trastuzumab to adjuvant chemotherapy for HER2-positive (HER2+) early breast cancer or to chemotherapy for HER2+ metastatic disease reduces the risk for recurrence or disease progression and prolongs survival as compared with chemotherapy alone.7–10 When added to neoadjuvant chemotherapy, trastuzumab improves rates of event-free survival and pathological complete response (pCR) over chemotherapy alone.11,12\n\nDespite the clinical benefits associated with HER2-directed therapy, physicians worldwide often encounter barriers to prescribing trastuzumab, leading to less than optimal treatment of patients with HER2+ breast cancer.13,14 The availability of biosimilars may expand access to biologic therapies such as trastuzumab and provide patients with additional safe and efficacious treatment options. Biosimilars are biologic drugs that are highly similar to a licensed (i.e., originator or reference) biologic product.15–17 To receive regulatory approval, a proposed biosimilar product must show no clinically meaningful differences in safety, purity or potency compared with the originator biologic, based on the totality of the evidence obtained from comparative assessments of the two products.15–17 Regulatory agencies recommend a stepwise approach to generating these data that begins with comprehensive analytical (i.e., structural and functional) characterisation followed by non-clinical testing and culminates with a comparative clinical study (or studies) to confirm similarity between the proposed biosimilar and originator product in pharmacokinetics, efficacy, safety and immunogenicity.15–17\n\nPF-05280014 is under development as a potential biosimilar of trastuzumab (Herceptin). Comparative non-clinical assessments of PF-05280014 and trastuzumab reference products marketed in the European Union (trastuzumab-EU; Herceptin, Roche Registration GmbH, Grenzach-Wyhlen, Germany) and United States (trastuzumab-US; Herceptin, South San Francisco, CA) demonstrated PF-05280014 has the same primary amino-acid sequence as the licensed trastuzumab, with similar in vitro functional properties and in vivo pharmacokinetics, antidrug antibody (ADA) responses and tolerability.18 Furthermore, two single-dose comparability studies conducted in healthy male volunteers demonstrated PF-05280014, trastuzumab-EU and trastuzumab-US have similar pharmacokinetics, safety and immunogenicity profiles.19,20 An additional, distinct comparative safety and efficacy study (NCT01989676) is evaluating PF-05280014 versus trastuzumab-EU, each administered in combination with paclitaxel, as first-line treatment for patients with HER2+ metastatic breast cancer.21\n\nWe report the results of a comparative clinical trial conducted to compare pharmacokinetics, efficacy, safety and immunogenicity of PF-05280014 versus trastuzumab-EU, each administered in combination with docetaxel and carboplatin, as neoadjuvant treatment for patients with operable HER2+ breast cancer.22 It was hypothesised that PF-05280014 was non-inferior to trastuzumab-EU, based on pharmacokinetics data.\n\nMethods\n\nStudy population\n\nEligible patients were women aged 18 years or older with histologically confirmed invasive breast cancer that exhibited HER2 gene amplification by fluorescent in situ hybridisation, chromogenic in situ hybridisation or dual in situ hybridisation, as defined by the manufacturer’s kit instruction; or HER2 overexpression by immunohistochemistry (IHC) categorised as IHC3+; or HER2 overexpression by IHC categorised as IHC2+ with fluorescent, chromogenic, or dual in situ hybridisation confirmation. HER2+ tumour status was determined by the site at the time of diagnosis, using either a sponsor-approved assay or two different analytical test methods that were not considered sponsor-approved but both demonstrated unequivocal (i.e., IHC3+) results, and confirmed retrospectively by the sponsor-provided central laboratory. If tumour HER2 status could not be determined via local testing, it was evaluated by central laboratory assessment.\n\nPatients with measurable disease (longest diameter ≥ 2.0 cm) in the breast after diagnostic biopsy and known hormone (oestrogen and progesterone) receptor status at study entry were included. For patients with unknown hormone receptor status, oestrogen and progesterone receptor status testing was performed at screening, via local or central laboratory assessment. Oestrogen and progesterone receptor positivity was determined by local site guidelines based on accepted standards. Baseline tumour assessments were performed within 6 weeks prior to randomisation and included computed tomography (CT), or magnetic resonance imaging of the chest if a CT scan could not be performed, and bilateral mammography or ultrasound of the breast. Patients were planned to undergo definitive surgical resection of breast tumour (i.e., lumpectomy or mastectomy with sentinel node biopsy or axillary lymph node dissection) and neoadjuvant chemotherapy. Other inclusion criteria included: Eastern Cooperative Oncology Group performance status 0–1; left ventricular ejection fraction (LVEF) ≥ 55% as measured by two-dimensional echocardiogram (ECHO) or multi-gated acquisition scan (MUGA); and normal laboratory values.\n\nKey exclusion criteria included bilateral breast cancer; inflammatory breast cancer; presence of known distant metastases, as determined by the investigator; prior chemotherapy, endocrine therapy, biologic therapy, radiation or surgery, except diagnostic biopsy for primary breast cancer; other concomitant active malignancy or history of malignancy in the past 5 years, except treated basal cell carcinoma of the skin or carcinoma in situ of the cervix; history of documented or current congestive heart failure; current high-risk uncontrolled arrhythmias; angina pectoris requiring treatment; clinically significant valvular disease; evidence of transmural infarction on electrocardiogram; or poorly controlled hypertension.\n\nStudy design, procedures and treatments\n\nThis was an international, double-blind, randomised clinical trial initiated at 67 sites in 10 countries across Europe (EudraCT registration number 2013-004679-11) and in the United States (ClinicalTrials.gov identifier NCT02187744).22,23\n\nPatients who satisfied the eligibility criteria were stratified by primary tumour size (< 5 cm vs ≥ 5 cm) and hormone receptor status (positive vs negative) and randomised 1:1 to receive PF-05280014 or trastuzumab-EU (Herceptin), each given in combination with docetaxel and carboplatin (Fig. 1a). On Day 1 Cycle 1, patients received a loading dose (8 mg/kg, over 90-min intravenous (IV) infusion) of PF-05280014 or trastuzumab-EU followed by docetaxel (75 mg/m2; 60-min IV infusion) and carboplatin (target area under the curve: 6; ≥ 15-min IV infusion). Subsequent infusions of PF-05280014 or trastuzumab-EU (6 mg/kg, over 30 to 90 min), docetaxel and carboplatin were administered every 3 weeks for six treatment cycles. Neoadjuvant therapy with trastuzumab in combination with docetaxel and carboplatin has demonstrated efficacy and safety in patients with HER2+ early breast cancer.24 Furthermore, the trastuzumab treatment regimen used in this study is consistent with trastuzumab-EU product labelling and is in line with the National Comprehensive Cancer Network recommendations on the preferred preoperative/adjuvant therapy regimens for HER2+ breast cancer.2,25 Patients who experienced toxicity attributed to PF-05280014 or trastuzumab-EU were required to temporarily or permanently discontinue trastuzumab treatment; dose reductions were not permitted. Granulocyte colony-stimulating factor was used for prophylactic or therapeutic management of haematologic toxicities attributed to docetaxel. Reductions in the docetaxel dose or discontinuation of treatment with docetaxel were permitted.Fig. 1 Overall study design and disposition of patients. a Study design and b patient disposition. aOn Day 1 Cycle 1, patients received a loading dose (8 mg/kg) of PF-05280014 or trastuzumab-EU infused over 90 min followed by docetaxel (75 mg/m2; 60-min intravenous infusion) and carboplatin (target AUC: 6; ≥ 15-min intravenous infusion). Subsequent infusions of PF-05280014 or trastuzumab-EU (6 mg/kg, over 30 to 90 min), docetaxel and carboplatin were administered every 3 weeks for a total of six treatment cycles. bBlood samples were collected predose (−2.5 h to −5 min prior to infusion) on Day 1 of Cycles 1, 2, 4, 5 and 6, and at 1-h post dose on Day 1 of Cycles 1 and 5 for determination of PF-05280014 or trastuzumab-EU serum concentrations. cThe intent-to-treat population consisted of all patients randomised to PF-05280014 or trastuzumab-EU. dThe safety population comprised all patients who received at least one dose of study drug. ePatients in the PF-05280014 group were excluded from the per protocol population for the following reasons: Cycle 5 trough sample taken outside protocol-specified window (n = 6, 46.2%), fewer than six cycles of trastuzumab (n = 5, 38.5%), no Cycle 5 trough pharmacokinetic sample (n = 2, 15.4%), and trastuzumab treatment delay > 1 week (n = 1, 7.7%). A patient may have met multiple criteria for exclusion and may have been counted more than once. fPatients in the trastuzumab-EU group were excluded from the per protocol population for the following reasons: Cycle 5 trough sample taken outside protocol-specified window (n = 13, 56.5%), fewer than six cycles of trastuzumab (n = 5, 21.7%), trastuzumab treatment delay > 1 week (n = 3, 13.0%), Cycle 5 trough sample taken post dose (n = 1, 4.3%), no lesion > 2 cm in breast (n = 1, 4.3%), and missing HER2 sample (n = 1, 4.3%). A patient may have met multiple criteria for exclusion and may have been counted more than once. gThe per protocol population consisted of all randomised patients who received six cycles of PF-05280014 or trastuzumab-EU and had no temporary delays in treatment lasting > 1 week or other significant protocol deviations. AUC = area under the curve; HER2 = human epidermal growth factor receptor 2; trastuzumab-EU = licensed trastuzumab sourced from the European Union\n\nPatients had a follow-up assessment, i.e., end of treatment (EOT) visit, 28 (±7) days after final study drug administration and underwent definitive surgical resection of their primary breast tumour within 3–7 weeks following the EOT visit. Systemic therapy given after resection was not mandated by the protocol and PF-05280014 or trastuzumab-EU was not provided for treatment in the adjuvant setting. Patients were not followed for clinical endpoints after resection.\n\nObjectives and endpoints\n\nThe primary objective was to determine whether PF-05280014 is non-inferior to trastuzumab-EU, based on pharmacokinetics data. The mechanism of action of trastuzumab is mediated through its binding to the target receptor HER2, and full receptor saturation is expected to drive efficacy of trastuzumab.1,2,26 Accordingly, similar trough plasma concentrations (Ctrough) for PF-05280014 and trastuzumab-EU would support similar efficacy between treatments. Furthermore, Ctrough > 20 μg/ml is a therapeutic target threshold concentration for trastuzumab and has been used to demonstrate noninferiority of subcutaneous trastuzumab to intravenous trastuzumab in the neoadjuvant setting.26 Therefore, non-inferiority was assessed by comparing the percentage of patients with Cycle 5 Ctrough (Cycle 6 predose) > 20 μg/ml (primary endpoint) in the PF-05280014 group with that in the trastuzumab-EU group. This time point (Cycle 5 Ctrough) was selected because it would be expected to reflect steady state drug concentration based on population predicted pharmacokinetic exposure values for the approved 3-weekly dosing regimen used in this study.2\n\nSecondary objectives were to evaluate the efficacy, safety, immunogenicity and other pharmacokinetic measures of PF-05280014 and trastuzumab-EU. Efficacy was measured by the percentage of patients with pCR, defined as the absence of invasive neoplastic cells in the breast and lymph nodes following surgery after treatment completion (remaining ductal carcinoma in situ was accepted),26 and objective response rate (ORR), defined as the percentage of patients who had complete or partial response at Cycle 6/EOT. Safety was characterised by the type, incidence, severity, timing, seriousness and relatedness of adverse events (AEs) to study drug, including cardiotoxicity, signs and symptoms of anaphylaxis, infusion-related reactions and laboratory abnormalities. Immunogenicity was measured by the incidence of ADAs, including neutralising antibodies (NAbs). Pharmacokinetics was further assessed by measuring Ctrough at Cycles 1 (Cycle 2 predose), 3 (Cycle 4 predose) and 4 (Cycle 5 predose), as well as Cmax (maximum drug concentration, 1 h post dose) at Cycles 1 and 5.\n\nAssessments\n\nBlood samples for determining PF-05280014 or trastuzumab-EU serum concentrations were collected predose (–2.5 h to –5 min prior to infusion) on Day 1 of Cycles 1, 2, 4, 5 and 6, and at 1-h post dose on Day 1 of Cycles 1 and 5. Samples were analysed using a validated enzyme-linked immunosorbent assay with a lower limit of quantification of 0.500 µg/ml. Pathological response status was determined by an investigator-designated qualified pathologist. Tumour assessments were performed at screening, end of Cycle 3, EOT and as clinically needed. Objective response status was determined by a central radiology laboratory and by the investigators using Response Evaluation Criteria in Solid Tumours, version 1.1. Central radiology assessments were used to calculate ORR at Cycle 6/EOT.\n\nAEs were monitored continuously from the time the patient received at least one dose of study drug through the last patient visit. The severity of AEs was graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Cardiac monitoring (MUGA scan or ECHO) was performed at screening, end of Cycle 3, EOT visit and as clinically indicated. Serum samples for detecting ADAs and NAbs were collected on Day 1 (predose) of Cycles 1, 2, 4 and 6 (Fig. 1a), and during the EOT visit. Samples were tested for ADAs following a tiered approach of screening, confirmation and titre. Samples were first analysed using a validated electrochemiluminescent immunoassay specific to PF-05280014 or trastuzumab-EU. ADA-positive samples were then analysed for cross-reactivity using the alternate assay. Confirmed ADA-positive samples were tested for NAb using a validated electrochemiluminescent immunoassay specific to the monoclonal antibody administered; NAb-positive samples were then analysed for cross-reactivity using the alternate assay.\n\nStatistical methods\n\nThis study tested the hypothesis that the percentage of patients exhibiting Cycle 5 Ctrough (Cycle 6 predose) > 20 μg/ml in the PF-05280014 group was non-inferior to that in the trastuzumab-EU group, using a margin of – 12.5%. This margin was selected based on clinical considerations rather than statistical considerations (e.g., a meta-analysis of previous data) as there is little previous evidence in the neoadjuvant setting outside of the HannaH trial, which evaluated non-inferiority of subcutaneous trastuzumab to intravenous trastuzumab based on pCR rate and using a margin of − 12.5%.26 A minimum of 188 patients (n = 94/arm) was required to provide 85% power to test for non-inferiority in the primary analysis. Considering a possible 15% attrition rate, a total sample size of ~ 220 patients (n = 110/arm) was planned to ensure the required minimum number of patients for the non-inferiority analysis.\n\nDifferences between groups in the percentage of patients with Cycle 5 Ctrough (Cycle 6 predose) > 20 μg/ml, the percentage of patients who had pCR and the ORR were estimated, along with corresponding 95% confidence intervals, using the normal approximation to the binomial distribution and adjusting for randomisation strata. If the lower limit of the CI for the primary endpoint was above – 12.5%, the null hypothesis was rejected and PF-05280014 was considered non-inferior to trastuzumab-EU. Cycle 5 Ctrough (Cycle 6 predose) values were log-transformed and the geometric ratio (PF-05280014 to trastuzumab-EU) of the means and corresponding 95% CI were also estimated (secondary pharmacokinetics endpoint).\n\nPharmacokinetics and efficacy analyses were performed in the per protocol population, defined as all randomised patients who received six cycles of PF-05280014 or trastuzumab-EU and had no temporary delays in treatment that lasted > 1 week and no other significant protocol deviations. Sensitivity analyses of the primary and efficacy endpoints were performed in the intent-to-treat population (i.e., all randomised patients). Safety analyses, including AE, ADA and NAb analyses, were performed using the safety population (i.e., all patients who received at least one dose of study drug).\n\nResults\n\nPatient disposition, demographics and baseline characteristics\n\nA total of 226 patients were randomised to PF-05280014 (n = 114) or trastuzumab-EU (n = 112) and were included in the intent-to-treat population. Of these, one patient was randomised to but did not receive treatment with PF-05280014; the remaining 225 patients received study treatment as assigned and were included in the safety population (Fig. 1b). Of the 226 randomised patients, 190 (PF-05280014, n = 101; trastuzumab-EU, n = 89) met the requirements for the per protocol population, and 36 (PF-05280014, n = 13; trastuzumab-EU, n = 23) were excluded for one or more of the following reasons, which were determined prior to breaking the blind (Fig. 1b): Cycle 5 trough sample taken outside the protocol-specified window, Cycle 5 trough sample taken post dose, fewer than six cycles of trastuzumab treatment, no Cycle 5 trough pharmacokinetics sample, no lesion > 2 cm in breast, missing HER2 sample and/or trastuzumab treatment delay > 1 week. Patient demographics and other baseline characteristics for the intent-to-treat population were comparable between treatment groups (Table 1).Table 1 Baseline demographics (intent-to-treat population)a\n\n\tPF-05280014 (n = 114)\tTrastuzumab-EU (n = 112)\tTotal (N = 226)\t\nAge, mean (±SD), years\t54.0 (11.9)\t51.2 (12.7)\t52.6 (12.3)\t\nRace, n (%)\t\n White\t112 (98.2)\t109 (97.3)\t221 (97.8)\t\n Black\t1 (0.9)\t0\t1 (0.4)\t\n Asian\t1 (0.9)\t3 (2.7)\t4 (1.8)\t\nEthnicity, n (%)\t\n Hispanic/Latino\t0\t1 (0.9)\t1 (0.4)\t\n Not Hispanic/Latino\t114 (100.0)\t111 (99.1)\t225 (99.6)\t\nMean body mass index (±SD), kg/m2\t28.2 (5.9)\t27.7 (6.2)\t27.9 (6.1)\t\nPrimary tumour size, n (%)\t\n <5 cm\t89 (78.1)\t89 (79.5)\t178 (78.8)\t\n ≥5 cm\t25 (21.9)\t23 (20.5)\t48 (21.2)\t\nOestrogen receptor status, n (%)\t\n Positive\t58 (50.9)\t54 (48.2)\t112 (49.6)\t\n Negative\t56 (49.1)\t58 (51.8)\t114 (50.4)\t\nProgesterone receptor status, n (%)\t\n Positive\t41 (36.0)\t40 (35.7)\t81 (35.8)\t\n Negative\t73 (64.0)\t72 (64.3)\t145 (64.2)\t\naBaseline was defined as the value recorded at Day 1 Cycle 1. If this value was missing, the value recorded at screening was used.\n\nTrastuzumab-EU = licensed trastuzumab sourced from the European Union; SD = standard deviation\n\nPharmacokinetic analyses\n\nIn an analysis of the primary endpoint using the per protocol population, 93 (92.1%) patients treated with PF-05280014 and 83 (93.3%) patients treated with trastuzumab-EU exhibited Cycle 5 Ctrough (Cycle 6 predose) >20 μg/ml (Table 2). The stratified estimated difference between PF-05280014 and trastuzumab-EU was – 0.76%, and the lower limit of the 95% CI (– 8.02%, 6.49%) was above the non-inferiority margin of – 12.5%. In an analysis of secondary pharmacokinetics endpoints using the per protocol population, the geometric mean Ctrough at Cycle 5 was 34.59 and 34.56 µg/ml for PF-05280014 and trastuzumab-EU, respectively; the PF-05280014 to trastuzumab-EU ratio was 100.06% (95% CI: 81.5%, 122.9%). In addition, at each study cycle, trastuzumab serum concentrations appeared comparable between PF-05280014 and trastuzumab-EU (Supplementary Tables S1 and S2).Table 2 Primary pharmacokinetics analysis of patients reporting Cycle 5 Ctrougha >20 μg/ml (per protocol population)\n\n\tPF-05280014 (n = 101)\tTrastuzumab-EU (n = 89)\t\nPatients with Cycle 5 Ctrougha > 20 μg/ml, % (95% CI)\t92.1 (85.0, 96.5)\t93.3 (85.9, 97.5)\t\nStratified difference between PF-05280014 and trastuzumab-EUb\t−0.76\t\n Standard error for the difference\t3.70\t\n 95% CI (stratified) for the difference\t−8.02, 6.49\t\naCycle 6 predose.\n\nbStratified analysis was based on the normal approximation to the binomial distribution, adjusting for randomisation strata (primary tumour size < 5 cm vs ≥5 cm; oestrogen receptor-positive vs oestrogen receptor-negative; and progesterone receptor-positive vs progesterone receptor-negative).\n\nCI = confidence interval; Ctrough = trough plasma concentration; trastuzumab-EU = licensed trastuzumab sourced from the European Union\n\nEfficacy analyses\n\nPathologic response and overall tumour response assessments for the per protocol population are summarised in Table 3. Of the patients in the PF-05280014 (n = 100) and trastuzumab-EU (n = 86) groups who had surgery, 47.0% (95% CI: 36.9%, 57.2%) and 50.0% (95% CI: 39.0%, 61.0%), respectively, had a pCR; the stratified estimated difference between groups was – 2.81% (95% CI: – 16.58%, 10.96%). The ORR at Cycle 6/EOT was 88.1% (95% CI: 80.2%, 93.7%) for PF-05280014 and 82.0% (95% CI: 72.5%, 89.4%) for trastuzumab-EU, based on central radiology assessments; the stratified estimated difference between groups was 5.96% (95% CI: –4.01%, 15.94%).Table 3 Pathological response and overall tumour response assessments (per protocol population)\n\n\tPF-05280014 (n = 101)\tTrastuzumab-EU (n = 89)\t\nPathological response assessment\t\n Response category, n (%)\t\n pCR\t47 (46.5)\t43 (48.3)\t\n pPR\t51 (50.5)\t40 (44.9)\t\n No pathological response\t2 (2.0)\t3 (3.4)\t\n Not donea\t1 (1.0)\t3 (3.4)\t\n Patients who had surgery\t\n n (%)\t100 (99.0)\t86 (96.6)\t\n Patients with pCR,b n (%)\t47 (47.0)\t43 (50.0)\t\n 95% CI\t36.9, 57.2\t39.0, 61.0\t\n Stratified difference in pCR between PF-05280014 and trastuzumab-EUc\t−2.81\t\n Standard error for the difference\t7.03\t\n 95% CI (stratified) for the difference\t−16.58, 10.96\t\nOverall response assessment (per central radiology review)\t\n Overall response category at Cycle 6/EOT, n (%)\t\n Complete response\t3 (3.0)\t0\t\n Partial response\t86 (85.1)\t73 (82.0)\t\n Stable disease\t7 (6.9)\t4 (4.5)\t\n Progressive disease\t2 (2.0)\t1 (1.1)\t\n Non-evaluable\t1 (1.0)\t6 (6.7)\t\n Non-complete response/non-progressive disease\t1 (1.0)\t3 (3.4)\t\n Missing\t1 (1.0)\t2 (2.2)\t\n ORRd\t\n n (%)\t89 (88.1)\t73 (82.0)\t\n 95% CI\t80.2, 93.7\t72.5, 89.4\t\n Stratified difference in ORR between PF-05280014 and trastuzumab-EUc\t5.96\t\n Standard error for the difference\t5.09\t\n 95% CI (stratified) for the difference\t−4.01, 15.94\t\naPathology data were not recorded or response was not assessed for the following reasons: completed the study but had no surgery (PF-05280014, n = 1; trastuzumab-EU, n = 1) or completed treatment but lost to follow-up prior to surgery (trastuzumab-EU, n = 2).\n\nbThe denominators for percentages of patients with pCR included only patients who had surgery.\n\ncStratified analysis was based on the normal approximation to the binomial distribution, adjusting for randomisation strata (primary tumour size < 5 cm vs ≥ 5 cm; oestrogen receptor-positive vs oestrogen receptor-negative; and progesterone receptor-positive vs progesterone receptor-negative).\n\ndORR was defined as the percentage of patients within each treatment group who achieved complete response or partial response by Cycle 6/EOT, in accordance with Response Evaluation Criteria in Solid Tumours, version 1.1.\n\nCI = confidence interval; EOT = end of treatment; ORR = objective response rate; pCR = pathological complete response; pPR = pathological partial response; trastuzumab-EU = licensed trastuzumab sourced from the European Union\n\nSafety\n\nAmong patients included in the safety population (PF-05280014, n = 113; trastuzumab-EU, n = 112), 109 (96.5%) in the PF-05280014 group and 109 (97.3%) in the trastuzumab-EU group received six cycles of trastuzumab. Six patients each in the PF-05280014 (5.3%) and trastuzumab-EU (5.4%) groups had a delay in trastuzumab treatment. Eight (7.1%) patients administered PF-05280014 and 7 (6.3%) who received trastuzumab-EU had an interrupted trastuzumab infusion.\n\nThe majority of all patients experienced at least one treatment-emergent AE (TEAE) owing to any cause, with a total of 569 events reported by 109 (96.5%) patients in the PF-05280014 group and 511 events reported by 106 (94.6%) patients in the trastuzumab-EU group (Table 4). The incidence of TEAEs and serious TEAEs was comparable between groups. The TEAEs most frequently reported by patients (n (%)) in the PF-05280014 and trastuzumab-EU groups, respectively, were alopecia (72 (63.7%) and 69 (61.6%)), anaemia (56 (49.6%) and 51 (45.5%)) and neutropaenia (38 (33.6%) and 41 (36.6%)). Grade 3–4 TEAEs were reported in 43 (38.1%) and 51 (45.5%) patients in the PF-05280014 and trastuzumab-EU groups, respectively. Seven (6.2%) patients treated with PF-05280014 experienced seven serious AEs (SAEs; febrile neutropaenia, neutropaenia, pancytopenia, proctitis, device-related sepsis, injection-site abscess and increased blood creatinine); six (5.4%) patients treated with trastuzumab-EU experienced 10 SAEs (anaemia, febrile neutropaenia (n = 2), neutropaenia (two SAEs, n = 1), gastrointestinal infection, tooth infection, hip fracture, dehydration and hypokalaemia).Table 4 All-causality, treatment-emergent adverse events (safety population)a\n\n\tPF-05280014 (n = 113)\tTrastuzumab-EU (n = 112)\t\nNumber of AEs\t569\t511\t\nPatients with event, n (%)\t\n AEs\t109 (96.5)\t106 (94.6)\t\n SAEsb\t7 (6.2)\t6 (5.4)\t\n Grade 3 or 4 AEs\t43 (38.1)\t51 (45.5)\t\n Grade 5 AEs\t1 (0.9)\t0\t\n Discontinued study due to AEs\t1 (0.9)\t3 (2.7)\t\n Discontinued from any treatmentc due to AEs\t4 (3.5)\t3 (2.7)\t\n Dose reduced or temporarily discontinued for any treatmentc due to AEs\t37 (32.7)\t30 (26.8)\t\naIncludes data up to 50 days after the last dose of study drug. Patients were counted only once per treatment in each row, except for the Number of AEs.\n\nbAs determined by investigator.\n\ncTrastuzumab (PF-05280014 or trastuzumab-EU), docetaxel or carboplatin.\n\nAE = adverse event; SAE = serious adverse event; trastuzumab-EU = licensed trastuzumab sourced from the European Union\n\nNo TEAEs indicative of infusion-related reactions were reported in the PF-05280014 group; two (1.8%) patients in the trastuzumab-EU group experienced non-serious events of pyrexia and tachypnea. Four (3.5%) and three (2.7%) patients in the PF-05280014 and trastuzumab-EU groups, respectively, permanently discontinued from any treatment due to AEs during the treatment period. One patient in the PF-05280014 group died due to a treatment-related SAE of pancytopenia; no other patients died during the study. No TEAEs of congestive heart failure or clinically significant LVEF abnormalities were reported by patients in either treatment group. There were no notable differences between the treatment groups in mean LVEF results (Supplementary Table S3). One (0.88%) and 10 (8.93%) patients in the PF-05280014 and trastuzumab-EU groups, respectively, had a decline in LVEF of ≥ 10% from baseline. However, no patient in either group had LVEF < 53% at any time point measured. Furthermore, no individual abnormalities or shifts in laboratory values were considered clinically relevant.\n\nImmunogenicity\n\nNo patients in the PF-05280014 group and one (0.89%) patient in the trastuzumab-EU group had positive ADA titres (Table 5). The single positive ADA titre of 2.39 was recorded at predose Cycle 1. This patient also recorded a cross-reactivity ADA assay titre of 2.58, but was negative in all subsequent ADA tests and also tested negative for NAbs.Table 5 Incidence of ADAs by visit and overall (safety population)a\n\nVisit\tADA status\tPF-05280014\tTrastuzumab-EU\t\nCycle 1\tPatients assessed, n\t113\t112\t\nNegative < 1.00, n (%)\t113 (100.00)\t110 (98.21)\t\nPositive ≥ 1.00, n (%)\t0\t1 (0.89)\t\nNot analysed, n (%)\t0\t1 (0.89)\t\nCycle 2\tPatients assessed, n\t111\t112\t\nNegative < 1.00, n (%)\t111 (100.00)\t112 (100.00)\t\nPositive ≥ 1.00, n (%)\t0\t0\t\nCycle 4\tPatients assessed, n\t108\t109\t\nNegative < 1.00, n (%)\t108 (100.00)\t109 (100.00)\t\nPositive ≥ 1.00, n (%)\t0\t0\t\nCycle 6\tPatients assessed, n\t108\t108\t\nNegative < 1.00, n (%)\t108 (100.00)\t108 (100.00)\t\nPositive ≥ 1.00, n (%)\t0\t0\t\nOverall\tPatients assessed, n\t113\t112\t\nNegative < 1.00, n (%)\t113 (100.00)\t111 (99.11)\t\nPositive ≥ 1.00, n (%)\t0\t1 (0.89)\t\naPercentages are based on the number of patients assessed at each visit. The unit of ADA titre was endpoint titre. Only predose assessments are summarised.\n\nADA = antidrug antibody; trastuzumab-EU = licensed trastuzumab sourced from the European Union\n\nDiscussion\n\nThe primary objective of this comparative clinical trial in patients with operable HER2+ breast cancer was to determine whether neoadjuvant treatment with PF-05280014, a potential trastuzumab biosimilar, was non-inferior to trastuzumab-EU, based on pharmacokinetic data. This objective was met; the study demonstrated non-inferiority for PF-05280014 versus trastuzumab-EU in the percentage of patients with Cycle 5 Ctrough (Cycle 6 predose) > 20 μg/ml. Furthermore, results from an analysis of secondary endpoints demonstrated comparable pharmacokinetic profiles for PF-05280014 and trastuzumab-EU.\n\nPF-05280014 and trastuzumab-EU also had comparable efficacy profiles, based on measures of tumour control, with no notable difference between treatment groups (PF-05280014 vs trastuzumab-EU, respectively) in pCR rate (47.0% vs 50.0%) or ORR (88.1% vs 82.0%). Importantly, pCR results were consistent with published data for trastuzumab administered in combination with neoadjuvant chemotherapy.27,28 Furthermore, both pCR and ORR were comparable to rates reported for other proposed trastuzumab biosimilars in development and evaluated in the neoadjuvant setting.29,30\n\nBoth treatments were generally well tolerated, with few patients discontinuing from any treatment due to AEs. There was no clinically significant imbalance between groups in TEAEs, serious TEAEs or other observed safety parameters. PF-05280014 and trastuzumab-EU also had comparable immunogenicity profiles, wherein no patients in the PF-05280014 group and one patient in the trastuzumab-EU group tested positive for ADAs. These data are consistent with previous studies demonstrating a low immunogenic potential for trastuzumab.19,31 As part of a stepwise comparison exercise to demonstrate biosimilarity, these findings build on those of previous analytical and non-clinical studies and two single-dose studies in healthy volunteers.18–20\n\nThe current study applied a non-inferiority design to compare PF-05280014 with trastuzumab-EU. Generally, biosimilarity studies use an equivalence design to show the biosimilar is neither superior nor inferior to the originator product and vice versa.16,17,32 However, in some cases, a non-inferiority design may be adequate to demonstrate that there are no clinically meaningful differences between the proposed biosimilar product and originator biologic.16 This study may be limited by its use of a margin for non-inferiority of the clinical endpoint pCR to establish non-inferiority using a primary endpoint based on pharmacokinetics data. However, a non-inferiority margin based on clinical considerations rather than statistical considerations is supported by a lack of previous evidence in the neoadjuvant setting outside of the HannaH trial.26 In addition, this study was not powered to evaluate non-inferiority in pCR or ORR, which may limit interpretation of clinical efficacy findings. However, a comparative study of PF-05280014 versus trastuzumab-EU, each in combination with paclitaxel, as first-line treatment in patients with HER2+ metastatic breast cancer used an equivalence design, and preliminary results demonstrated that this trial met its primary endpoint of similarity in ORR.33\n\nThe strengths of the current trial include its randomised, double-blind design, homogeneous patient population and use of clinical endpoints that measure activity (e.g., tumour response). The most frequently published definition of pCR (absence of invasive neoplastic cells in breast and lymph nodes following neoadjuvant therapy) was used, consistent with previous studies of trastuzumab administered concurrently with chemotherapy in the neoadjuvant setting.11,12,26 Furthermore, calculation of ORR for efficacy analysis was based on independent central radiologic review of tumour assessments. Finally, neoadjuvant use of trastuzumab is not currently approved by the US Food and Drug Administration1; however, it is authorised by the European Medicines Agency and is well known and used in clinical practice in Europe and the United States.2,25,34,35 Therefore, the finding of comparable efficacy in terms of pCR and ORR in this setting may be reassuring for patients and clinicians.\n\nIn conclusion, neoadjuvant treatment with the potential biosimilar PF-05280014 administered in combination with docetaxel and carboplatin demonstrated non-inferiority in pharmacokinetics and comparability in efficacy, safety and immunogenicity when compared with trastuzumab-EU in combination with docetaxel and carboplatin in patients with operable HER2+ breast cancer. These results support similarity of PF-05280014 to trastuzumab-EU as part of the stepwise comparison exercise for demonstrating biosimilarity. As a potential biosimilar of trastuzumab, PF-05280014 could broaden the number of treatment options for patients with HER2+ breast cancer and allow greater use of anti-HER2 therapy across clinical settings.\n\nElectronic supplementary material\n\nSupplementary Information\n\nElectronic supplementary material\n\nSupplementary information is available for this paper at 10.1038/s41416-018-0147-1.\n\nAcknowledgements\n\nMedical writing support was provided by Elyse Smith, PhD, of Engage Scientific Solutions and funded by Pfizer Inc. This study was funded by Pfizer Inc. Trial registration: ClinicalTrials.gov: NCT02187744; EU Clinical Trials Register EudraCT number: 2013-004679-11.\n\nAuthor contributions\n\nRichat Abbas, Fiona Hilton, Jennifer Coppola and Ira Jacobs contributed to study design and conduct. Fiona Hilton analysed the data and provided statistical support. Philip E. Lammers, Magdolna Dank and Riccardo Masetti contributed to acquisition of data. All authors made substantial contributions to interpretation of data, were involved in drafting the manuscript and/or revising it critically for important intellectual content, approved the final version for submission and agree to be accountable for all aspects of the work.\n\nEthics approval and consent to participate\n\nThe study was conducted in compliance with the provisions of the Declaration of Helsinki and in accordance with international standards of Good Clinical Practice. All patients provided informed consent prior to undergoing screening procedures. The final protocol, amendments and informed consent documentation were reviewed and approved by an institutional review board or independent ethics committee(s) at each of the participating investigational sites.\n\nFunding\n\nThis study was funded by Pfizer Inc.\n\nCompeting interests\n\nPhilip E. Lammers has participated on advisory boards with Pfizer Inc. Magdolna Dank has been a member of Biosimilars Oncology European Advisory Board with Pfizer Inc since 2013. Riccardo Masetti declares no conflicts of interest. Richat Abbas, Fiona Hilton, Jennifer Coppola and Ira Jacobs are full time employees of and declare stock holdings and/or stock options from Pfizer Inc.\n\nAvailability of data and materials\n\nPfizer’s policies on the provision of clinical trial data are set out on our website: http://www.pfizer.com/research/clinical_trials/trial_data_and_results. In addition to posting clinical trial results on the ClinicalTrials.gov registry, Pfizer will provide access to anonymised patient-level data in response to scientifically valid research protocols. Data from Pfizer-sponsored global interventional clinical studies are available from: trials conducted for medicines, vaccines and medical devices for indications that have been approved in the US and/or EU; trials conducted for medicines, vaccines and medical devices that have been terminated (i.e., development for all indications has been discontinued). Data from these trials will be made available 24 months after study completion. Pfizer will make reasonable efforts to fulfil all data requests for legitimate research purposes, but there may be instances in which retrieval or delivery of data is not feasible (for example, if Pfizer does not have legal authority to provide the data, if costs of retrieval of older or pre-electronic data are prohibitive, etc. See page 5* at the following link: https://www.pfizer.com/files/research/research_clinical_trials/A_Guide_to_Requesting_Pfizer_Patient-Level_Clinical_Trial_Data_2017.pdf). Further detail can be found at: http://www.pfizer.com/research/clinical_trials/trial_data_and_results/data_requests. Pfizer’s practices adhere to the principles for responsible data sharing laid out by the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA): http://phrma.org/sites/default/files/pdf/PhRMAPrinciplesForResponsibleClinicalTrialDataSharing.pdf.\n\nPublisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Genentech Inc. Herceptin (trastuzumab) US prescribing information. http://www.gene.com/download/pdf/herceptin_prescribing.pdf. Accessed 11 July 2017 (2017).\n2. European Medicines Agency. Herceptin (trastuzumab) summary of product characteristics. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000278/human_med_000818.jsp&mid=WC0b01ac058001d124. Accessed 13 July 2017 (2013).\n3. Press MF Her-2/neu expression in node-negative breast cancer: direct tissue quantitation by computerized image analysis and association of overexpression with increased risk of recurrent disease Cancer Res. 1993 53 4960 4970 8104689\n4. Seshadri R Clinical significance of HER-2/neu oncogene amplification in primary breast cancer. The South Australian Breast Cancer Study Group J. Clin. Oncol. 1993 11 1936 1942 10.1200/JCO.1993.11.10.1936 8105035\n5. Slamon DJ Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene Science 1987 235 177 182 10.1126/science.3798106 3798106\n6. Wolff AC Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update J. Clin. Oncol. 2013 31 3997 4013 10.1200/JCO.2013.50.9984 24101045\n7. Piccart-Gebhart MJ Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer N. Engl. J. Med. 2005 353 1659 1672 10.1056/NEJMoa052306 16236737\n8. Romond EH Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer N. Engl. J. Med. 2005 353 1673 1684 10.1056/NEJMoa052122 16236738\n9. Slamon D Adjuvant trastuzumab in HER2-positive breast cancer N. Engl. J. Med. 2011 365 1273 1283 10.1056/NEJMoa0910383 21991949\n10. Slamon DJ Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 N. Engl. J. Med. 2001 344 783 792 10.1056/NEJM200103153441101 11248153\n11. Buzdar AU Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer J. Clin. Oncol. 2005 23 3676 3685 10.1200/JCO.2005.07.032 15738535\n12. Gianni L Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort Lancet 2010 375 377 384 10.1016/S0140-6736(09)61964-4 20113825\n13. Cherny N Sullivan R Torode J Saar M Eniu A ESMO European Consortium Study on the availability, out-of-pocket costs and accessibility of antineoplastic medicines in Europe Ann. Oncol. 2016 27 1423 1443 10.1093/annonc/mdw213 27457309\n14. Lammers P Criscitiello C Curigliano G Jacobs I Barriers to the use of trastuzumab for HER2+breast cancer and the potential impact of biosimilars: a physician survey in the United States and emerging markets Pharmaceuticals (Basel) 2014 7 943 953 10.3390/ph7090943 25232798\n15. European Medicines Agency. Guideline on similar biological medicinal products. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf. Accessed 11 July 2017 (2014).\n16. US Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed 11 July 2017 (2015).\n17. World Health Organization. Guidelines on evaluation of similar biotherapeutic products (SBPs). http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf. Accessed 11 July 2017 (2009).\n18. Hurst S Comparative nonclinical assessments of the proposed biosimilar PF-05280014 and trastuzumab (Herceptin((R))) BioDrugs 2014 28 451 459 10.1007/s40259-014-0103-4 25001079\n19. Yin D A randomized phase 1 pharmacokinetic trial comparing the potential biosimilar PF-05280014 with trastuzumab in healthy volunteers (REFLECTIONS B327-01) Br. J. Clin. Pharmacol. 2014 78 1281 1290 10.1111/bcp.12464 25041377\n20. Vana AM Evaluating imbalances of adverse events during biosimilar development Mabs 2016 8 861 866 10.1080/19420862.2016.1171431 27050730\n21. ClinicalTrials.gov. A study of PF-05280014 [trastuzumab-Pfizer] or Herceptin® [trastuzumab-EU] plus paclitaxel in HER2 positive first line metastatic breast cancer treatment (REFLECTIONS B327-02). https://clinicaltrials.gov/ct2/show/NCT01989676. Accessed 22 March 2017 (2013).\n22. ClinicalTrials.gov. A study of PF-05280014 or trastuzumab plus Taxotere® and carboplatin in HER2 positive breast cancer in the neoadjuvant setting (REFLECTIONS B327-04). https://clinicaltrials.gov/ct2/show/NCT02187744?term=PF+05280014&rank=4. Accessed 11 July 2017 (2014).\n23. EU Clinical Trials Register. A randomized, double-blind pharmacokinetic study of PF-05280014 plus Taxotere and carboplatin versus Herceptin plus Taxotere and carboplatin for the neoadjuvant treatment of patients with operable HER2-positve breast cancer. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-004679-11. Accessed 11 July 2017 (2014).\n24. Coudert BP Multicenter phase II trial of neoadjuvant therapy with trastuzumab, docetaxel, and carboplatin for human epidermal growth factor receptor-2-overexpressing stage II or III breast cancer: results of the GETN(A)-1 trial J. Clin. Oncol. 2007 25 2678 2684 10.1200/JCO.2006.09.9994 17515572\n25. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: breast cancer, version 3.2013. https://www.nccn.org/. Accessed 11 July 2017 (2015).\n26. Ismael G Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial Lancet Oncol. 2012 13 869 878 10.1016/S1470-2045(12)70329-7 22884505\n27. Untch M Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial Lancet Oncol. 2012 13 135 144 10.1016/S1470-2045(11)70397-7 22257523\n28. Untch M Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study J. Clin. Oncol. 2010 28 2024 2031 10.1200/JCO.2009.23.8451 20308670\n29. Stebbing J CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial Lancet Oncol. 2017 8 917 928 10.1016/S1470-2045(17)30434-5\n30. Pivot XB A randomized, double-blind, phase III study comparing SB3 (trastuzumab biosimilar) with originator trastuzumab in patients treated by neoadjuvant therapy for HER2-positive early breast cancer [abstract] J. Clin. Oncol. 2017 35 509 10.1200/JCO.2017.35.15_suppl.509\n31. Wynne C Comparison of subcutaneous and intravenous administration of trastuzumab: a phase I/Ib trial in healthy male volunteers and patients with HER2-positive breast cancer J. Clin. Pharmacol. 2013 53 192 201 10.1177/0091270012436560 23436264\n32. Isakov L Jin B Jacobs IA Statistical primer on biosimilar clinical development Am. J. Ther. 2016 23 e1903 e1910 10.1097/MJT.0000000000000391 26766293\n33. Pegram M., et al. (2017) A randomized, double-blind study of PF-05280014 (a potential trastuzumab biosimilar) vs trastuzumab, both in combination with paclitaxel, as first-line treatment for HER2-positive metastatic breast cancer. Presented at: European Society for Medical Oncology (ESMO 2017), Madrid, Spain, 08–12 September 2017.\n34. Denduluri N Selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for human epidermal growth factor receptor 2–positive breast cancers: an American Society of Clinical Oncology Guideline adaptation of the Cancer Care Ontario Clinical Practice Guideline J. Clin. Oncol. 2016 34 1 12 10.1200/JCO.2016.67.0182 26578609\n35. Senkus E Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann. Oncol. 2015 26 v8 v30 10.1093/annonc/mdv298 26314782\n\n",
"fulltext_license": "CC BY",
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"issue": "119(3)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D059451:Biosimilar Pharmaceuticals; D001943:Breast Neoplasms; D005062:European Union; D005260:Female; D006801:Humans; D008408:Mastectomy; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D055815:Young Adult",
"nlm_unique_id": "0370635",
"other_id": null,
"pages": "266-273",
"pmc": null,
"pmid": "30002437",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "27050730;26314782;15738535;8105035;24101045;23436264;25001079;25232798;20113825;27457309;25041377;20308670;22257523;3798106;17515572;22884505;28592386;8104689;16236737;11248153;16236738;27091714;21991949;26766293",
"title": "Neoadjuvant PF-05280014 (a potential trastuzumab biosimilar) versus trastuzumab for operable HER2+ breast cancer.",
"title_normalized": "neoadjuvant pf 05280014 a potential trastuzumab biosimilar versus trastuzumab for operable her2 breast cancer"
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"abstract": "Patients with monoclonal gammopathy of undetermined significance (MGUS) have a higher risk for the development of concomitant primary cancers such as multiple myeloma (MM) and myelodysplastic syndrome (MDS). We report the case of patient initially suffering from MGUS of the IgG lambda subtype for more than 10 yr, which evolved to MM and MDS with deletion (5q) with severe pancytopenia. Due to pancytopenia, he received dose-reduced treatment with lenalidomide and dexamethasone. He achieved an ongoing transfusion independency after about 1 month of treatment. Bone marrow taken 14 months after start of treatment showed a complete cytogenetic response of the del(5q) clone and a plasma cell infiltration below 5%. In contrast to the development of MM in MGUS patients, the subsequent occurrence of MDS after diagnosis of MGUS is infrequent. Moreover, the biological association of MDS with MGUS is not sufficiently understood, but the non-treatment-related occurrence supports the pathogenetic role of pre-existing alterations of stem cells. Here, we summarize data on concomitant MDS and MGUS/MM with particular emphasis on molecular aspects.",
"affiliations": "Medical faculty Mannheim of the University of Heidelberg, Mannheim, Germany.;Medical faculty Mannheim of the University of Heidelberg, Mannheim, Germany.;Medical faculty Mannheim of the University of Heidelberg, Mannheim, Germany.;Medical faculty Mannheim of the University of Heidelberg, Mannheim, Germany.;Medical faculty Mannheim of the University of Heidelberg, Mannheim, Germany.;Medical faculty Mannheim of the University of Heidelberg, Mannheim, Germany.;Medical faculty Mannheim of the University of Heidelberg, Mannheim, Germany.;Medical faculty Mannheim of the University of Heidelberg, Mannheim, Germany.",
"authors": "Nolte|Florian|F|;Mossner|Maximilian|M|;Jann|Johann-Christoph|JC|;Nowak|Daniel|D|;Boch|Tobias|T|;Müller|Nadine Zoe|NZ|;Hofmann|Wolf-Karsten|WK|;Metzgeroth|Georgia|G|",
"chemical_list": "C473949:ASXL1 protein, human; D012097:Repressor Proteins",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.12827",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "98(3)",
"journal": "European journal of haematology",
"keywords": "hematopoiesis and hematopathology; multiple myeloma; myelodysplastic syndromes; stem cell biology",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001853:Bone Marrow; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D018450:Disease Progression; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008998:Monoclonal Gammopathy of Undetermined Significance; D009154:Mutation; D009190:Myelodysplastic Syndromes; D012097:Repressor Proteins",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "302-310",
"pmc": null,
"pmid": "27862375",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Concomitant MDS with isolated 5q deletion and MGUS: case report and review of molecular aspects.",
"title_normalized": "concomitant mds with isolated 5q deletion and mgus case report and review of molecular aspects"
} | [
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"companynumb": "DE-CELGENEUS-062-21880-13084211",
"fulfillexpeditecriteria": "1",
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"abstract": "Diffuse involvement of colorectal lymphoma masquerading as colitis is a very rare presentation of primary colorectal lymphoma. Detecting occult lymphoma is difficult in the setting of diffuse colonic involvement with no definite mass and inflammatory mucosal changes. We encountered a case of diffuse-type primary colorectal lymphoma simulating ulcerative colitis in a previously healthy 31-year-old woman. Despite multiple mucosal biopsies, the biopsy diagnosis was not made due to unawareness of atypical lymphocytes admixed with dense lymphoplasmacytic infiltration. The present case emphasizes the importance of being aware of this rare presentation of primary colorectal lymphoma in order to avoid misdiagnosis.",
"affiliations": "Department of Pathology, Inje University Ilsan Paik Hospital, Goyang, Korea.;Department of Pathology, Inje University Ilsan Paik Hospital, Goyang, Korea.;Department of Pathology, Inje University Ilsan Paik Hospital, Goyang, Korea.;Department of Pathology, Inje University Ilsan Paik Hospital, Goyang, Korea.",
"authors": "Kim|Ji-Ye|JY|;Chang|Sun Hee|SH|;Kim|Han Seong|HS|;Joo|Mee|M|",
"chemical_list": null,
"country": "Korea (South)",
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"doi": "10.4132/jptm.2019.07.12",
"fulltext": "\n==== Front\nJ Pathol Transl MedJ Pathol Transl MedJPTMJournal of Pathology and Translational Medicine2383-78372383-7845The Korean Society of Pathologists and the Korean Society for Cytopathology 3137038310.4132/jptm.2019.07.12jptm-2019-07-12Case StudyDiffuse Involvement of Primary Colorectal Lymphoma Simulating Ulcerative Colitis http://orcid.org/0000-0003-4291-2967Kim Ji-Ye http://orcid.org/0000-0002-7775-4711Chang Sun Hee http://orcid.org/0000-0003-3740-0588Kim Han Seong http://orcid.org/0000-0002-5886-0287Joo Mee \nDepartment of Pathology, Inje University Ilsan Paik Hospital, Goyang, KoreaCorresponding Author: Mee Joo, MD, PhD, Department of Pathology, Inje University Ilsan Paik Hospital, 170 Juhwa-ro, Ilsanseo-gu, Goyang 10380, Korea Tel: +82-31-910-7141, Fax: +82-31-910-7139, E-mail: mjoo@paik.ac.kr9 2019 2 8 2019 53 5 332 336 17 5 2019 2 7 2019 12 7 2019 © 2019 The Korean Society of Pathologists/The Korean Society for Cytopathology2019This 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.Diffuse involvement of colorectal lymphoma masquerading as colitis is a very rare presentation of primary colorectal lymphoma. Detecting occult lymphoma is difficult in the setting of diffuse colonic involvement with no definite mass and inflammatory mucosal changes. We encountered a case of diffuse-type primary colorectal lymphoma simulating ulcerative colitis in a previously healthy 31-year-old woman. Despite multiple mucosal biopsies, the biopsy diagnosis was not made due to unawareness of atypical lymphocytes admixed with dense lymphoplasmacytic infiltration. The present case emphasizes the importance of being aware of this rare presentation of primary colorectal lymphoma in order to avoid misdiagnosis.\n\nColorectal lymphomaPrimaryDiffuse typeColitis\n==== Body\nThe incidence of primary colorectal lymphoma is very rare, accounting for 0.2%–0.6% of colorectal malignancies [1]. Primary colorectal lymphomas manifest in a variety of ways, ranging from solitary fungating masses to multiple polyps. In 1968, Friedman et al. [2] reported four cases of “lymphomatous colitis,” a rare form of primary colorectal lymphoma mimicking ulcerative colitis (UC). Since then, a small number of patients with diffuse-type colorectal lymphoma have been reported, in whom a clinical and/or histological diagnosis of colitis, including inflammatory bowel disease (IBD), was made initially but were subsequently discovered to have diffuse lymphoma involvement of the colon within a short period of time [3-17]. IBD and immunosuppression have been reported as risk factors for primary colorectal lymphoma [18]. Most IBD-related lymphomas develop late in the course of an extensive longstanding disease. In that respect, these cases differ from most reports of primary colorectal lymphoma as a complication of longstanding IBD. We experienced a case of UC-like primary colorectal lymphoma in a 31-year-old woman who presented with profuse hematochezia, was misdiagnosed with UC, and died of a diffuse lymphoma involving the entire colon 12 months after hematochezia first developed.\n\nCASE REPORT\nA 31-year-old woman with no prior history of IBD presented with intermittent abdominal pain and mucoid diarrhea. Five months later, she developed hematochezia and was diagnosed with UC on the basis of endoscopic biopsy. She was treated with oral Pentasa and Pentasa enema. However, she continued to be symptomatic with marked weight loss (20 kg in 4 months). Follow-up colonoscopy revealed continuous mucosal changes from the rectum to the cecum, such as diffuse hyperemia, edematous changes, friability, loss of normal vascularity, and multiple variable-sized ulcers, consistent with UC (Fig. 1A). No mass-forming lesion was present throughout. Abdominal and pelvic computed tomography revealed diffuse edematous wall thickening in the whole colon and multiple enlargements of mesenteric lymph nodes. No hepatosplenomegaly was observed. Multiple biopsies were taken from the terminal ileum, cecum, transverse colon, sigmoid colon, and rectum. All biopsy specimens revealed diffuse infiltration of large, atypical lymphoid cells with a high nucleus-to-cytoplasmic ratio, occasional prominent nucleoli, and mitotic figures (Fig. 1B, C). They expanded the lamina propria, pushed the crypts apart, and invaded the submucosa. By immunochemistry, the tumor cells were diffusely positive for CD20, bcl2, and p53, and negative for CD3, CD5, CD10, and cyclin D1. The Ki-67 labeling index was about 60%. The overall histology and immunophenotype supported a diagnosis of diffuse large B-cell lymphoma. There was no detectable evidence of extra-abdominal lymphadenopathy or lymphomatous involvement elsewhere. Bone marrow evaluation was also negative for lymphoma. As no extraintestinal disease was found, we considered it as a primary colorectal lymphoma. The patient died while receiving the second cycle of R-CHOP chemotherapy.\n\nWe retrospectively reviewed the colonoscopic biopsy specimens that were initially diagnosed with UC. At low magnification view, the background mucosa displayed crypt architectural distortion and dense inflammatory cell infiltration, resembling chronic colitis. However, we found some lymphoma cells, which were admixed with other inflammatory cells or showed focal aggregation in the basal portion of the mucosa (Fig. 1D). Those lymphoma cells were more distinguishable on immunostaining for CD20 and Ki-67 (Fig. 1E, F).\n\nEthics statment\nThis study was approved by the Institutional Review Board of Inje University Ilsan Paik Hospital with a waiver of informed consent (IRB No. ISPAIK 2019-05-005) and performed in accordance with the principles of the Declaration of Helsinki.\n\nDISCUSSION\nTwenty cases (including the present one) of “colitis-like” diffuse-type colorectal lymphoma were reported in the English literature [2-17]. We excluded cases of colorectal lymphoma developed in patients with a longstanding IBD or prior established diagnosis of extracolonic lymphoma. The clinical and pathological findings of these patients are summarized in Table 1. There were 10 men, 8 women, and two children. Their mean age at presentation was 53.2 years (range, 6 to 82 years). The main symptoms were diarrhea/hematochezia (90%), loss of weight (50%), abdominal pain (25%), and fever (10%). Endoscopic findings were consistent with UC (55%), Crohn disease (20%), diffuse colitis (20%), and multiple ulcers (5%): no localized mass-like lesion was present. All cases were non-Hodgkin’s lymphoma: eight were B-cell type (four mantle cell lymphomas, two mucosa-associated lymphoid tissue lymphomas, one diffuse large B-cell lymphoma, and one follicular lymphoma), seven were T-cell type, one was natural killer cell lymphoma, and four other unclassified lymphoreticular malignancies (one malignant lymphoma, one reticulum cell sarcoma, one lymphosarcoma, and one lymphocytic lymphoma). Of note, there were nine patients in whom colitis was histologically confirmed with multiple biopsy or colectomy but were subsequently found to have lymphoma involvement in a retrospective review of previous slides. Taken together, diffuse type primary colorectal lymphoma is a very rare disease and is easily misdiagnosed, particularly in reliance on endoscopic biopsy examination alone. The possibility of a hidden lymphomatous involvement would have to be considered in patients with medically refractory and rapidly progressive colitis.\n\nLymphoma involvement of the gastrointestinal (GI) tract may occur either as an isolated primary neoplasm or as a manifestation of systemic generalized lymphoma. To distinguish between primary and secondary GI lymphoma, Dawson’s criteria is generally applied: (1) no palpable superficial lymphadenopathy at initial presentation, (2) a normal chest X-ray with no mediastinal lymphadenopathy, (3) no evidence of leukemia, (4) a predominant mass in the bowel with only local lymphadenopathy, and (5) no hepatosplenomegaly [19]. When the diagnostic criteria of primary colonic lymphoma are strictly applied, only seven of 20 cases of “colitis-like” colorectal lymphoma are eligible for diffuse-type primary colorectal lymphoma: 13 cases were excluded due to synchronous other organ involvement at initial presentation, such as superficial or generalized lymphadenopathy (six cases), upper GI involvement (five cases), bone marrow involvement (four cases), or hepatosplenomegaly (three cases), etc. Consequently, it is a reflection that “colitis-like” diffuse involvement of colorectal lymphoma seems to be more often secondary. Accurate discrimination between primary and secondary colorectal lymphoma is important for proper staging and management. In conclusion, since primary colorectal lymphoma can rarely manifest as “colitis-like” diffuse colonic involvement, awareness of this rare presentation is important to ensure proper diagnosis and treatment.\n\nAuthor contributions\n\nConceptualization: MJ.\n\nInvestigation: MJ.\n\nVisualization: MJ.\n\nWriting—original draft: JYK, MJ.\n\nWriting—review & editing: JYK, MJ, SHC, HK.\n\nConflicts of Interest\n\nThe authors declare that they have no potential conflicts of interest.\n\nFunding\n\nNo funding to declare.\n\nFig. 1. (A) Colonoscopy reveals diffuse hyperemic inflamed mucosa with total loss of normal vascularity and surface ulceration from the rectum to the cecum. (B, C) Representative microphotographs of diffuse lymphoma involvement on the biopsy specimens. (B) The mucosa and submucosa are diffusely involved by densely packed lymphocytes with the background remnants of colonic crypts. Monotonous large-sized lymphocytes have vesicular chromatin and often membrane-bound nucleoli, resembling centroblasts (C). (D–F) Retrospective examination of initial colonoscopic biopsy. (D) The biopsied colonic mucosa displays crypt architectural distortion and dense inflammatory cell infiltration, resembling chronic colitis. Atypical lymphoid cells are aggregated in the bottom right corner (below the yellow dotted line), which show not only strong expression on CD20 immunostaining (E) but also high Ki-67 labeling index (F).\n\nTable 1. Clinical and pathological findings of previously published cases of “colitis-like” diffuse-type colorectal lymphomas in the English literature\n\nYear\tAuthor\tSex/Age (yr)\tPathologic diagnosis\tEndoscopic findings\tRevision of initial diagnosis\tSuperficial LAP at presentation\tExtracolonic involvement\t\n1968\tFriedman et al. [2]\tM/37\tReticulum cell sarcoma\tUC\tNo\tNo\tLiver\t\n1968\tFriedman et al. [2]\tF/54\tMalignant lymphoma\tUC\tYes (colectomy)\tNo\tNo\t\n1968\tFriedman et al. [2]\tM/73\tLymphosarcoma\tUC\tYes (Bx)\tNo\tNo\t\n1980\tWeir et al. [3]\tF/67\tLymphocytic lymphoma\tCD\tYes (Bx)\tYes, generalized\tBM\t\n1992\tMcCullough et al. [4]\tM/44\tMantle cell lymphoma\tUC\tYes (Bx)\tYes, cervical axillary\tPancreas\t\n1995\tLenzen et al. [5]\tF/53\tMALT lymphoma\tUC\tNo\tNo\tUpper GI tract, BM\t\n1996\tRobert et al. [6]\tF/71\tMantle cell lymphoma\tUC\tYes (colectomy)\tNo\tNo\t\n1996\tHirakawa et al. [7]\tM/47\tT-cell lymphoma\tUC\tNo\tNo\tUpper GI tract\t\n1997\tSon et al. [8]\tF/40\tPeripheral T-cell lymphoma\tCD\tYes (Bx)\tNo\tNo\t\n2003\tIsomoto et al. [9]\tM/47\tAdult T-cell leukemia/lymphoma\tUC\tNo\tYes, generalized\tStomach, skin\t\n2004\tPayne et al. [10]\tF/76\tHigh-grade T-cell lymphoma\tColitis\tNo\tYes, generalized\tNo\t\n2004\tTamura et al. [11]\tM/61\tMantle cell lymphoma\tColitis\tNo\tNo\tTonsil, upper GI tract\t\n2008\tBerkelhammer et al. [12]\tF/82\tMALT lymphoma\tCD\tYes (Bx)\tNo\tNo\t\n2014\tKoksal et al. [13]\tM/73\tMantle cell lymphoma\tUC\tNo\tNo\tStomach\t\n2015\tZaheen et al. [14]\tM/74\tEBV-negative NK cell lymphoma\tColitis\tNo\tNo\tBM, pleural effusion\t\n2015\tWu et al. [15]\tM/56\tT-cell lymphoma\tUlcers\tYes (Bx)\tYes, generalized\tNo\t\n2016\tCheung et al. [16]\tNA/12\tEBV-positive T-cell lymphoma\tColitis\tNo\tNo\tHepatosplenomegaly\t\n2016\tCheung et al. [16]\tNA/6\tEBV-positive T-cell lymphoma\tCD\tNo\tNo\tNo\t\n2017\tZenda et al. [17]\tM/59\tFollicular lymphoma\tUC\tNo\tYes, cervical inguinal\tSpleen, BM\t\n\tPresent case\tF/32\tDiffuse large B-cell lymphoma\tUC\tYes (Bx)\tNo\tNo\t\nLAP, lymphadenopathy; M, male; UC, ulcerative colitis; F, female; Bx, biopsy; CD, Crohn’s disease; BM, bone marrow; MALT, mucosa-associated lymphoid tissue; GI, gastrointestinal; EBV, Epstein-Barr virus; NA, not available.\n==== Refs\nREFERENCES\n1 Wong MT Eu KW Primary colorectal lymphomas Colorectal Dis 2006 8 586 91 16919111 \n2 Friedman HB Silver GM Brown CH Lymphoma of the colon simulating ulcerative colitis: report of four cases Am J Dig Dis 1968 13 910 7 4878622 \n3 Weir AB Poon MC Groarke JF Wilkerson JA Lymphoma simulating Crohn’s colitis Dig Dis Sci 1980 25 69 72 6892563 \n4 McCullough JE Kim CH Banks PM Mantle zone lymphoma of the colon simulating diffuse inflammatory bowel disease: role of immunohistochemistry in establishing the diagnosis Dig Dis Sci 1992 37 934 8 1587200 \n5 Lenzen R Borchard F Lübke H Strohmeyer G Colitis ulcerosa complicated by malignant lymphoma: case report and analysis of published works Gut 1995 36 306 10 7883235 \n6 Robert ME Kuo FC Longtine JA Sklar JL Schrock T Weidner N Diffuse colonic mantle cell lymphoma in a patient with presumed ulcerative colitis: detection of a precursor monoclonal lymphoid population using polymerase chain reaction and immunohistochemistry Am J Surg Pathol 1996 20 1024 31 8712289 \n7 Hirakawa K Fuchigami T Nakamura S Primary gastrointestinal T-cell lymphoma resembling multiple lymphomatous polyposis Gastroenterology 1996 111 778 82 8780585 \n8 Son HJ Rhee PL Kim JJ Primary T-cell lymphoma of the colon Korean J Intern Med 1997 12 238 41 9439161 \n9 Isomoto H Furusu H Onizuka Y Colonic involvement by adult T-cell leukemia/lymphoma mimicking ulcerative colitis Gastrointest Endosc 2003 58 805 8 14997894 \n10 Payne S Phillips M Reffitt D An unusual case of colitis Gut 2004 53 1824 15542522 \n11 Tamura S Ohkawauchi K Yokoyama Y Non-multiple lymphomatous polyposis form of mantle cell lymphoma in the gastrointestinal tract J Gastroenterol 2004 39 995 1000 15549454 \n12 Berkelhammer C Mohammed A Zalzaleh G Grela J Blumstein A Stein R Spontaneous multiperforation in lymphomatous colitis masquerading as Crohn’s disease: 2 cases Inflamm Bowel Dis 2008 14 1172 3 18338762 \n13 Koksal AS Taskiran I Kalkan IH Kayacetin E A rare endoscopic appearance of primary gastrointestinal mantle cell lymphoma resembling ulcerative colitis Bratisl Lek Listy 2014 115 800 1 25520232 \n14 Zaheen A Delabie J Vajpeyi R Frost DW The first report of a previously undescribed EBV-negative NK-cell lymphoma of the GI tract presenting as chronic diarrhoea with eosinophilia BMJ Case Rep 2015 2015 bcr2015212103 \n15 Wu PH Chu KE Lin YM Huang SH Wu CC T-cell lymphomas presenting as colon ulcers and eosinophilia Case Rep Gastroenterol 2015 9 246 52 26351412 \n16 Cheung FM Tong Y Wang Y Epstein-Barr virus-positive T-cell-associated colitis mimicking inflammatory bowel disease: clinicopathological study of two cases Histopathology 2016 68 465 8 26156622 \n17 Zenda T Nakagawa N Maruyama H Follicular lymphoma-related colitis resembling ulcerative colitis Clin J Gastroenterol 2017 10 147 53 28013449 \n18 Farrell RJ Ang Y Kileen P Increased incidence of non-Hodgkin’s lymphoma in inflammatory bowel disease patients on immunosuppressive therapy but overall risk is low Gut 2000 47 514 9 10986211 \n19 Dawson IM Cornes JS Morson BC Primary malignant lymphoid tumours of the intestinal tract. Report of 37 cases with a study of factors influencing prognosis Br J Surg 1961 49 80 9 13884035\n\n",
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"keywords": "Colitis; Colorectal lymphoma; Diffuse type; Primary",
"medline_ta": "J Pathol Transl Med",
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"title": "Diffuse Involvement of Primary Colorectal Lymphoma Simulating Ulcerative Colitis.",
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"abstract": "OBJECTIVE\nFOLFOX is a standard chemotherapy regimen used to treat colorectal cancer. Adverse events associated with FOLFOX treatment include peripheral neuropathy and myelosuppression. This report discusses the case of a 64-year-old man with rectal cancer who developed hyperammonemia and impaired consciousness following initiation of mFOLFOX6 as a postoperative adjuvant therapy.\n\n\nMETHODS\nThis case study reports on the clinical disease progression of the aforementioned patient.\n\n\nRESULTS\nFollowing preoperative chemoradiotherapy, the patient underwent low anterior resection for rectal cancer. mFOLFOX6 was then initiated as postoperative adjuvant therapy. During the 5th cycle of mFOLFOX6 treatment, the patient presented with impaired consciousness and upper extremity convulsions. Blood testing revealed marked hyperammonemia (349 µg/dL (normal range: 12 - 66 µg/dL)). Imaging did not reveal any intracranial lesions that could cause impaired consciousness. The patient recovered within a day after rehydration and BCAA substitution.\n\n\nCONCLUSIONS\nAlthough impaired consciousness is a rare adverse reaction of FOLFOX, it has a major psychological impact on the patient and his/her family. Hyperammonemia should therefore be considered a potential cause of impaired consciousness during FOLFOX therapy and should be appropriately diagnosed and treated.",
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"authors": "Kurokawa|Tomohiro|T|;Kanemoto|Yoshiaki|Y|;Azuma|Yuki|Y|;Iimura|Yohei|Y|;Kuroda|Seiichiro|S|;Yazawa|Kentaro|K|;Tsurita|Giichiro|G|",
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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003243:Consciousness; D005260:Female; D005472:Fluorouracil; D006801:Humans; D022124:Hyperammonemia; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012004:Rectal Neoplasms",
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"title": "Hyperammonemia-induced impaired consciousness following mFOLFOX6 therapy in a patient with recurrent rectal cancer.",
"title_normalized": "hyperammonemia induced impaired consciousness following mfolfox6 therapy in a patient with recurrent rectal cancer"
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"abstract": "Atypical teratoid/rhabdoid tumor (AT/RT) is a rare tumor that is most frequently encountered in the pediatric patient population. AT/RT accounts for approximately 1%-2% of all pediatric central nervous system tumors and roughly 10%-20% of tumors in patients younger than 3 years of age. While AT/RT has been encountered in the adult population, the vast majority of the cases reported occur in the supratentorial space. In the existing literature, only 3 adult cases that arise from the cerebellum have ever been reported.\n\n\n\nA 38-year-old female presented with 6 months of worsening nausea, emesis, vertigo, diplopia, and coordination difficulty. Magnetic resonance imaging revealed a T1 avidly contrast-enhancing mass, composed of both cystic and solid areas, extending from the cerebellum into the fourth ventricle. Following a gross total resection, surgical pathology was consistent with AT/RT, with tumor cell loss of integrase interactor-1 (INI-1) observed via immunohistochemical staining.\n\n\n\nThis case represents just the fourth ever reported case of AT/RT arising from the cerebellum in an adult and the oldest reported age to date of a cerebellar AT/RT occurring in a female. Due to the paucity of reported adult AT/RT cases, little is known about adults with AT/RT. Further reports will function to improve the general understanding of AT/RT in the adult population.",
"affiliations": "Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA. Electronic address: gpgreeneway@gmail.com.;Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.;Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.;Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.",
"authors": "Greeneway|Garret P|GP|;Page|Paul S|PS|;Patel|Viharkumar|V|;Ahmed|Azam S|AS|",
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"keywords": "Adult; Atypical teratoid/rhabdoid tumor; Brain tumor; Cerebellar tumor; Cerebellum; Rhabdoid tumor",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000328:Adult; D002528:Cerebellar Neoplasms; D002531:Cerebellum; D005260:Female; D020546:Fourth Ventricle; D006801:Humans; D008279:Magnetic Resonance Imaging; D019635:Neurosurgical Procedures; D018335:Rhabdoid Tumor; D013724:Teratoma; D016896:Treatment Outcome",
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"title": "Atypical Teratoid/Rhabdoid Tumor of the Cerebellum in an Adult: Case Report and Literature Review.",
"title_normalized": "atypical teratoid rhabdoid tumor of the cerebellum in an adult case report and literature review"
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"abstract": "We present the case of a man with acute lymphoblastic leukemia and prolonged profound neutropenia, who developed an invasive infection by Fusarium graminearum, acquired via non-cutaneous entry, with gastrointestinal symptoms, sigmoid perforation and liver abscesses due to portal dissemination. The etiologic agent was identified using the 18S-ITS1-5.8S-ITS2-28S rRNA sequence gene, from a liver biopsy. The infection was resolved with surgical drainage and antifungal treatment based on voriconazole. As far as we know, there are no previous reports in the literature of cases of human infection due to Fusarium graminearum.",
"affiliations": "Infectious Disease Department, National Institute of Cancer, Mexico City 14080, Mexico.;Infectious Disease Department, National Institute of Cancer, Mexico City 14080, Mexico.;Hematology Department, National Institute of Cancer, Mexico City 14080, Mexico.;Pathology Department, National Institute of Cancer, Mexico City 14080, Mexico.;Ecology of Pathogen Agents Department, General Hospital Manuel Gea González, Mexico City 14080, Mexico.;Infectious Disease Department, National Institute of Cancer, Mexico City 14080, Mexico.",
"authors": "Uscamayta|Mary Gabriela|MG|;Martin-Onraet|Alexandra|A|;Espinosa-Bautista|Karla|K|;Herrera-Goepfert|Roberto|R|0000-0001-7901-2378;Hernández-Castro|Rigoberto|R|;Perez-Jimenez|Carolina|C|0000-0002-0212-9436",
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"fulltext": "\n==== Front\nInfect Dis Rep\nInfect Dis Rep\nidr\nInfectious Disease Reports\n2036-7430 2036-7449 MDPI \n\n33401374\n10.3390/idr13010002\nidr-13-00002\nCase Report\nPortal Dissemination of Fusarium graminearum in a Patient with Acute Lymphoblastic Leukemia and Febrile Neutropenia\nUscamayta Mary Gabriela 1 Martin-Onraet Alexandra 1 Espinosa-Bautista Karla 2 https://orcid.org/0000-0001-7901-2378Herrera-Goepfert Roberto 3 Hernández-Castro Rigoberto 4 https://orcid.org/0000-0002-0212-9436Perez-Jimenez Carolina 1* 1 Infectious Disease Department, National Institute of Cancer, Mexico City 14080, Mexico; gabriela-mary@hotmail.com (M.G.U.); alexitemaon@gmail.com (A.M.-O.)\n2 Hematology Department, National Institute of Cancer, Mexico City 14080, Mexico; karlaadrianae@gmail.com\n3 Pathology Department, National Institute of Cancer, Mexico City 14080, Mexico; rhgoepfert@gmail.com\n4 Ecology of Pathogen Agents Department, General Hospital Manuel Gea González, Mexico City 14080, Mexico; rigo37@gmail.com\n* Correspondence: capeji@hotmail.com\n01 1 2021 \n3 2021 \n13 1 11 17\n29 10 2020 02 12 2020 © 2021 by the authors.2021Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).We present the case of a man with acute lymphoblastic leukemia and prolonged profound neutropenia, who developed an invasive infection by Fusarium graminearum, acquired via non-cutaneous entry, with gastrointestinal symptoms, sigmoid perforation and liver abscesses due to portal dissemination. The etiologic agent was identified using the 18S-ITS1-5.8S-ITS2-28S rRNA sequence gene, from a liver biopsy. The infection was resolved with surgical drainage and antifungal treatment based on voriconazole. As far as we know, there are no previous reports in the literature of cases of human infection due to Fusarium graminearum.\n\nFusarium graminearumportal disseminationinvasive fungal infectionrRNA sequence genefebrile neutropenia\n==== Body\n1. Introduction\nIn the last decades, there has been an increase in the incidence of invasive fungal infections (IFI), related to new immunosuppressive treatments and improved diagnosis with new molecular techniques and higher diagnostic yields [1,2]. We present the case of a male patient with acute lymphoblastic leukemia and prolonged profound neutropenia, who developed an invasive infection by Fusarium graminearum, acquired via non-cutaneous entry, presenting an atypical clinical course, gastrointestinal symptoms, sigmoid perforation and liver abscesses due to portal dissemination. The etiologic agent was identified using the 18S-ITS1-5.8S-ITS2-28S rRNA sequence gene from a liver biopsy. This is the first reported case of portal dissemination by Fusarium genus and the first report of Fusarium graminearum infection in humans.\n\n2. Ethical Considerations\nThe case we submit for publication is about a single patient who provided his verbal consent for this purpose. We do not include any details or information that could lead to patient identification\n\n3. Case Report\nMale patient, 26 years old, kitchen assistant, originated from Taxco, Guerrero and living there until he emigrated to Texas, United States, in 2016, where he was diagnosed with B lymphoblastic leukemia in January 2017. He received four cycles of unspecified chemotherapy with apparent remission of the disease and came back to Mexico (Cuernavaca, Morelos). He was admitted to the National Institute of Cancer in Mexico City in November 2017, where he was diagnosed with early relapse. From November 2017 to January 2018, he received chemotherapy for relapse with BFM like protocol (L-Asparaginase, Vincristine, Daunorubicin, and Prednisone). He did not receive any antifungal prophylaxis. On day +23 he was presented with febrile neutropenia, with no etiologic agent identified. An empirical treatment of five days of Meropenem was administered, with resulting in fever remission. He was discharged 6 days after his admission, asymptomatic but with persistent neutropenia.\n\nTwo days later, he had come back with an acute abdomen, although afebrile. Vital constants at admission were: BP: 107/78 mmHg, HR: 90 bpm, RR: 20 rpm, T °: 36.5 °C, weight: 55 Kg, height: 1.62 m, BMI: 21 Kg/m2. His blood tests showed leukocytes of 0.32 × 103/μL, absolute neutrophils 0.0032 x103/μL, hemoglobin 5.7 g/dL, platelets 35 × 103/μL, creatinine 0.66 mg/dL, ALT 174 IU/L, AST 82 IU/L, ALP 1004 IU/L, GGT 572 IU/L, total bilirubin 8 mg/dL, conjugated bilirubin 6.4 mg/dL, unconjugated bilirubin 1.62 mg/dL, LDH 287 IU/L, albumin 1.7 mg/dL, C reactive protein 8.4 mg/dL. The patient underwent exploratory laparotomy which revealed sigmoid perforation. Sigmoidectomy and colostomy were performed. The initial pathology report was diverticulum perforation. Forty-eight hours later, he presented moderate diffuse abdominal pain, and temperature > 38 °C. The blood cultures were negative. Administration of Meropenem, caspofungin and Filgastrim was empirically initiated. Contrast abdominal tomography (CT) showed diffuse liver lesions consistent with liver abscesses (Figure 1).\n\nA liver biopsy of the lesions was performed under ultrasound guidance; the aerobic, anaerobic and Sabouraud dextrose agar cultures were negative. The pathology showed granulomatous hepatitis with extensive necrosis; Grocott’s stain evidenced hyaline hyphae. The histopathology of the sigmoid surgical specimen was reviewed again and then reported as transmural ischemic necrosis, acute and chronic peritonitis, and positive Grocott’s stain with the same hyphae described in the liver (Figure 2).\n\nHyalohyphomycosis was concluded. The serum galactomannan was negative. Pulmonary involvement was not seen by tomography. The antifungal treatment was changed from caspofungin to intravenous Voriconazole on day 23. The patient had gradual clinical improvement the neutropenia was remitted and was discharged with a treatment of oral voriconazole 200 mg bid. He was, at that time, in complete remission of leukemia.\n\nThree weeks later he was readmitted for abdominal pain in the right hypochondrium with fever without neutropenia; he reported bad adherence to oral antifungal treatment for economic reasons. The new abdominal CT showed the persistence of liver abscesses. Exploratory laparotomy plus drainage were performed finding abscesses in segments II, IV and VI. The anaerobic culture grew Bacteroides fragilis; he completed 14 days of Metronidazole. The fungal culture was negative. The pathology report was extensive granulomatous hepatitis with necrosis and negative Grocott’s stain. The patient received 2 weeks of intravenous Voriconazole plus 6 weeks of the same oral antifungal. At the end of treatment, the abdominal CT showed only one residual lesion of 16 mm. A timeline of the case is shown in Figure S1.\n\nHe did not present further complications of the infectious process. However, six months later, while undergoing hematopoietic stem-cell transplant evaluations, he presented a relapse of leukemia and he decided to stop the antineoplastic treatment. He died seven months later.\n\nMaterials and Methods for Identification of the Causative Agent\nA paraffin block of the first liver biopsy was requested, and DNA extraction was performed. Genomic DNA was extracted from the paraffin-embedded tissue sample using a DNeasy blood and tissue kit (Qiagen, Ventura, CA, USA) according to the manufacturer’s instructions before preliminary removal of paraffin by extraction with xylene protocol. The molecular identification was performed by 18S-ITS1-5.8S-ITS2-25S rRNA gene amplification using a set of primers previously reported to identify fungi species (5′-TCCGTAGGTGAACCTTGCGG-3′) and ITS4 (5′-TCCTCCGCTTATTGATATGC-3′). A PCR product of 500 bp was amplified, purified and sequenced in both directions; nucleotide sequence was determined with Taq FS Dye Terminator Cycle Sequencing Fluorescence-Based Sequencing and analyzed on an Applied Biosystems 3730 DNA sequencing system (Foster City, CA, USA). The sequence was edited with Vector NTI program and homology search was performed in the GenBank database (nucleotide blast), finding a 100% identity with Fusarium graminearum complex strain HUT59 [3]. (Figure 3). The sequences used are shown in Supplementary Figure S2.\n\n4. Discussion\nIn the last ten years, there has been an increasing incidence of disseminated filamentous fungal infections in patients with severe immunosuppression [1,2,4]. Hematological malignancies have a risk of 6.5% for IFI [5], mainly in the induction and consolidation phases. This increase is due to severe immunosuppression conditions by myelotoxic treatments and related clinical conditions but also to new technologies such as molecular biology [6,7] that have increased the diagnosis ability.\n\nHialohifomycetes are opportunistic filamentous fungi that usually cause infection after environmental exposure [6]. Infection occurs through inhalation or skin breakdown (wounds, burns) [8]. Fusarium spp. is the second cause of infections by filamentous fungi after Aspergillus spp. More than 50 Fusarium species have been identified, but only about 12 are associated with infection in humans. F. incarnatum, F. moniliforme, F. oxysporum and F. solani usually cause allergic reactions and superficial infections such as keratitis and onychomycosis in immunocompetent hosts. In immunocompromised patients, it can cause from locally invasive diseases such as sinusitis and pneumonia, to fungemia and disseminated disease [9,10]. In neutropenic patients, it usually manifests as fever not responding to empirical antibiotics. Profound and prolonged neutropenia is the most important risk factor for dissemination and death due to fusariosis [8,11]. The most frequently isolated species in this setting are F. solani (50%) and F. oxysporum (20%) [6,8].\n\nFusarium graminearum plays a major role as the etiological agent of one important disease of small grain cereals and corn. First identified in 1884 in England, it is considered a major threat to wheat and barley [12]. The fungi, transmitted by seed, can survive up to 10 years as spores or resting structures in and on the seed. In Mexico, F. graminearum has been found in Hidalgo, Jalisco, Mexico, Michoacán and Tlaxcala [13,14,15,16]. This fungus can produce several mycotoxins, which have shown abortive estrogenic, gastric (nausea and vomiting) and neurotoxic toxicity in swine, cattle, dogs, cats, and ducks [16,17]. Grain that has been infected with the fungus can be incorporated into basic diets and could be a source of infection in humans. So far, no infections due to F. graminareum have been reported. Considering the patient’s occupation (kitchen helper) and the high corn content in the Mexican diet, we supposed that the patient was colonized with F. graminearum through the daily ingestion and handling of corn. He possibly got the mould through oral ingestion, and symptoms were gastrointestinal due to portal dissemination, which explains why we did not document any fungemia or cutaneous infection, despite an invasive disease. Usually, in disseminated fusariosis, blood cultures are positive in more than 75% of cases [6,8].\n\nIn our patient, the diagnosis of hyalohyphomycosis was first made by pathologic specimen. The biopsy revealed the presence of septate hyaline hyphae 3–6 μm diameter, indistinguishable from other hyalohyphomycosis such as Aspergillus, Acremonium [Cephalosporium], and Pseudallescheria [17]. Recently, the Mycotic Diseases Branch, from the Center for Disease Control and Prevention in Atlanta, described a new entity of invasive fungal infections (IFI), which they called “foodborne IFI”, in a recently published systematic review [18], foodborne IFI are infections acquired through ingestion of food or water contaminated with the fungi causing the infection. Reports describe molds and yeasts as etiologic agents. Rhizopus sp is the most frequently described mold, but one case of IFI due to Fusarium moniliforme is reported in a man with acute lymphoblastic leukemia who ingested cereals. The diagnosis of foodborne IFI is difficult, clinical presentation is usually atypical, and mainly gastrointestinal. Fungi can spoil food that is ingested, and it is suggested that this category of fungal infections could be related to food insecurity. The source of the fungi should be identified to be able to classify the IFI as foodborne, which is often difficult to the ubiquitous nature of these fungi. As previously mentioned, although we suspect that our patient acquired the infection orally and this could correspond to foodborne IFI, we cannot corroborate the above because we could not have samples of the food that the patient ingested prior to his hospitalization and we did not perform stool cultures.\n\nToday, comparative identification strategies based on gene sequencing can be considered the new gold standard for the identification of fungal species. Gene sequencing is characterized by PCR amplification of the ITS region, and sequencing of the resulting amplicon (s). The ITS region can be amplified reliably for most fungi [19]. These molecular biology techniques provide better discrimination of species morphologically indistinguishable from Fusarium spp, and can be performed on different types of materials, including paraffin blocks, which is why it is considered an emerging and promising methodology to be used in the routine identification of Fusarium spp. In our case, no other fungal species were identified in the studied specimen or in any other specimen from the patient. The Fusarium graminearum complex includes 13 species; biogeographic data suggest that the majority of the species within the complex have evolutionary origins in the Southern hemisphere and Asia. According to the surveys to date, F. austroamericanum, F. meridionale, F. cortaderiae, and F. brasilicum appear to be endemic to South America; F. acaciae-mearnsii to Australia or less likely Africa; F. asiaticum, F. vorosii and F. ussurianum to Asia; F. aethiopicum to Africa; F. boothii and F. mesoamericanum to Central America; F. gerlachii to the US and F. graminearum sensu stricto (F. graminearum s.s.) it is the most cosmopolitan species and has been found in Asia, Africa, America, Europe, and Oceania [20].\n\nFinally, the treatment in localized disease can benefit from surgical debridement especially in disseminated disease together with the use of systemic antifungals. Fusarium species are relatively resistant in vitro to most antifungal agents, showing different susceptibility patterns between species. In general, most Fusarium isolates have lower inhibitory concentrations (MIC) for Amphotericin B higher than Aspergillus species. F. solani and F. verticillioides are usually resistant to azoles and they have higher MIC for azoles than other Fusarium species. In contrast, F. oxysporum and F. moniliforme may be susceptible to voriconazole and posaconazole [9]. Echinocandins show the highest MIC values [21]. As far as we know there are no previous reports in the medical literature of identification of F.graminearum as a pathogen in humans; therefore antifungal therapy was initiated based on is the antifungals reported in the literature for the Fusarium species and on the clinical response.\n\n5. Conclusions\nProlonged profound neutropenia and alteration of the intestinal flora, secondary to myelotoxic chemotherapies and environmental exposure in patients with hematological neoplasms, are important risk factors for the development of invasive infections by filamentous fungi. This is the first reported case of invasive fungal infection by F. graminearum and the first case of portal dissemination of Fusarium spp. The anamnesis and exposure to environmental factors are important during clinical evaluation. F.graminearum was not identifiable by traditional methods such as culture and pathology. Access to molecular biology is extremely valuable to increase the performance of diagnostic tests in the identification of new species such as the F. graminearum reported in our paper.\n\nAcknowledgments\nTo all the infectious disease fellows who participated in the approach of this case, especially to Aaron Molina. And Rodrigo Toral-Villanueva for his technical support with the edition of figures.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary Materials\nThe following are available online at https://www.mdpi.com/2036-7449/13/1/2/s1, Supplementary material 1 (Figure S1) is a timeline of the present case. Supplementary material 2 (Figure S2) is a figure with the genetic sequences used for the identification of the etiologic agent (Fusarium graminearum complex). \n\nClick here for additional data file.\n\n Author Contributions\nM.G.U. was in charge of the data curation of the patient; A.M.-O. and M.G.U. were in charge of the writing of the original manuscript; R.H.-C. was in charge of the methodology for the identification by molecular biology of the etiologic agent ; C.P.-J. was responsible for reviewing and editing the manuscript as well as submitting it for publication. R.H.-G. was in charge of the methodology for the identification of the agent in the pathology specimen. K.E.-B. also participated in the data curation of the patient and in the writing of the original manuscript.All authors have read and agreed to the published version of the manuscript. \n\nFunding\nNo source of funding was used for the preparation of this report.\n\nInstitutional Review Board Statement\nNot applicable. Due to the fact that our study is only descriptive (without any type of intervention) on the case of a single patient, and he provided his consent, the evaluation by the Institution's ethics committee was not considered necessary.\n\nInformed Consent Statement\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\nData is contained within the article or supplementary material.\n\nConflicts of Interest\nAll authors report having no conflict of interest.\n\nFigure 1 Abdominal CT scan with intravenous contrast, which shows: Diffuse and poorly defined hypodense lesions, one located in the liver segment II measuring 3.4 cm, another located in the caudate lobe measuring 7 cm, and another located in the hepatic segment VII with extension to segment VI measuring 7 cm; consistent with liver abscesses.\n\nFigure 2 (A) Non-pigmented, separated hyphae with acute angle branching in liver biopsy tissue, Grocott methenamine silver-stained specimen, 40×. (B) Non-pigmented, separated hyphae with acute angle branching in intestinal tissue, Grocott methenamine silver-stained specimen, 10×.\n\nFigure 3 The 18S-ITS1-5.8S-ITS2-25S rRNA gene amplification. Lane 1: Molecular weight marker 100 bp DNA ladder; Lane 2: Liver biopsy sample; Lane 3: Negative control.\n==== Refs\nReferences\n1. Liu Y.S. Wang N.C. Ye R.H. Kao W.Y. Disseminated Fusarium infection in a patient with acute lymphoblastic leukemia: A case report and review of the literature Oncol Lett. 2014 7 334 336 10.3892/ol.2013.1738 24396442 \n2. Slavin M. Van Hal S. Sorrell T.C. Lee A. Marriott D.J. Daveson K. Kennedy K. Hajkowicz K. Halliday C. Athan E. Invasive infections due to filamentous fungi other than Aspergillus: Epidemiology and determinants of mortality Clin Microbiol Infect. 2015 21 490.e1 490.e10 10.1016/j.cmi.2014.12.021 25677259 \n3. Korabecna M. Liska V. Fajfrlík K. PrimersITS1, ITS2 andITS4 detect the intraspecies variability in the internal transcribed spacers and 5.8S rRNA gene region in clinical isolates of fungi Folia Microbiol. 2003 48 233 238 10.1007/BF02930961 12800508 \n4. Wanke B. Lazéra M.D.S. Nucci M. Fungal infections in the immunocompromised host Memórias Inst. Oswaldo Cruz 2000 95 153 158 10.1590/S0074-02762000000700025 11142705 \n5. Pagano L. Girmenia C. Mele L. Ricci P. Tosti M.E. Nosari A. Buelli M. Picardi M. Allione B. Corvatta L. Infections caused by filamentous fungi in patients with hematologic malignancies. A report of 391 cases by GIMEMA Infection Program Haematologica 2001 86 862 870 11522544 \n6. Fariñas M.C. Fernandez-Sampedro M. Armiñanzas C. Clinical forms and treatment of infections caused by other filamentous fungi Enferm. Infecc. Microbiol. Clin. 2012 30 414 419 10.1016/j.eimc.2012.02.001 22459687 \n7. Ruiz-Camps I. Jarque I. Invasive mould disease in haematological patients Rev. Iberoam. Micol. 2014 31 249 254 10.1016/j.riam.2014.06.002 25434346 \n8. Muhammed M. Anagnostou T. Desalermos A. Kourkoumpetis T.K. Carneiro H.A. Glavis-Bloom J. Coleman J.J. Mylonakis E. Fusarium infection Medicine 2013 92 305 316 10.1097/MD.0000000000000008 24145697 \n9. Nucci M. Anaissie E. Fusarium infections in immunocompromised patients Clin. Microbiol Rev. 2007 20 695 704 10.1128/CMR.00014-07 17934079 \n10. Campo M. Lewis R.E. Kontoyiannis D.P. Invasive fusariosis in patients with hematologic malignancies at a cancer center: 1998–2009 J. Infect. 2010 60 331 337 10.1016/j.jinf.2010.01.010 20138081 \n11. Nucci M. Anaissie E.J. Queiroz-Telles F. Martins C.A. Trabasso P. Solza C. Mangini C. Simoes B.P. Colombo A.L. Vaz J. Outcome predictors of 84 patients with hematologic malignancies and Fusarium infection Cancer 2003 98 315 319 10.1002/cncr.11510 12872351 \n12. Goswami R.S. Kistler H.C. Heading for disaster: Fusarium graminearum on cereal crops Mol. Plant Pathol. 2004 5 515 525 10.1111/j.1364-3703.2004.00252.x 20565626 \n13. Ireta M.J. Gilchrist L. Fusarium Head Scab of Wheat (Fusarium Graminareum Schwabe) CIMMYT Texcoco, Mexico 1994 25 \n14. Leyva-Mir S.G. Vega-Portillo H.E. Villaseñor-Mir H.E. Tlapal-Bolaños B. Vargas-Hernandez M. Camacho-Tapia M. Tovar-Pedraza J.M. Characterization of Fusarium species causing root rot of wheat in the Bajío, Mexico Chil. J. Agric Anim Sci. 2017 33 142 151 \n15. Sandoval-Martínez E. Leyva Mir S.G. Villaseñor-Mir H.E. Rodríguez-García M.F. Mariscal-Amaro L.A. Diversity of fungi in grain of wheat of temporary Rev. Mex. Fitopatol. 2012 30 145 149 \n16. García-Aguirre G. Martinez-Flores R. Fusarium species from corn kernels recently harvested and shelled in the fields in the Ciudad Serdán Region, Puebla Rev. Mex. Biodivers. 2010 81 15 20 \n17. Bonifaz A. Hialohifomicosis y Otras Micosis Poco Frecuentes McGraw-Hill New York, NY, USA 2010 \n18. Benedict K. Chiller T.M. Mody R.K. Invasive fungal infections acquired from contaminated food or nutritional supplements: A review of the literature Foodborne Pathog. Dis. 2016 13 343 349 10.1089/fpd.2015.2108 27074753 \n19. Jain P.K. Gupta V.K. Misra A.K. Gaur R. Bajpai V. Isaar S. Current status of fusarium infection in human and animal Asian J. Anim. Vet. Adv. 2011 6 201 227 10.3923/ajava.2011.201.227 \n20. Wang J.H. Ndoye M. Zhang J.B. Li H.P. Liao Y.C. Population structure and genetic diversity of the Fusarium graminearum species complex Toxins 2011 3 1020 1037 10.3390/toxins3081020 22069755 \n21. Taj-Aldeen S.J. Reduced multidrug susceptibility profile is a common feature of opportunistic Fusarium Species: Fusarium multi-drug resistant pattern J. Fungi 2017 3 18 10.3390/jof3020018 29371536\n\n",
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"keywords": "Fusarium graminearum; febrile neutropenia; invasive fungal infection; portal dissemination; rRNA sequence gene",
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"title": "Portal Dissemination of Fusarium graminearum in a Patient with Acute Lymphoblastic Leukemia and Febrile Neutropenia.",
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"abstract": "Immune-checkpoint inhibitors (ICIs) provide a promising treatment option for advanced tumors including small cell lung cancer (SCLC). Nevertheless, in addition to immune-related adverse events (irAEs), an increased risk of infection including tuberculosis has been previously described. Here, we report a case of long-term remission of a patient with SCLC after reactivation of lung tuberculosis following ICI therapy. Our case illustrates the complexity of ICI-associated immune modulation in tuberculosis. Since new lesions in lung cancer patients are commonly associated with tumor progression, infections with mycobacterial tuberculosis may be underdiagnosed in lung cancer.",
"affiliations": "Department of Medical Oncology and Pneumology, University Hospital Tuebingen, Tuebingen, Germany.;Department of Medical Oncology and Pneumology, University Hospital Tuebingen, Tuebingen, Germany.;Department of Diagnostic and Interventional Radiology, University Hospital Tuebingen, Tuebingen, Germany.;Department of Medical Oncology and Pneumology, University Hospital Tuebingen, Tuebingen, Germany.;Department of Medical Oncology and Pneumology, University Hospital Tuebingen, Tuebingen, Germany.;Department of Medical Oncology and Pneumology, University Hospital Tuebingen, Tuebingen, Germany.;Department of Medical Oncology and Pneumology, University Hospital Tuebingen, Tuebingen, Germany.",
"authors": "Sirgiovanni|Mattia|M|;Hinterleitner|Clemens|C|;Horger|Marius|M|;Atique|Naushad Bijoy|NB|;Lauer|Ulrich M|UM|;Zender|Lars|L|;Hinterleitner|Martina|M|0000-0001-7137-0541",
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"fulltext": "\n==== Front\nThorac Cancer\nThorac Cancer\n10.1111/(ISSN)1759-7714\nTCA\nThoracic Cancer\n1759-7706 1759-7714 John Wiley & Sons Australia, Ltd Melbourne \n\n33458956\n10.1111/1759-7714.13821\nTCA13821\nCase Report\nCase Reports\nLong‐term remission of small cell lung cancer after reactivation of tuberculosis following immune‐checkpoint blockade: A case report\nSirgiovanni et al.Sirgiovanni Mattia \n1\n\n2\n Hinterleitner Clemens \n1\n\n2\n Horger Marius \n3\n Atique Naushad Bijoy \n1\n\n2\n Lauer Ulrich M. \n1\n\n2\n Zender Lars \n1\n\n2\n\n4\n Hinterleitner Martina https://orcid.org/0000-0001-7137-0541\n1\n\n2\nmartina.hinterleitner@med.uni-tuebingen.de \n1 \nDepartment of Medical Oncology and Pneumology\nUniversity Hospital Tuebingen\nTuebingen\nGermany\n\n\n2 \nCluster of Excellence iFIT (EXC 2180) “Image‐Guided and Functionally Instructed Tumor Therapies”\nUniversity of Tuebingen\nTuebingen\nGermany\n\n\n3 \nDepartment of Diagnostic and Interventional Radiology\nUniversity Hospital Tuebingen\nTuebingen\nGermany\n\n\n4 \nGerman Cancer Research Consortium (DKTK), Partner Site Tuebingen\nGerman Cancer Research Center (DKFZ)\nHeidelberg\nGermany\n\n* Correspondence\n\nMartina Hinterleitner, Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tuebingen, Otfried‐Mueller‐Str. 10, 72076 Tuebingen, Germany.\n\nEmail: martina.hinterleitner@med.uni-tuebingen.de\n\n17 1 2021 \n3 2021 \n12 5 10.1111/tca.v12.5699 702\n11 11 2020 16 12 2020 16 12 2020 © 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ 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\nImmune‐checkpoint inhibitors (ICIs) provide a promising treatment option for advanced tumors including small cell lung cancer (SCLC). Nevertheless, in addition to immune‐related adverse events (irAEs), an increased risk of infection including tuberculosis has been previously described. Here, we report a case of long‐term remission of a patient with SCLC after reactivation of lung tuberculosis following ICI therapy. Our case illustrates the complexity of ICI‐associated immune modulation in tuberculosis. Since new lesions in lung cancer patients are commonly associated with tumor progression, infections with mycobacterial tuberculosis may be underdiagnosed in lung cancer.\n\nOur case illustrates the complexity of ICI‐associated immune modulation in tuberculosis. Since new lesions in lung cancer patients are commonly associated with tumor progression, infections with mycobacterial tuberculosis may be underdiagnosed in lung cancer.\n\n\nimmune‐checkpoint inhibitorslung cancerPD‐L1tuberculosisDeutsche Forschungsgemeinschaft (DFG, German Research Foundation) 10.13039/501100001659EXC 2180 ‐ 39090067 source-schema-version-number2.0cover-dateMarch 2021details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.9 mode:remove_FC converted:01.03.2021\n\n\nSirgiovanni \nM \n, \nHinterleitner \nC \n, \nHorger \nM \n, et al. Long‐term remission of small cell lung cancer after reactivation of tuberculosis following immune‐checkpoint blockade: A case report\n. Thoracic Cancer . 2021 ;12 :699 –702\n. 10.1111/1759-7714.13821 \n\n\n\n\nFunding information Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Grant/Award Number: EXC 2180 ‐ 39090067\n==== Body\nINTRODUCTION\nSmall cell lung cancer (SCLC) is characterized by its high proliferative capacity and a high tendency to relapse after initial remission upon treatment with cytotoxic therapy. SCLC has a poor prognosis with a five‐year survival rate of only 7%.\n1\n SCLC is commonly associated with smoking and a subsequent high tumor mutational burden (TMB), as well as TP53 and retina blastoma protein (RB) mutations.\n2\n, \n3\n Although conventional platinum/etoposide‐based chemotherapy commonly results in striking tumor remissions, long‐term tumor control is a rare event.\n4\n Antibodies targeting the immune‐checkpoint molecules PD‐1/PDL‐1 and CTLA4 have shown promising results in SCLC.\n5\n, \n6\n In addition to immune‐related adverse events (irAEs), a known side effect of such therapies is the increased risk of infectious diseases including tuberculosis (TBC).\n7\n, \n8\n Here, we report on a rare case of a long‐term remission of a young SCLC patient after reactivation of lung tuberculosis following combined immune‐checkpoint blockade.\n\nCASE REPORT\nA 44‐year‐old man with a smoking history of 15 pack‐years was admitted to hospital complaining of recurrent episodes of cough and progressive dyspnoea. A diagnostic work‐up showed an extensive tumor mass in the right lung, originating from the upper lobe with infiltration of the middle and lower lobes. Histopathological analysis revealed the diagnosis of a small cell neuroendocrine tumor with a proliferation index (Ki67) of 80%. Upon confirmation of extensive disease stage (cT4, cN2, cMx), the patient underwent six cycles of palliative chemotherapy with cisplatinum/etoposide followed by radiotherapy of the primary tumor location with 42 Gy.\n\nTwelve months after radiotherapy, the patient's general condition decreased rapidly and a computed tomography (CT) scan revealed a tumor relapse in the middle lobe of the right lung. A biopsy of the pulmonary lesion confirmed the diagnosis of the SCLC histopathologically. Genetic profiling was subsequently performed and showed a high mutational burden (up to 1166 missense variants), as well as alterations in TP53 (c.671_672insTTTGA, p.E224Dfs*25 and loss of wild‐type allele) and RB1 (c.2501C > G, p.S834*); two phenotypic mutations found in small cell cancers.\n9\n, \n10\n In addition, a BRCA1 (c.1529C > T; p.S510L and loss of wild‐type allele) mutation was identified. A second‐line therapy with the topoisomerase inhibitor topotecan failed after six cycles and resulted in a further progress of the central pulmonary tumor site (Figure 1a). Unfortunately, a cMRI‐scan revealed multiple cerebral lesions (Figure 1b). Radiotherapy to the brain (30 Gy) was concurrently administered. In consideration of the high mutational burden, combined immunotherapy with nivolumab and ipilimumab was initiated.\n5\n\n\n\nFIGURE 1 Clinical presentation of the SCLC patient and treatment scheme. (a) CT scan of the pulmonary SCLC lesion before and after ICI treatment. (b) Assessment of brain metastasis (white arrow) via cMRI prior to ICI treatment and after six months. (c) CT scan of the pulmonary MTB lesion before and after anti‐infective treatment. (d) Bronchoscopy of the primary MTB lesion in the left upper bronchus. (e) Neuron specific enolase (NSE) and CRP levels during the entire treatment (PD, progressive disease; SD, stable disease)\n\nAfter three cycles of ICIs, a CT scan showed a relevant decrease in the central pulmonary mass (Figure 1a). However, a new lesion in the left and right upper lobe was demonstrated (Figure 1c). Laboratory tests showed elevated C‐reactive protein plasma levels (8–10 mg/dl, normal range up to 0.5 mg/dl) (Figure 1e). Interestingly, at this time, the patient presented with no clinical symptoms such as persistent cough or signs of clinical deterioration. Several enlarged mediastinal lymph nodes were associated with lymph node metastasis of the underlying SCLC. Bronchoscopy revealed a large cavity in the area of the left upper lobe connected to the bronchial system (Figure 1d). A Ziehl‐Neelsen (ZN) stain of the bronchoalveolar lavage showed a positive result for mycobacteria. In addition, a positive polymerase chain reaction of mycobacteria tuberculosis (MTB) was detected. Subsequently performed acid‐fast bacillus staining confirmed positive results in sputum samples and gastric lavage. Of note, a quantiferon test performed by a pneumologist prior to diagnosis of SCLC was negative. Susceptibility testing showed sensitivity to all tested antimycobacterial agents, beyond termination of ICI treatment, and a four‐drug combination of isoniazid, rifampicin, ethambutol, and pyrazinamide was commenced. After completion of this anti‐infective therapy, a relevant decrease in the size of both lung lesions was observed (Figure 1c), and the cerebral metastases were no longer detectable (Figure 1b).\n\nRemarkably, without any further treatment, several CT scans showed no signs of tumor progression. To date, 24 months after the last treatment with ICIs, the patient shows a highly favorable physical condition as well as stable disease of all former detectable tumor manifestations.\n\nDISCUSSION\nThe case presented here illustrates the concomitance of an active MTB infection upon ICI therapy and a prolonged remission of an advanced SCLC. Interestingly, reactivation of tuberculosis in cancer patients undergoing treatment with ICIs has been reported in a small number of cases.\n7\n In contrast to other infectious complications upon ICI treatment, which are commonly related to immune inhibitory treatment to control irAEs, exacerbation of MTB does not seem to be correlated with the use of corticosteroids or TNF inhibitors.\n7\n Even in our case, no irAE was detected or a subsequent immune inhibitory treatment administered. As a result, MTB reactivation might be directly correlated to ICI treatment. However, the underlying mechanisms triggering the reactivation in this context are only partially understood.\n\nThe role of T cells in MTB infections has been investigated in several preclinical models and showed that CD4+ T cells (Th1) play a major role in mycobacterial infections.\n11\n, \n12\n, \n13\n In contrast to data showing that blocking of PD‐1/PD‐L1 can partially prevent T cell exhaustion and subsequently restore T cell activity, lack of PD‐1 in MTB‐specific effector CD4+ T cells led to dysregulated IFN‐γ production and fatal immune‐mediated pathology.\n14\n In virus‐specific CD8+ T cells, PD‐1 knockdown (PD‐1−/−) led to a deeper T cell exhaustion compared to PD‐1 wild‐type.\n15\n In addition, PD‐1−/− mice had more severe and sometimes lethal causes of MTB infection.\n12\n, \n16\n These observations highlight the complex role of inhibitory immune‐checkpoint signaling mediating T cell exhaustion and immune surveillance during infections and cancer. Nevertheless, more data are urgently needed to better understand the particular role of ICI in MTB.\n\nOur case, however not only describes a reactivation of MTB. We also observed a long‐term remission of the underlying tumor disease. Accordingly, the question arises whether the reactivation of MTB might additionally contribute to long‐term cancer immunosurveillance. It is known that TBC pathogens stimulate the activation of both innate and cellular immunity via different classes of cytokines.\n17\n Since mycobacteria associated antigens have also been described to enforce the antitumor immune response, a contribution of MTB to cancer immunosurveillance may be conceivable.\n18\n Hereby, it might be speculated that the exacerbation of MTB stimulated the host's immune response, thus leading to a reinforcement of the antitumor immune activity. This particular effect might be further enhanced after PD‐1/CTLA4 inhibition. However, more clinical and preclinical evidence is needed to prove such a hypothesis. Interestingly, an improved survival in non‐small cell lung cancer (NSCLC) patients affected by active tuberculosis compared to nonaffected NSCLC patients has already been described.\n19\n\n\n\nIn summary, our case highlights the complex orchestra of immunomodulation in infection and cancer. Due to the fact that radiological signs of MTB including mediastinal or hilar lymphadenopathy, infiltrates, consolidations or cavities are commonly observed in lung cancer patients, diagnosis of MTB in lung cancer patients remains challenging. Moreover, since new lesions in lung cancer patients are commonly associated with tumor progression, MTB infections associated with ICIs might be underdiagnosed. As a consequence, specific testing for MTB in cancer patients receiving ICIs might be beneficial, even without strong clinical evidence.\n\nIn conclusion, this case report in a patient with long‐term remission of SCLC after infection with mycobacteria tuberculosis following immune‐checkpoint inhibitor (ICI) therapy emphasizes the need for further investigation of the complex crosstalk of ICI treatment, infection and cancer.\n\nACKNOWLEDGMENTS\nThis work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy ‐ EXC 2180–39090067. Open access funding enabled and organized by Projekt DEAL.\n==== Refs\nREFERENCES\n1 \n\nGazdar \nAF \n, \nBunn \nPA \n, \nMinna \nJD \n. Small‐cell lung cancer: what we know, what we need to know and the path forward\n. Nat Rev Cancer . 2017 ;17 (12 ):725 –37\n.29077690 \n2 \n\nTravis \nWD \n, \nBrambilla \nE \n, \nNicholson \nAG \n, \nYatabe \nY \n, \nAustin \nJH \n, \nBeasley \nMB \n, et al. The 2015 World Health Organization Classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification\n. J Thorac Oncol . 2015 ;10 (9 ):1243 –60\n.26291008 \n3 \n\nPleasance \nED \n, \nStephens \nPJ \n, \nO'Meara \nS \n, \nMcBride \nDJ \n, \nMeynert \nA \n, \nJones \nD \n, et al. A small‐cell lung cancer genome with complex signatures of tobacco exposure\n. Nature . 2010 ;463 (7278 ):184 –90\n.20016488 \n4 \n\nPovsic \nM \n, \nEnstone \nA \n, \nWyn \nR \n, \nKornalska \nK \n, \nPenrod \nJR \n, \nYuan \nY \n. Real‐world effectiveness and tolerability of small‐cell lung cancer (SCLC) treatments: a systematic literature review (SLR)\n. PLoS One . 2019 ;14 (7 ):e0219622.31318909 \n5 \n\nAntonia \nSJ \n, \nLópez‐Martin \nJA \n, \nBendell \nJ \n, \nOtt \nPA \n, \nTaylor \nM \n, \nEder \nJP \n, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small‐cell lung cancer (CheckMate 032): a multicentre, open‐label, phase 1/2 trial\n. Lancet Oncol . 2016 ;17 (7 ):883 –95\n.27269741 \n6 \n\nTay \nRY \n, \nHeigener \nD \n, \nReck \nM \n, \nCalifano \nR \n. Immune checkpoint blockade in small cell lung cancer\n. Lung Cancer . 2019 ;137 :31 –7\n.31525648 \n7 \n\nAnastasopoulou \nA \n, \nZiogas \nDC \n, \nSamarkos \nM \n, \nKirkwood \nJM \n, \nGogas \nH \n. Reactivation of tuberculosis in cancer patients following administration of immune checkpoint inhibitors: current evidence and clinical practice recommendations\n. J Immunother Cancer. \n2019 ;7 (1 ):239 .31484550 \n8 \n\nElkington \nPT \n, \nBateman \nAC \n, \nThomas \nGJ \n, \nOttensmeier \nCH \n. Implications of tuberculosis reactivation after immune checkpoint inhibition\n. Am J Respir Crit Care Med. \n2018 ;198 (11 ):1451 –3\n.30141960 \n9 \n\nRoss \nJS \n, \nWang \nK \n, \nElkadi \nOR \n, \nTarasen \nA \n, \nFoulke \nL \n, \nSheehan \nCE \n, et al. Next‐generation sequencing reveals frequent consistent genomic alterations in small cell undifferentiated lung cancer\n. J Clin Pathol . 2014 ;67 (9 ):772 –6\n.24978188 \n10 \n\nGeorge \nJ \n, \nLim \nJS \n, \nJang \nSJ \n, \nCun \nY \n, \nOzretić \nL \n, \nKong \nG \n, et al. Comprehensive genomic profiles of small cell lung cancer\n. Nature . 2015 ;524 (7563 ):47 –53\n.26168399 \n11 \n\nWherry \nEJ \n. T cell exhaustion\n. Nat Immunol . 2011 ;12 (6 ):492 –9\n.21739672 \n12 \n\nBarber \nDL \n, \nMayer‐Barber \nKD \n, \nFeng \nCG \n, \nSharpe \nAH \n, \nSher \nA \n. CD4 T cells promote rather than control tuberculosis in the absence of PD‐1‐mediated inhibition\n. J Immunol. \n2011 ;186 (3 ):1598 –607\n.21172867 \n13 \n\nMayer‐Barber \nKD \n, \nBarber \nDL \n. Innate and adaptive cellular immune responses to Mycobacterium tuberculosis infection\n. Cold Spring Harb Perspect Med . 2015 ;5 (12 ):1 –13\n.\n14 \n\nSakai \nS \n, \nKauffman \nKD \n, \nSallin \nMA \n, \nSharpe \nAH \n, \nYoung \nHA \n, \nGanusov \nVV \n, et al. CD4 T cell‐derived IFN‐γ plays a minimal role in control of pulmonary mycobacterium tuberculosis infection and must be actively repressed by PD‐1 to prevent lethal disease\n. PLoS Pathog. \n2016 ;12 (5 ):e1005667.27244558 \n15 \n\nOdorizzi \nPM \n, \nPauken \nKE \n, \nPaley \nMA \n, \nSharpe \nA \n, \nWherry \nEJ \n. Genetic absence of PD‐1 promotes accumulation of terminally differentiated exhausted CD8+ T cells\n. J Exp Med . 2015 ;212 (7 ):1125 –37\n.26034050 \n16 \n\nLázár‐Molnár \nE \n, \nChen \nB \n, \nSweeney \nKA \n, \nWang \nEJ \n, \nLiu \nW \n, \nLin \nJ \n, et al. Programmed death‐1 (PD‐1)‐deficient mice are extraordinarily sensitive to tuberculosis\n. Proc Natl Acad Sci U S A . 2010 ;107 (30 ):13402 –7\n.20624978 \n17 \n\nWinslow \nGM \n, \nCooper \nA \n, \nReiley \nW \n, \nChatterjee \nM \n, \nWoodland \nDL \n. Early T‐cell responses in tuberculosis immunity\n. Immunol Rev . 2008 ;225 :284 –99\n.18837789 \n18 \n\nAhmad \nF \n, \nMani \nJ \n, \nKumar \nP \n, \nHaridas \nS \n, \nUpadhyay \nP \n, \nBhaskar \nS \n. Activation of anti‐tumor immune response and reduction of regulatory T cells with Mycobacterium indicus pranii (MIP) therapy in tumor bearing mice\n. PLoS One . 2011 ;6 (9 ):e25424.21984926 \n19 \n\nKuo \nCH \n, \nLo \nCY \n, \nChung \nFT \n, \nLee \nKY \n, \nLin \nSM \n, \nWang \nCH \n. Concomitant active tuberculosis prolongs survival in non‐small cell lung cancer: a study in a tuberculosis‐endemic country\n. PLoS One. \n2012 ;7 (3 ):e33226.22438899\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1759-7706",
"issue": "12(5)",
"journal": "Thoracic cancer",
"keywords": "PD-L1; immune-checkpoint inhibitors; lung cancer; tuberculosis",
"medline_ta": "Thorac Cancer",
"mesh_terms": "D000328:Adult; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008297:Male; D012074:Remission Induction; D055752:Small Cell Lung Carcinoma; D014376:Tuberculosis",
"nlm_unique_id": "101531441",
"other_id": null,
"pages": "699-702",
"pmc": null,
"pmid": "33458956",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "31318909;30141960;26034050;31525648;20624978;24978188;31484550;26291008;21984926;22438899;27269741;21739672;26187873;18837789;29077690;20016488;27244558;26168399;21172867;33458956",
"title": "Long-term remission of small cell lung cancer after reactivation of tuberculosis following immune-checkpoint blockade: A case report.",
"title_normalized": "long term remission of small cell lung cancer after reactivation of tuberculosis following immune checkpoint blockade a case report"
} | [
{
"companynumb": "DE-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-009440",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "BACKGROUND\nCisplatin is commonly used in hyperthermic intraperitoneal chemotherapy (HIPEC) for the management of peritoneal carcinomatosis. Little is known about the nephrotoxic effects of cisplatin use in HIPEC.\n\n\nOBJECTIVE\nTo report the incidence of nephrotoxicity post-HIPEC using cisplatin 50 mg/m(2) plus doxorubicin 15 mg/m(2). The incidence of hypomagnesemia was investigated as a secondary endpoint.\n\n\nMETHODS\nThis is a retrospective study evaluating patients who received cisplatin with doxorubicin during HIPEC. RIFLE classification was used to assess the development of nephrotoxicity. Variables, such as comorbidities and nephrotoxic medications were obtained. Renal function parameters were also collected, including serum creatinine levels and serum magnesium levels at baseline and at days 3, 7 and 30 after HIPEC. Perioperative urine output (UO) was also recorded.\n\n\nRESULTS\nFifty-three patients were identified. Based on the RIFLE classification, two patients (3.7%) developed acute kidney injury (AKI) following HIPEC with cisplatin. One patient met criteria for renal failure and progressed to chronic renal failure. The other patient had renal injury. Comparable mean creatinine levels were observed at baseline and on day 30 following HIPEC (p > 0.05). The incidence of hypomagnesemia increased to 24.5% by day 7 (p = 0.041) and 30.1% by day 30 (p < 0.001) following HIPEC. Low intraoperative UO, angiotensin II receptor antagonist use and hypertension were associated with development of AKI (p < 0.05).\n\n\nCONCLUSIONS\nNephrotoxicity can complicate HIPEC with cisplatin therapy and that permanent renal dysfunction may rarely occur. More attention to be directed toward monitoring magnesium levels after cisplatin use with HIPEC.",
"affiliations": "Pharmaceutical Care Division, King Faisal Specialist Hospital & Research Centre, College of Pharmacy, King Saud University , Riyadh , Saudi Arabia .",
"authors": "Hakeam|Hakeam A|HA|;Breakiet|Mohammed|M|;Azzam|Ayman|A|;Nadeem|Ashraf|A|;Amin|Tarek|T|",
"chemical_list": "D000970:Antineoplastic Agents; D004317:Doxorubicin; D008274:Magnesium; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.3109/0886022X.2014.949758",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0886-022X",
"issue": "36(10)",
"journal": "Renal failure",
"keywords": "Chemotherapy; HIPEC; RIFLE; cisplatin; nephrotoxicity",
"medline_ta": "Ren Fail",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000970:Antineoplastic Agents; D002945:Cisplatin; D065426:Cytoreduction Surgical Procedures; D004317:Doxorubicin; D005260:Female; D006358:Hot Temperature; D006801:Humans; D007263:Infusions, Parenteral; D007430:Intraoperative Care; D008274:Magnesium; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms; D012189:Retrospective Studies",
"nlm_unique_id": "8701128",
"other_id": null,
"pages": "1486-91",
"pmc": null,
"pmid": "25155314",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The incidence of cisplatin nephrotoxicity post hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery.",
"title_normalized": "the incidence of cisplatin nephrotoxicity post hyperthermic intraperitoneal chemotherapy hipec and cytoreductive surgery"
} | [
{
"companynumb": "SA-MYLANLABS-2015M1015050",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LOSARTAN"
},
"drugadditional": null,
... |
{
"abstract": "Hepatic angiosarcoma is an extremely rare disease entity that accounts for approximately 0.1%-2% of primary liver malignancy. It is three times more common in men than women and usually affects the former in their sixth or seventh decade of life. Risk factors for the development of hepatic angiosarcoma include the use of oral contraceptives, exposure to anabolic steroids, radiation, thorium dioxide, arsenic and vinyl chloride. The prognosis of hepatic angiosarcoma is extremely poor which is attributable to early metastases to other organs, resistance to traditional chemotherapy and radiotherapy regimens and rapid progression of the tumour. Optimal management of patients is poorly demarcated due to the rarity of the tumour. We present a case series of two patients: one who passed away due to acute hepatic failure secondary to hepatic angiosarcoma and the second who underwent a liver transplantation and was subsequently diagnosed with hepatic angiosarcoma based on his explant histology.",
"affiliations": "Liver Transplant Unit, Austin Health, Heidelberg, Victoria, Australia.;Liver Transplant Unit, Austin Health, Heidelberg, Victoria, Australia.;Liver Transplant Unit, Austin Health, Heidelberg, Victoria, Australia.;Liver Transplant Unit, Austin Health, Heidelberg, Victoria, Australia.",
"authors": "Singh|Gurpreet|G|;Mills|Christopher|C|;Asadi|Khashayar|K|;Testro|Adam|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225896",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "cirrhosis; liver disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D017809:Fatal Outcome; D006394:Hemangiosarcoma; D006801:Humans; D061705:Image-Guided Biopsy; D017114:Liver Failure, Acute; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30093472",
"pubdate": "2018-08-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11149588;3623214;19179547;25984668;20537949;29151516;3927870;12122869;26019478;22280556;27718433;18814083;24384851;25815217;18826593;27073495;16521200;27721730;22865805;26144270;24284733;25880743",
"title": "Hepatic angiosarcoma as a cause of acute liver failure.",
"title_normalized": "hepatic angiosarcoma as a cause of acute liver failure"
} | [
{
"companynumb": "AU-ACCORD-072070",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "We investigated the hypothesis that gemtuzumab ozogamicin (GO), an anti-CD33 immunotoxin would improve the efficacy of fludarabine/melphalan as a preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in a phase I/II trial. Toxicity was defined as grades III-IV organ damage, engraftment failure or death within 30 days. 'Response' was engraftment and remission (CR) on day +30. We sought to determine the GO dose (2, 4 or 6 mg m(-2)) giving the best trade-off between toxicity and response. All patients were not candidates for myeloablative regimens. Treatment plan: GO (day -12), fludarabine 30 mg m(-2) (days -5 to -2), melphalan 140 mg m(-2) (day -2) and HSCT (day 0). GVHD prophylaxis was tacrolimus and mini-methotrexate. Diagnoses were AML (n=47), MDS (n=4) or CML (n=1). Median age was 53 years (range, 13-72). All but three patients were not in CR. Donors were related (n=33) or unrelated (n=19). Toxicity and response rates at 4 mg m(-2) were 50% (n=4) and 50% (n=4). GO dose was de-escalated to 2 mg m(-2): 18% had toxicity (n=8) and 82% responded (n=36). 100-day TRM was 15%; one patient had reversible hepatic VOD. Median follow-up was 37 months. Median event-free and overall survival was 6 and 11 months. GO 2 mg m(-2) can be safely added to fludarabine/melphalan, and this regimen merits further evaluation.",
"affiliations": "Department of Stem Cell Transplantation and Cell Therapy, U.T.M.D. Anderson Cancer Center, Houston, TX 77030-4009, USA. mdelima@mdanderson.org",
"authors": "de Lima|M|M|;Champlin|R E|RE|;Thall|P F|PF|;Wang|X|X|;Martin|T G|TG|;Cook|J D|JD|;McCormick|G|G|;Qazilbash|M|M|;Kebriaei|P|P|;Couriel|D|D|;Shpall|E J|EJ|;Khouri|I|I|;Anderlini|P|P|;Hosing|C|C|;Chan|K W|KW|;Andersson|B S|BS|;Patah|P A|PA|;Caldera|Z|Z|;Jabbour|E|E|;Giralt|S|S|",
"chemical_list": "D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3; D000079982:Gemtuzumab; D014740:Vidarabine; C024352:fludarabine; D008558:Melphalan",
"country": "England",
"delete": false,
"doi": "10.1038/sj.leu.2405014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "22(2)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000971:Antineoplastic Combined Chemotherapy Protocols; D018572:Disease-Free Survival; D005260:Female; D000079982:Gemtuzumab; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007951:Leukemia, Myeloid; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D012074:Remission Induction; D063268:Sialic Acid Binding Ig-like Lectin 3; D015996:Survival Rate; D014184:Transplantation, Homologous; D014740:Vidarabine",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "258-64",
"pmc": null,
"pmid": "17989720",
"pubdate": "2008-02",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Phase I/II study of gemtuzumab ozogamicin added to fludarabine, melphalan and allogeneic hematopoietic stem cell transplantation for high-risk CD33 positive myeloid leukemias and myelodysplastic syndrome.",
"title_normalized": "phase i ii study of gemtuzumab ozogamicin added to fludarabine melphalan and allogeneic hematopoietic stem cell transplantation for high risk cd33 positive myeloid leukemias and myelodysplastic syndrome"
} | [
{
"companynumb": "US-PFIZER INC-2018148082",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMTUZUMAB OZOGAMICIN"
},
"drugadditional": "3... |
{
"abstract": "Invasive fungal disease of the head and neck is a potentially fatal infection most commonly seen in immunocompromised patients. Even in the setting of combined surgical and medical treatment, prognosis is generally poor. We report the first pediatric case of invasive fungal pharyngitis and summarize a review of the literature. A 10-year-old female patientwith aplastic anemia status post-bone marrow transplant and accompanying immunosuppression initially presented with a diagnosis of a peritonsillar abscess. Incision and drainage did not show purulence, but culture grew out Rhizopus species. Immediately after diagnosis, the patient was treated successfully with aggressive staged surgical debridement and antifungal medications and had an excellent functional outcome 2 years after initial presentation. Invasive fungal disease is most common in the sinonasal region, but alternative sites of disease must be considered in immunocompromised patients who present with atypical symptoms.",
"affiliations": "ENT and Facial Plastic Surgery, Children's of Minnesota, Minneapolis, MN, USA.;Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati, Cincinnati, OH, USA.;Division of Bone Marrow Transplant and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;Division of Pediatric Infectious Disease, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.",
"authors": "Redmann|Andrew J|AJ|https://orcid.org/0000-0003-4620-2508;Myer|Charles M|CM|;Khandelwal|Pooja|P|https://orcid.org/0000-0002-8627-6408;Danzinger-Isakov|Lara|L|https://orcid.org/0000-0002-5691-5221",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13853",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "25(5)",
"journal": "Pediatric transplantation",
"keywords": "\nRhizopus\n; immunocompromise; invasive fungal disease; surgery",
"medline_ta": "Pediatr Transplant",
"mesh_terms": null,
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13853",
"pmc": null,
"pmid": "33484226",
"pubdate": "2021-08",
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"abstract": "We present a 74-year-old woman who developed a portal vein thrombosis following an elective total knee replacement. She had atrial fibrillation for which she was taking warfarin for anticoagulation. Seven days prior to surgery, she was instructed to discontinue warfarin and replace it with prophylactic low-molecular-weight heparin. On postoperative day 1, routine blood tests revealed deranged hepatic synthetic function, despite standard anticoagulation management. Doppler ultrasonography confirmed a portal vein thrombosis. She was treated with therapeutic doses of low-molecular-weight heparin until her international normalised ratio reached therapeutic levels. Her liver function results had normalised 2 weeks later. Portal vein thrombosis is a potentially fatal complication that is reversible if identified and treated early.",
"affiliations": "Department of Trauma and Orthopaedics, Northwick Park Hospital, Middlesex, Harrow, United Kingdom.",
"authors": "Martin|Guy|G|;Rashid|Abbas|A|;Abdul-Jabar|Hani B|HB|;Jennings|Simon|S|",
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"mesh_terms": "D000368:Aged; D019645:Arthroplasty, Replacement, Knee; D005260:Female; D006801:Humans; D011169:Portal Vein; D020246:Venous Thrombosis",
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"title": "Portal vein thrombosis after total knee replacement: a case report.",
"title_normalized": "portal vein thrombosis after total knee replacement a case report"
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"abstract": "One of the primary targets of immune checkpoint inhibition is the negative immune regulatory molecule CTLA-4. Immune-related adverse events are commonly observed following CTLA-4 inhibition in melanoma treatment, and a spectrum of these conditions are also observed in individuals with germline haploinsufficiency of CTLA4. Here we describe a heterozygous de novo missense variant of CTLA4 in a young girl with childhood-onset autoimmune hepatitis and polyarthritis, the latter responding to treatment with CTLA-4-Ig fusion protein. This variant lay within the highly conserved MYPPPY motif of CTLA-4: a critical structural determinant of ligand binding, which is also bound by the anti-CTLA-4 monoclonal antibody ipilimumab. Within the spectrum of CTLA4 variants reported, missense variants in the MYPPPY motif were overrepresented when compared to variants within a control population, highlighting the physiological importance of this motif in both the genetic and pharmacological regulation of autoimmunity and anti-tumor immunity.",
"affiliations": "Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.;The Children's Hospitals Network, The University of New South Wales, Sydney, NSW, Australia.;The Children's Hospitals Network, The University of New South Wales, Sydney, NSW, Australia.;The Children's Hospitals Network, The University of New South Wales, Sydney, NSW, Australia.;The Children's Hospitals Network, The University of New South Wales, Sydney, NSW, Australia.;The Children's Hospitals Network, The University of New South Wales, Sydney, NSW, Australia.;The Children's Hospitals Network, The University of New South Wales, Sydney, NSW, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.",
"authors": "Siggs|Owen M|OM|;Russell|Amanda|A|;Singh-Grewal|Davinder|D|;Wong|Melanie|M|;Chan|Pearl|P|;Craig|Maria E|ME|;O'Loughlin|Ted|T|;Stormon|Michael|M|;Goodnow|Christopher C|CC|",
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"fulltext": "\n==== Front\nFront ImmunolFront ImmunolFront. Immunol.Frontiers in Immunology1664-3224Frontiers Media S.A. 10.3389/fimmu.2019.01544ImmunologyCase ReportPreponderance of CTLA4 Variation Associated With Autosomal Dominant Immune Dysregulation in the MYPPPY Motif Siggs Owen M. 12*Russell Amanda 1Singh-Grewal Davinder 3Wong Melanie 3Chan Pearl 3Craig Maria E. 3O'Loughlin Ted 3Stormon Michael 3Goodnow Christopher C. 141Garvan Institute of Medical Research, Darlinghurst, NSW, Australia2Department of Ophthalmology, Flinders University, Adelaide, SA, Australia3The Children's Hospitals Network, The University of New South Wales, Sydney, NSW, Australia4St. Vincent's Clinical School, The University of New South Wales, Sydney, NSW, AustraliaEdited by: Huji Xu, Tsinghua University, China\n\nReviewed by: Xiaoyu Hu, Tsinghua University, China; Eirik Bratland, University of Bergen, Norway\n\n*Correspondence: Owen M. Siggs owen.siggs@flinders.edu.auThis article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology\n\n23 7 2019 2019 10 154414 3 2019 20 6 2019 Copyright © 2019 Siggs, Russell, Singh-Grewal, Wong, Chan, Craig, O'Loughlin, Stormon and Goodnow.2019Siggs, Russell, Singh-Grewal, Wong, Chan, Craig, O'Loughlin, Stormon and GoodnowThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.One of the primary targets of immune checkpoint inhibition is the negative immune regulatory molecule CTLA-4. Immune-related adverse events are commonly observed following CTLA-4 inhibition in melanoma treatment, and a spectrum of these conditions are also observed in individuals with germline haploinsufficiency of CTLA4. Here we describe a heterozygous de novo missense variant of CTLA4 in a young girl with childhood-onset autoimmune hepatitis and polyarthritis, the latter responding to treatment with CTLA-4-Ig fusion protein. This variant lay within the highly conserved MYPPPY motif of CTLA-4: a critical structural determinant of ligand binding, which is also bound by the anti-CTLA-4 monoclonal antibody ipilimumab. Within the spectrum of CTLA4 variants reported, missense variants in the MYPPPY motif were overrepresented when compared to variants within a control population, highlighting the physiological importance of this motif in both the genetic and pharmacological regulation of autoimmunity and anti-tumor immunity.\n\nCTLA4ipilimumabCTLA-4de novo variantautoimmune hepatitisabataceptjuvenile rheumatoid arthritis (JRA)National Health and Medical Research Council10.13039/5011000009251108800\n==== Body\nIntroduction\nImmune checkpoint inhibition, exemplified by inhibition of the CTLA-4 or PD-1 pathways, has become a pillar of cancer therapy. Monoclonal antibody-mediated inhibition of CTLA-4 has been shown to have striking anti-tumor effects, first in mice (1), and subsequently in humans (2). CTLA-4 itself is a negative regulator of T cell activation, with insufficiency of CTLA-4 associated with severe T cell-mediated autoimmunity in mice (3, 4), and with autosomal dominant immune dysregulation in humans (5, 6). The broad clinical spectrum of CTLA4 insufficiency has close parallels with the immune-related adverse event profile observed in anti-CTLA-4 therapy (2), namely dermatologic and gastrointestinal (7), but also a significant proportion of carriers (>32%) with no clinical phenotype at all.\n\nDespite the effectiveness of immune checkpoint inhibition in cancer therapy, acquired resistance can occasionally occur as a consequence of somatic mutations in the interferon receptor signaling or antigen presentation pathways (8). Similar processes may be at play in a recently described case of CTLA4 haploinsufficiency associated with melanoma (9).\n\nAs larger numbers of CTLA4 haploinsufficient cases are described, it has become possible to assess the distribution of variants across its distinct structural domains. Here we describe a case of CTLA4 haploinsufficiency associated with a missense variant in the MYPPPY motif of CTLA-4, document their response to CTLA-4-Ig therapy, and present an analysis of the contribution of MYPPPY variants to the prevalence of CTLA4-associated immune dysregulation.\n\nResults\nAs part of an effort to understand the genetic basis of exceptional immunological phenotypes, we ascertained a girl born to non-consanguineous parents with a constellation of immune-related conditions (Figure 1A). She was of European ancestry, with no family history of early-onset autoimmune or inflammatory disease. She was initially diagnosed with autoimmune hepatitis at 20 months of age, with serological studies revealing the presence of low-titer antinuclear autoantibodies (1:80 nucleolar), hypergammaglobulinemia, and IgA deficiency. Rheumatoid factor, anti-smooth muscle autoantibodies, and anti-liver-kidney-microsomal autoantibodies were not detected.\n\nFigure 1 Identification of a de novo heterozygous p.(Tyr139Cys) variant in CTLA4, and response to abatacept treatment. (A) Pedigree and segregation of the CTLA4 p.(Tyr139Cys) variant. (B) Exon structure of the CTLA4 locus (indicating approximate boundaries of topological domains encoded by each exon) and location of the c.416A>G;p.Tyr139Cys) variant in exon 2. (C) Time course of liver enzymes, and inflammatory markers (CRP, ESR) and their response to systemic treatment. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; Pred+AZA, prednisolone and azathioprine. Horizontal broken lines indicate upper limits of normal.\n\nFollowing her initial diagnosis, the patient was treated with a tapering dose of oral prednisolone (from 20 mg per day), but due to steroid dependency azathioprine was introduced (20 mg per day). On this regime her liver enzymes normalized. However, 18 months later (aged 3 years, 2 months) she presented with polyarticular arthritis affecting large and small joints of the upper and lower limbs including the knees, ankles, elbows, and multiple small hand joints. This was initially treated with intra-articular steroid injections and subsequently a switch from azathioprine to mycophenolate with a good response. A flare of arthritis in a similar articular distribution occurred 6 months later (aged 3 years, 8 months), leading to repeated intra-articular injections and consideration of introduction of a biological agent to replace mycophenolate. Methotrexate was not used due to her underlying liver disease. As an alternative, subcutaneous adalimumab injections (20 mg every 2 weeks) were commenced 6 months later (aged 4 years, 4 months), and were partially effective, yet she continued to exhibit ongoing small joint disease of the metatarsophalangeal and metacarpophalangeal joints with stiffness and pain.\n\nGenomic DNA samples isolated from peripheral blood from the patient and her parents were subjected to short-read genome sequencing. Variants were filtered by depth (≥ 10 reads), quality (QUAL ≥ 200), allele frequency (≤ 0.001 across 1000 Genomes, ExAC 0.2, and ESP populations), and medium or high impact (based on Ensembl classification categorization). When restricted to the canonical transcripts of 307 genes associated with inborn errors of immunity (10), with a Phred-scaled CADD score threshold of ≥ 15, only two variants were identified: the first a heterozygous missense variant in a gene associated with autosomal recessive kappa chain deficiency and also present in the unaffected father [IGKC, ENST00000390237.2:c.193C>A, ENSP00000374777.2:p. (Thr65Asn)], and the second a heterozygous variant in CTLA4 [ENST00000302823.3:c.416A>G, ENSP00000303939.3:p.(Tyr139Cys)] (Figures 1B,C). This variant was absent from both biological parents, from the gnomAD r2.0.2 variant collection, and from a collection of 500 genomes sequenced contemporaneously at the same facility. The variant was predicted to be damaging by the PolyPhen-2 and SIFT algorithms, with a Phred-scaled CADD score of 24.1. Tyr139 itself lies within the highly conserved MYPPPY motif, and has previously been shown by site-directed alanine mutagenesis to be the most critical residue in this motif for binding of CTLA-4 and CD28 to their common ligands, CD80 and CD86 (11, 12). It has also recently been described in a kindred with incompletely penetrant splenomegaly, lymphadenopathy, hypogammaglobulinemia, and hypothyroidism (13).\n\nBased on her genetic diagnosis, treatment of the patient's refractory juvenile rheumatoid arthritis (JRA) was switched from anti-TNF therapy (adalimumab) to CTLA-4-Ig (abatacept) therapy at age 4 years, 10 months. Initially started at 160 mg per month, her abatacept dosing was increased to 240 mg per month at age 5 years, 2 months. This regime initially gave a good response, yet was typically followed by breakthrough arthritis 2 weeks after each infusion. Since increasing her dosing regimen to 240 mg every 2 weeks (at age 5 years 4 months), she had sustained remission of her joint disease for more than 12 months.\n\nIn order to assess the relative contribution of variants to the prevalence of CTLA4-associated immune dysregulation, we assembled a collection of CTLA4 variants from published reports (5–7, 13–15), from additional pathogenic and likely pathogenic variants deposited in ClinVar, and the de novo CTLA4 variant described in this report.\n\nA total of 65 variants in unrelated families were identified (including the case described here), 26 of which (40%) were loss-of-function variants (defined as essential splice, frameshift, or stop gain variants), and 39 of which (60%) were missense variants (Figure 2A). Despite representing only 2.7% of the total protein sequence length (6/223 residues), variants in the MYPPPY motif represented 30.8% (12/39) of the disease-associated missense variant pool, including five independent missense variants at Pro136, four at Pro137, one at Pro138, and two at Tyr139 including the variant described here. A six-amino acid sliding window revealed a left-shifted peak incidence of disease-associated missense variants at codons 134–136 (Figure 2B). When compared with CTLA4 missense variants within gnomAD controls (n = 82), missense variants in the MYPPPY motif were significantly more likely to be disease-associated than missense variants elsewhere in the CTLA4 gene (Fisher's exact test, P = 3.342 × 10−7). The MYPPPY motif, including Tyr139, is highly conserved across both CTLA-4 and its immune stimulatory paralog CD28 (Figure 2C), and interfaces directly with both CD80 and with the CTLA-4 inhibitor ipilimumab (Figures 3A,B). A second enrichment of variants was noted at the Arg75 residue, where five independent missense variants were observed (5/39, 12.8%). Arg75 itself promotes the structural integrity of CTLA-4 by forming a critical salt bridge with Asp123 [Figures 3A,B; (16)].\n\nFigure 2 Preponderance of disease-associated variants in within the MYPPPY motif of CTLA-4. (A) Location of disease-associated CTLA4 missense variants, demonstrating enrichment at Arg75, and the MYPPPY motif. Topological domains of the CTLA-4 protein are indicated in color below. (B) Mean incidence of disease-associated (affected) or control (gnomAD) missense variants across the CTLA4 coding sequence using a 6-amino acid left-shifted sliding window. (C) Multi-species sequence conservation at Arg75 and the MYPPPY motif across CTLA-4 and its paralog, CD28.\n\nFigure 3 Structural significance of Arg75 and MYPPPY residues within CTLA-4. (A) Location of Arg75 and MYPPPY residues relative to the ligand-binding surface of CTLA-4 [PDB: 18IL (18)]. (B) Location of Arg75 and MYPPPY residues relative to the ipilimumab-binding surface of CTLA-4 [PDB: 5TRU (16)].\n\nDiscussion\nWe describe a single case of childhood-onset autoimmune hepatitis and polyarthritis associated with a de novo CTLA4 variant. The de novo CTLA4 variant described here occurs within the highly conserved MYPPPY motif, which contributes ~80% of the interfacial contacts with CD80 and CD86 ligands (17, 18). Binding of CTLA-4 to the anti-CTLA-4 monoclonal antibody ipilimumab results in the direct steric occlusion of this ligand binding surface, including the MYPPPY motif (16). The MYPPPY motif contributes ~60% of the total buried surface area provided by CTLA-4 in the CTLA-4:ipilimumab interaction, with Tyr139 being the dominant contributor within it (16). A second critical structural interface is the Arg75-Asp123 salt bridge, which when mutated results in loss of ipilimumab binding (16). A structural survey of missense variant distribution revealed that almost half of all disease-associated CTLA4 missense variants (17/39, 43.6%) disrupted either the MYPPPY motif, or the Arg75-Asp123 salt bridge. This structural convergence emphasizes the importance of these two domains in both the genetic and pharmacological modulation of CTLA-4 function.\n\nThe same CTLA4 variant as the one described here [c.416A>G;p.(Tyr139Cys)] has also been described in a second individual diagnosed with common variable immunodeficiency (13). This clinical presentation included splenomegaly, lymphadenopathy, hypogammaglobulinemia, and hypothyroidism, yet no evidence of hepatitis or polyarthritis. The CTLA4 variant was inherited from the patient's unaffected father, with incomplete penetrance attributed to a maternally inherited JAK3 variant present in the proband, identified through a search of 25 candidate genes. Although we could not exclude oligogenic inheritance in the case described here, the most parsimonious explanation is that a second rare variant was not required for disease. We did not perform any direct functional assessments, although previous experimental validation of the p.(Tyr139Cys) variant indicated reduced expression, an inability to bind CD80 or CD86, and absent suppressor activity in a T cell proliferation assay (13), consistent with earlier site-directed alanine mutagenesis experiments at the same codon (11, 12).\n\nThe p.(Tyr139Cys) variant exemplifies the poorly understood phenomena of incomplete penetrance and variable expressivity, which is commonly encountered in CTLA4-associated disease (7). Phenotypic manifestations of the same variant can range from hepatitis and polyarthritis in one individual, to common variable immunodeficiency in a second, or a complete absence of clinical signs and symptoms in a third. Liver involvement and arthritis are relatively rare clinical manifestations of CTLA4-associated immune dysregulation, respectively occurring in 12 and 14% of a series of 90 cases (7). CTLA4 genotype does not appear to be important in this sense, with no observed association with disease phenotype, age of onset, or penetrance (7). We can only speculate as to the cause, although differences in genetic ancestry, either in the form of one or more common or rare genetic variants, may go some way toward explaining these differences, with environmental exposures sharing culpability. Beyond a single heterozygous variant of uncertain significance in IGKC, we did not identify any other rare predicted damaging variants in genes associated with Mendelian errors of immunity.\n\nThe present case also illustrates several important aspects of “precision medicine.” Genome sequencing provided a clear diagnosis for a previously idiopathic case, but more importantly revealed the pathogenesis: a single-gene defect leading to partial deficiency of an essential inhibitory immune receptor, CTLA-4. This result connected immediately to a strong laboratory and clinical evidence base that the patient would likely respond to targeted CTLA-4-Ig therapy: an agent that normally would not have been considered as first, second or third-line therapy in this case. In the patient's country of residence (Australia), the federal pharmaceutical benefits scheme normally requires JRA to be treated with methotrexate as first line, followed by anti-TNF or anti-IL-6R biological disease-modifying antirheumatic drugs, each requiring a 20-week therapeutic test period. Abatacept was not approved for JRA due to the low response rate in cases that had already responded poorly to anti-TNF therapy. Currently, there are no established mechanisms for government-subsidized treatment with abatacept in cases where a genetic diagnosis indicates it is the targeted treatment of choice.\n\nMaterials and Methods\nHuman Subjects\nThis study was carried out in accordance with the recommendations of the National Health and Medical Research Council's National Statement on Ethical Conduct in Human Research (M), with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the South Eastern Sydney Local Health District Human Research Ethics Committee.\n\nGenome Sequencing\nParent-proband trio genomes were sequenced on the Illumina HiSeq X platform using DNA isolated from whole blood (19). Libraries were generated using the Illumina TruSeq PCR-free protocol. Raw reads were aligned to the hs37d5 reference using BWA-MEM v0.7.10-r789, and sorted and duplicate-marked with Novosort v1.03.01 (Novocraft Technologies). The GATK suite v3.3-0-g37228af was used for local indel realignment and base quality score recalibration. gVCFs generated with GATK HaplotypeCaller were joint-called as trios using GATK GenotypeGVCFs, and variants recalibrated using GATK Variant Quality Score Recalibrator (VQSR). VCF files were annotated with Variant Effect Predictor (VEP) v76 using the LoFTEE and dbNSFP plugins (including CADD v1.3), and assembled into GEMINI databases (v0.18.3).\n\nCTLA4 Variant Collection\nCTLA4 variants were collected from a series of published reports (5–7, 13–15), and from pathogenic and likely pathogenic variants listed on ClinVar (accessed October 3, 2018). Large deletion or duplication alleles were not included. Structural representations were generated from previously described structures [Protein Data Bank accession IDs: 18IL (18), and 5TRU (16)] using UCSF Chimera (20) and Adobe Illustrator.\n\nData Availability\nThe variant described here has been deposited in ClinVar (accession number: SCV000891105).\n\nEthics Statement\nThis study was carried out in accordance with the recommendations of the National Health and Medical Research Council's National Statement on Ethical Conduct in Human Research (2007), with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the South Eastern Sydney Local Health District Human Research Ethics Committee.\n\nAuthor Contributions\nOS performed sequence and structure analysis, and wrote the paper with input from all authors. AR coordinated genome sequencing. DS-G, MW, PC, MC, TO'L, and MS coordinated patient recruitment and were responsible for clinical care. CG obtained funding and supervised research.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nWe thank Dr. Gulbu Uzel (National Institutes of Health) for her clinical guidance, the patient and her family for their participation, The Clinical Immunogenomics Research Consortium Australia (CIRCA) for making this study possible, and the staff of the Kinghorn Center for Clinical Genomics for genome sequencing. Supported by the National Health and Medical Research Council (Project Grant 1108800) and the Bill and Patricia Ritchie Foundation.\n==== Refs\nReferences\n1. Leach DR Krummel MF Allison JP . Enhancement of antitumor immunity by CTLA-4 blockade . Science. (1996 ) 271 :1734 –6 . 10.1126/science.271.5256.1734 8596936 \n2. Hodi FS O'Day SJ McDermott DF Weber RW Sosman JA Haanen JB . 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Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations . Nat Med. (2014 ) 20 :1410 –6 . 10.1038/nm.3746 25329329 \n7. Schwab C Gabrysch A Olbrich P Patiño V Warnatz K Wolff D . Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects . J Allergy Clin Immunol. (2018 ) 142 :1932 –46 . 10.1016/j.jaci.2018.02.055 29729943 \n8. Zaretsky JM Garcia-Diaz A Shin DS Escuin-Ordinas H Hugo W Hu-Lieskovan S . Mutations associated with acquired resistance to PD-1 blockade in melanoma . N Engl J Med. (2016 ) 375 :819 –29 . 10.1056/NEJMoa1604958 27433843 \n9. Egg D Schwab C Gabrysch A Arkwright PD Cheesman E Giulino-Roth L . Increased risk for malignancies in 131 affected mutation carriers . Front Immunol. (2018 ) 9 :2012 . 10.3389/fimmu.2018.02012 30250467 \n10. Picard C Bobby Gaspar H Al-Herz W Bousfiha A Casanova J-L Chatila T . 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"journal": "Frontiers in immunology",
"keywords": "CTLA-4; CTLA4; abatacept; autoimmune hepatitis; de novo variant; ipilimumab; juvenile rheumatoid arthritis (JRA)",
"medline_ta": "Front Immunol",
"mesh_terms": "D000069594:Abatacept; D020816:Amino Acid Motifs; D018501:Antirheumatic Agents; D001171:Arthritis, Juvenile; D060908:CTLA-4 Antigen; D002675:Child, Preschool; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D020125:Mutation, Missense",
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"title": "Preponderance of CTLA4 Variation Associated With Autosomal Dominant Immune Dysregulation in the MYPPPY Motif.",
"title_normalized": "preponderance of ctla4 variation associated with autosomal dominant immune dysregulation in the mypppy motif"
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... |
{
"abstract": "OBJECTIVE\nInter-individual thiopurine metabolism variability can influence treatment outcomes in inflammatory bowel disease (IBD) patients. Genetic polymorphisms in thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) were linked with toxicity of azathioprine (AZA). The aim of the study was to investigate frequencies of TPMT and ITPA polymorphisms in Lithuanian IBD patients and analyze their association with AZA-related adverse events.\n\n\nMETHODS\nPolymorphisms in TPMT (TPMT*2,*3B,*3C,*3A) and ITPA (rs1127354, rs7270101) genes were determined using PCR-RFLP and TaqMan(®) genotyping assays. 551 consecutive Lithuanian IBD patients were genotyped. The use of AZA and its side effects were assessed retrospectively according to hospital medical records.\n\n\nRESULTS\nFrequencies of TPMT*3A, TPMT*3B and TPMT*3C alleles were 3.1%, 0.5% and 0.1%, respectively. TPMT*2 genetic variant was not detected in the study group. The distribution of minor alleles for ITPA rs1127354 and rs7270101 polymorphisms was 9.9% and 10.5%, respectively. AZA was prescribed in 82 patients and it provoked myelotoxicity in 11%, hepatotoxicity in 6.1%, dyspepsia in 6.1%, and pancreatitis in 3.6% of cases. Among patients who had AZA-related myelotoxicity, 11.1% were TPMT compound heterozygous, 44.4% had heterozygous genotype (P<0.01). Frequencies of ITPA minor alleles were similar among the patients with and without AZA-related side effects.\n\n\nCONCLUSIONS\nFrequencies of TPMT and ITPA variant alleles in Lithuanian IBD group were similar to those observed in the Northern-Eastern Europe Caucasian populations. Polymorphisms in TPMT might be associated with myelotoxicity and leukopenia in AZA treated patients, while ITPA variant alleles appear not to be linked with treatment-related side effects.",
"affiliations": "Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.;Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania; Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.;Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.;Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.;Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania; Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.;Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania; Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.;Clinic of Gastroenterology, Nephrourology and Surgery, Medical Faculty of Vilnius University, Vilnius University, Vilnius, Lithuania.;Clinic of Gastroenterology, Nephrourology and Surgery, Medical Faculty of Vilnius University, Vilnius University, Vilnius, Lithuania.;Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.;Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania; Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. Electronic address: l.kupcinskas@gmail.com.",
"authors": "Steponaitiene|Ruta|R|;Kupcinskas|Juozas|J|;Survilaite|Santa|S|;Varkalaite|Greta|G|;Jonaitis|Laimas|L|;Kiudelis|Gediminas|G|;Denapiene|Goda|G|;Valantinas|Jonas|J|;Skieceviciene|Jurgita|J|;Kupcinskas|Limas|L|",
"chemical_list": "D008780:Methyltransferases; C022745:thiopurine methyltransferase; D011755:Pyrophosphatases; C511829:ITPA protein, human; D001379:Azathioprine",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1896-1126",
"issue": "61(1)",
"journal": "Advances in medical sciences",
"keywords": "Azathioprine; IBD; ITPA; Polymorphism; TPMT",
"medline_ta": "Adv Med Sci",
"mesh_terms": "D000328:Adult; D001379:Azathioprine; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D015212:Inflammatory Bowel Diseases; D008097:Lithuania; D008297:Male; D008780:Methyltransferases; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011755:Pyrophosphatases",
"nlm_unique_id": "101276222",
"other_id": null,
"pages": "135-40",
"pmc": null,
"pmid": "26674571",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "TPMT and ITPA genetic variants in Lithuanian inflammatory bowel disease patients: Prevalence and azathioprine-related side effects.",
"title_normalized": "tpmt and itpa genetic variants in lithuanian inflammatory bowel disease patients prevalence and azathioprine related side effects"
} | [
{
"companynumb": "LT-ALKEM LABORATORIES LIMITED-LT-ALKEM-2022-01228",
"fulfillexpeditecriteria": "1",
"occurcountry": "LT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"dru... |
{
"abstract": "Beta-thalassemia major is a subtype component of hemoglobinopathies; autosomal recessive disorders complicated with anemia that affect at least 50,000 babies each year. It contributes to problems in reproductive entities such as infertility due to iron deposition in the endocrine organs, which leads to malfunction of the hypothalamus-pituitary axis. Due to this, there have been very few pregnancies discovered and reported with this type of condition as they usually required an ovulation-induction agent with assisted reproductive technique to achieved pregnancy. We report a successful spontaneous pregnancy in a woman with beta-thalassemia major who underwent splenectomy with lifelong transfusion-dependence complicated with myocardial siderosis and osteoporosis. The close monitoring and regular blood transfusion are a core of successful support to this type of pregnancy. The unintentional consumption of Fosamax, hydroxyurea and deferiprone (Ferriprox) up till 20 weeks of gestation did not show any adverse effects on fetal well-being. As expected, this pregnancy ended with the preterm delivery via cesarean section due to intrauterine growth restriction with oligohydramnios, and currently, this child is thriving. We concluded that pregnancy is not a contraindication in beta-thalassemia major; complex individual care is needed to achieve a safe outcome for the mother.",
"affiliations": "Obstetrics and Gynecology, National University of Malaysia (UKM), UKMMC, Jalan Yacob Latiff, 56000 Cheras, Kuala Lumpur, Malaysia, Phone: +60122152401.;Obstetrics and Gynecology, National University of Malaysia (UKM), UKMMC, Jalan Yacob Latiff, Kuala Lumpur, Malaysia.;Obstetrics and Gynecology, National University of Malaysia (UKM), UKMMC, Jalan Yacob Latiff, Kuala Lumpur, Malaysia.;Obstetrics and Gynecology, National University of Malaysia (UKM), UKMMC, Jalan Yacob Latiff, Kuala Lumpur, Malaysia.;Obstetrics and Gynecology, National University of Malaysia (UKM), UKMMC, Jalan Yacob Latiff, Kuala Lumpur, Malaysia.;Obstetrics and Gynecology, National University of Malaysia (UKM), UKMMC, Jalan Yacob Latiff, Kuala Lumpur, Malaysia.;Obstetrics and Gynecology, National University of Malaysia (UKM), UKMMC, Jalan Yacob Latiff, Kuala Lumpur, Malaysia.",
"authors": "Ahmad|Mohd Faizal|MF|;Zakaria|Nur Zawani|NZ|;Arsad|Noorazizah|N|;Chew|Kah Teik|KT|;Abu|Muhammad Azrai|MA|https://orcid.org/0000-0002-0383-572X;Shafiee|Mohd Nasir|MN|;Omar|Mohd Hashim|MH|",
"chemical_list": "D007502:Iron Chelating Agents; D055544:beta-Globins; D000077543:Deferiprone",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1868-1883",
"issue": "39(2)",
"journal": "Hormone molecular biology and clinical investigation",
"keywords": "beta-thalassemia major; hemoglobinopathies; pregnancy; preterm delivery",
"medline_ta": "Horm Mol Biol Clin Investig",
"mesh_terms": "D001803:Blood Transfusion; D009202:Cardiomyopathies; D000077543:Deferiprone; D005260:Female; D006720:Homozygote; D006801:Humans; D007502:Iron Chelating Agents; D010024:Osteoporosis; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012806:Siderosis; D013156:Splenectomy; D055815:Young Adult; D055544:beta-Globins; D017086:beta-Thalassemia",
"nlm_unique_id": "101538885",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31301670",
"pubdate": "2019-07-13",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A case of post-splenectomy transfusion-dependent homozygous beta-thalassemia major complicated with myocardial siderosis and osteoporosis and usage of iron-chelating therapy with deferiprone in pregnancy.",
"title_normalized": "a case of post splenectomy transfusion dependent homozygous beta thalassemia major complicated with myocardial siderosis and osteoporosis and usage of iron chelating therapy with deferiprone in pregnancy"
} | [
{
"companynumb": "MY-VALIDUS PHARMACEUTICALS LLC-MY-2020VAL000199",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEFEROXAMINE MESYLATE"
},
... |
{
"abstract": "Purpose: To describe tuberculous uveitis (TU) presenting as a bullous retinal detachment (RD) and to perform a comprehensive literature review on TU with similar features. Methods: Observational case report and systematic literature review. Results: An 84-year-old woman presented with bilateral granulomatous uveitis and bullous RD in the left eye. The interferon gamma release assay was strongly positive, but all other tests were unremarkable. The patient was diagnosed with TU and started on anti-tubercular therapy (ATT) and systemic steroids with excellent treatment response. Twenty-six articles (32 cases) reported TU with exudative RD. Choroidal tuberculoma was the most common clinical manifestation, followed by optic disc edema and retinal exudate. Systemic steroids with ATT improved vision in more patients (78.6%) than ATT alone (50.0%) or oral steroids followed by ATT (50.0%). Conclusion: Atypical presentations of TU make diagnosis and treatment difficult. A high level of suspicion for TU is needed to minimize ocular morbidity.",
"affiliations": "Department of Ophthalmology, Ajou University School of Medicine , Suwon , South Korea.;Department of Ophthalmology, Northwestern University, Feinberg School of Medicine , Chicago , Illinois , USA.;Department of Ophthalmology, Northwestern University, Feinberg School of Medicine , Chicago , Illinois , USA.",
"authors": "Song|Ji Hun|JH|;Koreishi|Anjum F|AF|;Goldstein|Debra A|DA|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2018.1485958",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": "27(6)",
"journal": "Ocular immunology and inflammation",
"keywords": "Anti-tubercular therapy; choroiditis; ocular tuberculosis; retinal detachment; tuberculosis; uveitis",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000369:Aged, 80 and over; D000995:Antitubercular Agents; D005260:Female; D005451:Fluorescein Angiography; D006099:Granuloma; D006801:Humans; D059425:Interferon-gamma Release Tests; D009169:Mycobacterium tuberculosis; D012163:Retinal Detachment; D014392:Tuberculosis, Ocular; D014605:Uveitis",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "998-1009",
"pmc": null,
"pmid": "29969330",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Tuberculous Uveitis Presenting with a Bullous Exudative Retinal Detachment: A Case Report and Systematic Literature Review.",
"title_normalized": "tuberculous uveitis presenting with a bullous exudative retinal detachment a case report and systematic literature review"
} | [
{
"companynumb": "KR-SA-2019SA254777",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Subcutaneous (SC) administration of ertapenem in outpatient parenteral antimicrobial therapy (OPAT) services may be a practical alternative to intravenous delivery for complicated infections. The clinical features and outcomes according to route of administration were compared from a large Australian OPAT service. Chronic renal impairment was more common in the SC group, reflecting an opportunity for route of administration as a vein preservation strategy. Adverse events were uncommon and successful outcomes were not different between the groups.",
"affiliations": "Multidisciplinary Diabetic Foot Ulcer Service, Fiona Stanley Hospital, Perth, Western Australia, Australia.;Department of Infectious Diseases, Fiona Stanley Hospital, Perth, Western Australia, Australia.;Multidisciplinary Diabetic Foot Ulcer Service, Fiona Stanley Hospital, Perth, Western Australia, Australia.;Department of Infectious Diseases, Fiona Stanley Hospital, Perth, Western Australia, Australia.;Multidisciplinary Diabetic Foot Ulcer Service, Fiona Stanley Hospital, Perth, Western Australia, Australia.;Multidisciplinary Diabetic Foot Ulcer Service, Fiona Stanley Hospital, Perth, Western Australia, Australia.",
"authors": "Hiew|Jonathan|J|https://orcid.org/0000-0002-8109-0778;Whitmore|Timothy|T|;McEvoy|Mahalia|M|;Weatherall|Deborah|D|;Ingram|Paul R|PR|https://orcid.org/0000-0001-7733-7072;Manning|Laurens|L|https://orcid.org/0000-0003-4334-5351",
"chemical_list": "D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D000077727:Ertapenem",
"country": "Australia",
"delete": false,
"doi": "10.1111/imj.15511",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1444-0903",
"issue": "51(10)",
"journal": "Internal medicine journal",
"keywords": "ertapenem; outpatient parenteral antimicrobial therapy; subcutaneous",
"medline_ta": "Intern Med J",
"mesh_terms": "D000553:Ambulatory Care; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D001315:Australia; D000077727:Ertapenem; D006801:Humans; D007263:Infusions, Parenteral; D010045:Outpatients; D012189:Retrospective Studies",
"nlm_unique_id": "101092952",
"other_id": null,
"pages": "1717-1721",
"pmc": null,
"pmid": "34664365",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Subcutaneous ertapenem delivered by an Australian outpatient parenteral antimicrobial therapy service: a retrospective comparative efficacy study.",
"title_normalized": "subcutaneous ertapenem delivered by an australian outpatient parenteral antimicrobial therapy service a retrospective comparative efficacy study"
} | [
{
"companynumb": "AU-009507513-2110AUS008931",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ERTAPENEM SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "We have reviewed the histopathological features of 11 patients with pustular drug eruptions. Two main histological patterns were seen. Eight cases revealed features of toxic pustuloderma with the presence of spongiform intraepidermal pustules in association with papillary oedema and a mixed inflammatory cell infiltrate around upper dermal blood vessels. Pustules were present at different levels within the epidermis. The other three cases exhibited leucocytoclastic vasculitis with neutrophil collections both below and within the epidermis. One case showed continuity between the subepidermal and intra-epidermal pustules. These findings suggest a dynamic process in which neutrophils collect around upper dermal blood vessels and are then eliminated via the overyling epidermis. The presence of extravasated red blood cells within the intra-epidermal pustules indicates that this process is passive rather than the result of specific chemotaxis or cell migration.",
"affiliations": "Department of Dermatology, Ealing Hospital NHS Trust, Middlesex, UK.",
"authors": "Burrows|N P|NP|;Russell Jones|R R|RR|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-2559.1993.tb00178.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0309-0167",
"issue": "22(6)",
"journal": "Histopathology",
"keywords": null,
"medline_ta": "Histopathology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D012872:Skin Diseases, Vesiculobullous; D014657:Vasculitis",
"nlm_unique_id": "7704136",
"other_id": null,
"pages": "569-73",
"pmc": null,
"pmid": "8354488",
"pubdate": "1993-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pustular drug eruptions: a histopathological spectrum.",
"title_normalized": "pustular drug eruptions a histopathological spectrum"
} | [
{
"companynumb": "GB-PFIZER INC-2019273593",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": "3",
... |
{
"abstract": "This review will summarize the most recent and pertinent evidence regarding immune checkpoint inhibitor (ICI)-induced hypophysitis to describe diagnostic and management algorithm with the help of a case report.\n\n\n\nHypophysitis is the most common endocrine adverse event from CTLA-4 inhibitors and much less with PD-1/PD-L1 inhibitors. Its pathophysiology appears to be lymphocytic, predominantly affecting the anterior pituitary. The utility of high-dose glucocorticoids for treatment has been questioned, as they do not influence recovery of hypopituitarism and may reduce survival. A survival benefit with hypophysitis has been suggested.\n\n\n\nThe nonspecific nature of symptoms underlies the importance of clinical and hormonal monitoring especially in the first 6 months of CTLA-4 inhibitor cancer therapy. Adrenal insufficiency can be a diagnostic and management challenge, which persists in most cases; hence, a multidisciplinary team of oncologists and endocrinologists is essential for providing high-quality care to these patients. High-dose glucocorticoids should be reserved for mass effect or optic chiasm impingement. The ICI may need to be temporarily withheld but not discontinued. A survival advantage in cancer patients that develop ICI-induced hypophysitis may be a silver lining, especially as ICIs are being investigated for advanced endocrine malignancies.",
"affiliations": "Division of Diabetes, Endocrinology and Metabolism, University of Nebraska Medical Center, Omaha, Nebraska, USA.",
"authors": "Kotwal|Anupam|A|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1097/MED.0000000000000652",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1752-296X",
"issue": "28(4)",
"journal": "Current opinion in endocrinology, diabetes, and obesity",
"keywords": null,
"medline_ta": "Curr Opin Endocrinol Diabetes Obes",
"mesh_terms": "D000309:Adrenal Insufficiency; D006801:Humans; D000072659:Hypophysitis; D007018:Hypopituitarism; D000082082:Immune Checkpoint Inhibitors; D009369:Neoplasms; D010902:Pituitary Gland",
"nlm_unique_id": "101308636",
"other_id": null,
"pages": "427-434",
"pmc": null,
"pmid": "34183541",
"pubdate": "2021-08-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hypophysitis from immune checkpoint inhibitors: challenges in diagnosis and management.",
"title_normalized": "hypophysitis from immune checkpoint inhibitors challenges in diagnosis and management"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-073569",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "BACKGROUND Radial artery access during coronary angiography has gained popularity as there are fewer associated complications when compared with femoral artery access. However sporadic complications can occur following radial artery catheterization. A rare case of axillary, chest wall and abdominal hematoma is presented following radial artery catheterization. CASE REPORT A 58-year-old man with hypertension, type 2 diabetes, with a history of smoking, underwent elective coronary artery angiography via the right radial artery route. He was discharged from care without event, before returning 24 hours later with a large hematoma of the right axilla, extending to the anterior chest wall and abdomen. One year previously, he underwent coronary artery angiography with catheterization of the femoral artery, which was without complications. On this occasion, after resolution of the hematoma, he underwent coronary artery bypass graft (CABG) surgery. CONCLUSIONS This case has reported a rare complication of radial artery catheterization that involved extensive hematoma involving the chest, abdominal wall, and axilla. Although such complications may be rare, a high level of vigilance should be maintained for rare complications in patients undergoing radial artery catheterization.",
"affiliations": "Department of Internal Medicine, Jackson Memorial Hospital/University of Miami, Miami, FL, USA.;Department of Cardio-Thoracic Surgery, Advanced Cardiovascular Institute Surgical Therapies, Port of Spain, Trinidad and Tobago.;Department of Interventional Cardiology, Advanced Cardiovascular Institute, Port of Spain, Trinidad and Tobago.",
"authors": "Grant|Jelani K|JK|;Rawlins|Randolph|R|;Henry|Ronald E|RE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.909091",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3051483010.12659/AJCR.909091909091ArticlesAxillary, Chest Wall and Abdominal Hematoma as a Rare Complication of Radial Artery Catheterization Grant Jelani K. EF1Rawlins Randolph BDE2Henry Ronald E. DE3\n1 Department of Internal Medicine, Jackson Memorial Hospital/University of Miami, Miami, FL, U.S.A.\n2 Department of Cardio-Thoracic Surgery, Advanced Cardiovascular Institute Surgical Therapies, Port of Spain, Trinidad and Tobago\n3 Department of Interventional Cardiology, Advanced Cardiovascular Institute, Port of Spain, Trinidad and TobagoAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Jelani K. Grant, e-mail: jelani_grant@live.com2018 05 12 2018 19 1441 1444 21 1 2018 17 7 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 58\n\nFinal Diagnosis: Axillary • chest and abdominal wall hematoma\n\nSymptoms: Discolored/bruised chest and abdominal wall\n\nMedication: —\n\nClinical Procedure: Coronary angiogram via trans radial route\n\nSpecialty: Cardiology\n\nObjective:\nDiagnostic/therapeutic accidents\n\nBackground:\nRadial artery access during coronary angiography has gained popularity as there are fewer associated complications when compared with femoral artery access. However sporadic complications can occur following radial artery catheterization. A rare case of axillary, chest wall and abdominal hematoma is presented following radial artery catheterization.\n\nCase Report:\nA 58-year-old man with hypertension, type 2 diabetes, with a history of smoking, underwent elective coronary artery angiography via the right radial artery route. He was discharged from care without event, before returning 24 hours later with a large hematoma of the right axilla, extending to the anterior chest wall and abdomen. One year previously, he underwent coronary artery angiography with catheterization of the femoral artery, which was without complications. On this occasion, after resolution of the hematoma, he underwent coronary artery bypass graft (CABG) surgery.\n\nConclusions:\nThis case has reported a rare complication of radial artery catheterization that involved extensive hematoma involving the chest, abdominal wall, and axilla. Although such complications may be rare, a high level of vigilance should be maintained for rare complications in patients undergoing radial artery catheterization.\n\nMeSH Keywords:\nCardiac CatheterizationCoronary AngiographyHematomaRadial Artery\n==== Body\nBackground\nRadial artery access during coronary angiography has gained popularity as there are fewer associated complications when compared with femoral artery access, and there is early mobilization following femoral artery catheterization, but sporadic complications do occur [1]. Femoral artery catheterization is recognized to be associated with significant bleeding, myocardial infarction, and stroke, which can be fatal. This report is of a case of a 58-year-old patient with a large hematoma of the axilla, extending to the chest and abdominal wall following radial artery catheterization. To our knowledge, this is the first reported case of these complications.\n\nCase Report\nA 58-year-old Trinidadian man of East Indian descent, presented for an elective repeat left heart catheterization with coronary angiography in preparation for coronary artery bypass graft (CABG) surgery. One year previously, he underwent coronary artery angiography with catheterization of the femoral artery, which was without complications. His medical history included hypertension, type 2 diabetes mellitus, and a previous smoking history of 20 pack-years.\n\nHis symptoms at presentation included angina at rest, associated with shortness of breath.\n\nOn hospital admission, his medications included aspirin 81 mg once daily, which was stopped five days before the procedure, sublingual glyceryl trinitrate (GTN) tablets as needed, which he used each day, perindopril 4.0 mg and indapamide 1.25mg once daily, trimetazidine dihydrochloride 35 mg twice daily, simvastatin 40 mg at night, atenolol 25 mg once daily, gliclazide 80 mg once daily, and insulin glargine 10 units at night. He was known to be allergic to clopidogrel. His usual aspirin treatment had been stopped, as the usual clinical policy, to reduce the risk of bleeding before CABG surgery, which had been planned to follow coronary angiography.\n\nOn physical examination, his blood pressure was 158/76 mmHg with a pulse of 78 beats per minute and oxygen saturation of 100% on room air. His first and second heart sounds were normal with no murmurs or additional heart sounds. Air entry was equal and adequate bilaterally throughout the lung fields with no evidence of wheezing or crackles. Tests of radial artery patency, including the modified Allen test (application of pressure to the radial vessels when the hand is elevated, and the fist is clenched), and the Barbeau test (pulse oximetry of the index finger or thumb) were used to demonstrate collateral blood supply to the distal right hand before radial artery puncture. The remainder of his physical examination was unremarkable.\n\nPre-operative laboratory tests included a full blood count, which showed a hemoglobin (Hb) of 13.4 g/dl, a platelet count of 246×109/L, a coagulation profile that included a prothrombin time (PT) of 12.3 seconds, a partial thromboplastin time (PTT) of 25.1 seconds, and a basic metabolic profile that were all within normal limits. A two-dimensional A transthoracic echo-cardiogram (TTE) demonstrated mild concentric left ventricular hypertrophy with a left ventricular ejection fraction of 70%.\n\nThe right forearm and wrist were supinated and extended respectively. The right radial artery was palpated. A local anesthetic with 1% lidocaine was injected in the skin at the site of the puncture. Using the Seldinger technique a 5 French (Fr) sized catheter and the hydrophilic guidewire was inserted into the right radial artery. Heparin was administered intravenously at the beginning of the procedure, before radial artery cannulation, at a dose of 5000 units (70 units/kg). Coronary angiography showed a left main stem coronary artery stenosis and advanced triple vessel coronary artery disease. Following angiography, the wound was immediately sealed using an arterial puncture-closing device (APCD), composed of natural fiber cellulose hemostatic gauze placed in direct contact with the puncture site. Manual compression was then applied using a trans-radial band (TR band) to the radial area for two hours to minimize bleeding and blood loss.\n\nThe patients was observed for four hours following the procedure with no evidence of bleeding or hematoma and was referred to cardiothoracic surgery for an urgent CABG. The radial artery was assessed as an easily palpable, large caliber vessel, which was easily cannulated without evidence of vasospasm. Therefore, glyceryl trinitrate and verapamil, which are normally administered for radial artery vasospasm, were not required in this case.\n\nTwenty-four hours following radial artery catheterization, unnoticed by the patient, he was found to have ecchymosis (bruising) affecting the right axilla, anterior chest wall and anterior abdominal wall (Figures 1, 2). His blood hemoglobin level dropped to 11.1 g/dl on repeat full blood count 24 hours following radial artery catheterization, and the platelet count was 217×109/L. He remained hemodynamically stable with a blood pressure of 156/75 mmHg and a pulse rate of 61 beats per minute. Serial hemoglobin levels then remained stable. A chest X-Ray was performed and showed no evidence of pleural collections or widened mediastinum and the lung fields were clear. One week later, he proceeded to successful on-pump CABG without complications.\n\nDiscussion\nFor the performance of coronary artery angiography, arterial catheterization using the radial route has gained popularity as it has been reported to be associated with fewer complications than femoral artery catheterization [2,3]. Major complications during diagnostic coronary angiography are rare and are reported in less than 1% of procedures, with vascular complications being the most common [4]. Complications associated with arterial catheterization, when they do occur, include minor bleeding and hematomas at the puncture site, which are usually well managed with manual compression or the use of mechanical compression devices. During the immediate observation period, the patient in this report showed no signs of bleeding or other complications until 24 hours following the arterial catheterization procedure.\n\nPrecautionary post-procedure protocols used in arterial catheterization include the immediate placement of hemostatic adhesive gauze at the puncture site, radial band compression for one to two hours following the procedure, and continuous monitoring of blood pressure, pulse rate, and pulse-oximetry monitoring for four hours before discharge, as were performed in this case. However, this patient developed bruising to the axillary region, which tracked superficially, to the lower anterior chest wall and abdomen. While the hematoma appeared more intense on the left side of the abdominal wall, the ecchymosis (bruising) started in the right axilla and chest wall and spread further to the abdomen.\n\nFactors that may have increased this patient’s risk of bleeding were considered, but he had a normal coagulation screen, full blood count, and basic metabolic profile pre-procedure, with no use of glycoprotein IIb/IIIa inhibitors or antiplatelet therapy. Intravenous (IV) heparin was given at the recommended 70 units/kg (5,000 units). The use of the 4Ts clinical scoring system, as a pretest probability method to detect heparin-induced thrombocytopenia (HIT), was negative with a score of 0 points. There was no significant drop in the patient’s platelet levels, no evidence of venous or arterial thrombosis, and this patient proceeded to CABG where higher doses and longer durations of heparin exposure were used, and the surgery was without event [5]. Following recognition of the hematoma, and after discussion with the interventional cardiologist, it was decided that computed tomography (CT) would be performed if there were signs of deterioration. The patient remained stable at 48 hours with no further drop in hemoglobin and a CT scan was not performed. An initial chest X-ray was normal.\n\nAs in this case, hydrophilic guidewires are used during the trans-radial arterial catheterization approach to traverse tortuous arterial segments and to prevent radial artery spasm, but when a vascular complication does occur it is usually in the form of a forearm hematoma. These hematomas have been described as avulsions of a small branch of the radial artery, or due to ‘recurrent radial artery,’ arising from a radial loop proximal to the access site during the passage of the guide-wire [6]. The morbidity associated with avulsion of a recurrent radial artery, including compartment syndrome and distal hand ischemia, makes this a well-documented complication. However, perforations or avulsions affecting more proximal segments of the upper extremity during the trans-radial approach remain unexplained.\n\nVascular injury due to perforation or dissection and subsequent complications of bleeding can occur anywhere along the course of the wire or catheter manipulation, including the radial, axillary, subclavian arteries or any of the side branches. Upper limb arterial anomalies have a prevalence of 4–18.5%, according to autopsy studies [7,8]. Artery anomalies include a high bifurcating radial artery, radial artery tortuosity, and tortuous subclavian arteries. Following a review of the available literature, the possible mechanism of the complication that occurred in this patient may have been an injury to a small vessel or branch in the region of the axillary or subclavian artery that resulted in a slow hemorrhage. This mechanism would explain the gradual development of the hematomas and bruising, which were not apparent on discharge, and which started at the right axilla and progressed to the anterior chest and abdominal wall 24 hours following arterial catheterization.\n\nThe presentation of the complication described in this patient resulted in a clinical dilemma, as CABG surgery had to be delayed by one week in a patient with critical coronary artery disease, and careful consideration had to be given before further antiplatelet and anticoagulation (heparin) treatment. This case resulted in several questions, including whether there are complications associated with radial access during coronary angiography that remain unknown, whether there may be a subgroup of patients with an anomalous blood supply to the upper extremity that might increase the risk of similar complications, and whether there should be there be closer follow-up following trans-radial angiography. Finally, the question remains as to how the development of the complications found in this patient impact on cardiothoracic surgeons when planning urgent CABG surgery.\n\nConclusions\nThis case report has shown that radial artery catheterization can be associated with complication, which may be rare but could include chest, abdominal wall and axillary hematomas. A high level of vigilance and reporting should be maintained for rare complications in patients undergoing all forms of arterial catheterization, including catheterization of the radial artery.\n\nConflict of interest\n\nNone.\n\nFigure 1. Following radial artery catheterization, a right axillary hematoma is shown in a 58-year-old-man.\n\nFigure 2. Following radial artery catheterization, a right axillary hematoma tracking to the chest wall and abdomen is shown in a 58-year-old-man.\n==== Refs\nReferences:\n1. Jolly SS Yusuf S Cairns J Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL) trial group Lancet 2011 377 9775 1409 20 21470671 \n2. Valgimigli M Gagnor A Calabró P Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: A randomised multicentre trial. MATRIX Investigators Lancet 2015 385 9986 2465 70 25791214 \n3. Ferrante G Rao SV Jüni P Radial versus femoral access for coronary interventions across the entire spectrum of patients with coronary artery disease: A meta-analysis of randomized trials JACC Cardiovasc Interv 2016 9 14 1419 34 27372195 \n4. Popma JJ Satler LF Pichard AD Vascular complications after balloon and new device angioplasty Circulation 1993 88 4 Pt 1 1569 8403304 \n5. Cuker A Crowther MA 2013 Clinical Practice Guideline on the Evaluation and Management of Adults with Suspected Heparin-Induced Thrombocytopenia (HIT). Summary of selected recommendations from: Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th edition) 2013 \n6. Chugh SK Chugh Y Chugh S How to tackle complications in radial procedures: Tip and tricks Indian Heart J 2015 67 3 275 81 26138190 \n7. Barbeau GR Radial loop and extreme vessel tortuosity in the transradial approach: advantage of hydrophilic-coated guidewires and catheters Catheter Cardiovasc Interv 2003 59 4 442 50 12891603 \n8. Yokoyama N Takeshita S Ochiai M Anatomic variations of the radial artery in patients undergoing transradial coronary intervention Catheter Cardiovasc Interv 2000 49 4 357 62 10751755\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "19()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000005:Abdomen; D006328:Cardiac Catheterization; D017023:Coronary Angiography; D006406:Hematoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D017534:Radial Artery; D013896:Thoracic Diseases",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "1441-1444",
"pmc": null,
"pmid": "30514830",
"pubdate": "2018-12-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10751755;12891603;21470671;25791214;26138190;27372195;8403304",
"title": "Axillary, Chest Wall and Abdominal Hematoma as a Rare Complication of Radial Artery Catheterization.",
"title_normalized": "axillary chest wall and abdominal hematoma as a rare complication of radial artery catheterization"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0107231",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditiona... |
{
"abstract": "Current guidelines recommend deferring liver transplantation (LT) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection until clinical improvement occurs and two PCR tests collected at least 24 hours apart are negative. We report a case of an 18-year-old, previously healthy African-American woman diagnosed with COVID-19, who presents with acute liver failure (ALF) requiring urgent LT in the context of SARS-CoV-2 polymerase chain reaction (PCR) positivity. The patient was thought to have acute Wilsonian crisis on the basis of hemolytic anemia, alkaline phosphatase:bilirubin ratio <4, AST:ALT ratio >2.2, elevated serum copper, and low uric acid, although an unusual presentation of COVID-19 causing ALF could not be excluded. After meeting criteria for status 1a listing, the patient underwent successful LT, despite ongoing SARS-CoV-2 PCR positivity. Remdesivir was given immediately posttransplant, and mycophenolate mofetil was withheld initially and the SARS-CoV-2 PCR test eventually became negative. Three months following transplantation, the patient has made a near-complete recovery. This case highlights that COVID-19 with SARS-CoV-2 PCR positivity may not be an absolute contraindication for transplantation in ALF. Criteria for patient selection and timing of LT amid the COVID-19 pandemic need to be validated in future studies.",
"affiliations": "Division of Transplant Surgery, The William J. Von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic Rochester, Minnesota, USA.;Division of Gastroenterology, Mayo Clinic Health System, Mankato, Minnesota, USA.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic Rochester, Minnesota, USA.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic Rochester, Minnesota, USA.;Division of Pulmonology and Critical Care, Mayo Clinic Rochester, Minnesota, USA.;Department of Anesthesia, Mayo Clinic, Rochester, Minnesota, USA.;Department ofLaboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic Rochester, Minnesota, USA.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Transplant Surgery, The William J. Von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota, USA.;Division of Transplant Surgery, The William J. Von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic Rochester, Minnesota, USA.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Yohanathan|Lavanya|L|;Campioli|Cristina C|CC|;Mousa|Omar Y|OY|;Watt|Kymberly|K|;Friedman|Daniel Z P|DZP|0000-0002-3442-7454;Shah|Vijay|V|0000-0001-7620-573X;Ramkissoon|Resham|R|;Hines|Alexander S|AS|;Kamath|Patrick S|PS|;Razonable|Raymund R|RR|;Badley|Andrew D|AD|;DeMartino|Erin S|ES|;Joyner|Michael J|MJ|;Graham|Rondell|R|;Vergidis|Paschalis|P|0000-0002-6581-3956;Simonetto|Doug A|DA|;Sanchez|William|W|;Taner|Timucin|T|0000-0003-0641-2930;Heimbach|Julie K|JK|0000-0002-3567-1328;Beam|Elena|E|0000-0002-5807-2299;Leise|Michael D|MD|0000-0002-5811-230X",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.16582",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "21(8)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research / practice; immunosuppressive regimens - induction; infection and infectious agents - viral; liver disease: metabolic; liver transplantation / hepatology",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000293:Adolescent; D000086382:COVID-19; D005260:Female; D006801:Humans; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D058873:Pandemics; D016133:Polymerase Chain Reaction; D000086402:SARS-CoV-2",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2890-2894",
"pmc": null,
"pmid": "33792185",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Liver transplantation for acute liver failure in a SARS-CoV-2 PCR-positive patient.",
"title_normalized": "liver transplantation for acute liver failure in a sars cov 2 pcr positive patient"
} | [
{
"companynumb": "US-TEVA-2021-US-1984952",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "4",
... |
{
"abstract": "Primary cauda equina lymphoma (CEL) is a rare malignant tumor among various neoplasms that affects the cauda equina nerve roots. The present case report described the case of a 65-year-old man who presented with cauda equina syndrome with progressive motor palsy in the legs and gait disturbance over the last 5 months. Magnetic resonance (MR) images showed enlargement of the cauda equina occupying the dural sac from the L1-S1 level with isointensity to the spinal cord signal on both T1- and T2-weighted imaging. Enhancement of the cauda equina was seen on contrast MR images. On F-18 2-fluoro-2-deoxy-glucose positron emission tomography examination, diffuse accumulation of 2-fluoro-2-deoxy-glucose was observed in the cauda equina with a maximum standardized uptake value of 4.9. Based on elevation of soluble interleukin 2 receptor in cerebrospinal fluid and a biopsy of the enlarging cauda equina, a diagnosis of CEL of the diffuse large B-cell type was made. The present case report provided a detailed case discussion and a review of the available literature on this rare entity, focusing on clinical characteristics and imaging of primary CEL.",
"affiliations": "Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan.;Department of Human Science 1, Faculty of Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan.",
"authors": "Suzuki|Kayo|K|;Yasuda|Taketoshi|T|;Hiraiwa|Toshihito|T|;Kanamori|Masahiko|M|;Kimura|Tomoatsu|T|;Kawaguchi|Yoshiharu|Y|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2018.8629",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-1074",
"issue": "16(1)",
"journal": "Oncology letters",
"keywords": "FDG-PET/CT; MR imaging; cauda equina lymphoma; nerve biopsy; sIL-2R",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "623-631",
"pmc": null,
"pmid": "29928449",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": "2207891;15130553;20368468;12672282;20440506;26610022;3286832;22768968;8073994;22399193;19910757;18827688;17603246;25368124;27668300;6344666;8958028;23006886;16286555;23079891;25741044;24831985;24082685;26753799;21898094;19767089;14592623;2494834;22183251;10460458;24899982;28640701",
"title": "Primary cauda equina lymphoma diagnosed by nerve biopsy: A case report and literature review.",
"title_normalized": "primary cauda equina lymphoma diagnosed by nerve biopsy a case report and literature review"
} | [
{
"companynumb": "JP-TEVA-2018-JP-922840",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "Sarcomas are a relatively rare cancer, but often incurable at the late metastatic stage. Oncolytic immunotherapy has gained attention over the past years, and a wide range of oncolytic viruses have been delivered via intratumoral injection with positive safety and promising efficacy data. Here, we report preclinical and clinical results from treatment of sarcoma with oncolytic adenovirus Ad5/3-D24-GMCSF (CGTG-102). Ad5/3-D24-GMCSF is a serotype chimeric oncolytic adenovirus coding for human granulocyte-macrophage colony-stimulating factor (GM-CSF). The efficacy of Ad5/3-D24-GMCSF was evaluated on a panel of soft-tissue sarcoma (STS) cell lines and in two animal models. Sarcoma specific human data were also collected from the Advanced Therapy Access Program (ATAP), in preparation for further clinical development. Efficacy was seen in both in vitro and in vivo STS models. Fifteen patients with treatment-refractory STS (13/15) or primary bone sarcoma (2/15) were treated in ATAP, and treatments appeared safe and well-tolerated. A total of 12 radiological RECIST response evaluations were performed, and two cases of minor response, six cases of stable disease and four cases of progressive disease were detected in patients progressing prior to virus treatment. Overall, the median survival time post treatment was 170 days. One patient is still alive at 1,459 days post virus treatment. In summary, Ad5/3-D24-GMCSF appears promising for the treatment of advanced STS; a clinical trial for treatment of refractory injectable solid tumors including STS is ongoing.",
"affiliations": "Cancer Gene Therapy Group Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.",
"authors": "Bramante|Simona|S|;Koski|Anniina|A|;Kipar|Anja|A|;Diaconu|Iulia|I|;Liikanen|Ilkka|I|;Hemminki|Otto|O|;Vassilev|Lotta|L|;Parviainen|Suvi|S|;Cerullo|Vincenzo|V|;Pesonen|Saila K|SK|;Oksanen|Minna|M|;Heiskanen|Raita|R|;Rouvinen-Lagerström|Noora|N|;Merisalo-Soikkeli|Maiju|M|;Hakonen|Tiina|T|;Joensuu|Timo|T|;Kanerva|Anna|A|;Pesonen|Sari|S|;Hemminki|Akseli|A|",
"chemical_list": "D016178:Granulocyte-Macrophage Colony-Stimulating Factor",
"country": "United States",
"delete": false,
"doi": "10.1002/ijc.28696",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-7136",
"issue": "135(3)",
"journal": "International journal of cancer",
"keywords": "GM-CSF; animal models of cancer; cancer gene therapy; oncolytic adenovirus; sarcoma",
"medline_ta": "Int J Cancer",
"mesh_terms": "D000256:Adenoviridae; D000818:Animals; D005260:Female; D015316:Genetic Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D015552:Injections, Intralesional; D008647:Mesocricetus; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D011379:Prognosis; D012509:Sarcoma; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays",
"nlm_unique_id": "0042124",
"other_id": null,
"pages": "720-30",
"pmc": null,
"pmid": "24374597",
"pubdate": "2014-08-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Serotype chimeric oncolytic adenovirus coding for GM-CSF for treatment of sarcoma in rodents and humans.",
"title_normalized": "serotype chimeric oncolytic adenovirus coding for gm csf for treatment of sarcoma in rodents and humans"
} | [
{
"companynumb": "FI-ROXANE LABORATORIES, INC.-2015-RO-01087RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadd... |
{
"abstract": "Recent literature has demonstrated concern over the risk of Pneumocystis jirovecii pneumonia (PJP) when administering rituximab with combination chemotherapy such as in R-CHOP; however, the exact risk and potential need for prophylaxis is unknown. We sought to determine the incidence of PJP infection following R-CHOP administration in patients with B-cell lymphoma. Consecutive patients diagnosed with B-cell lymphoma receiving R-CHOP were evaluated from chemotherapy initiation until 180 days after the last administration. The primary outcome was cumulative incidence of PJP infection. Secondary endpoints included the association of rituximab, prednisone and subsequent chemotherapy with PJP infection risk. A total of 689 patients (53% male, median age 66 years) were included. Seventy-three percent of patients completed at least 6 cycles of R-CHOP treatment. Median rituximab and prednisone cumulative doses were 3950 mg and 5325 mg, respectively. Median daily prednisone dose through end of treatment was 45 mg (range 7.6 mg to 119 mg). The cumulative incidence of PJP was 1.51% (95% CI 0.57-2.43, at maximum follow-up of 330 days), below 3.5%, the conventional threshold for prophylaxis. Univariate analysis did not detect a statistically significant association between PJP and rituximab, steroids, or receipt of additional chemotherapy in this patient population. Our results demonstrate a low occurrence of Pneumocystis pneumonia during R-CHOP treatment of B-cell lymphoma and argue against universal anti-Pneumocystis prophylaxis in this setting. Further investigations should focus on targeted anti-Pneumocystis prophylaxis for patients presenting with high-risk baseline characteristics or when receiving rituximab-inclusive intensive combination chemotherapy regimens as treatment for other aggressive lymphoma subtypes. Am. J. Hematol. 91:1113-1117, 2016. © 2016 Wiley Periodicals, Inc.",
"affiliations": "Department of Pharmacy Services, Mayo Clinic, Rochester, Minnesota.;Department of Pharmacy, Spectrum Health, Grand Rapids, Michigan.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Infectious Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Infectious Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.;Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. limper.andrew@mayo.edu.",
"authors": "Barreto|Jason N|JN|;Ice|Lauren L|LL|;Thompson|Carrie A|CA|;Tosh|Pritish K|PK|;Osmon|Douglas R|DR|;Dierkhising|Ross A|RA|;Plevak|Matthew F|MF|;Limper|Andrew H|AH|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1002/ajh.24499",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-8609",
"issue": "91(11)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D018890:Chemoprevention; D015331:Cohort Studies; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D015994:Incidence; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D011020:Pneumonia, Pneumocystis; D016133:Polymerase Chain Reaction; D011241:Prednisone; D012189:Retrospective Studies; D000069283:Rituximab; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "7610369",
"other_id": null,
"pages": "1113-1117",
"pmc": null,
"pmid": "27472910",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Low incidence of pneumocystis pneumonia utilizing PCR-based diagnosis in patients with B-cell lymphoma receiving rituximab-containing combination chemotherapy.",
"title_normalized": "low incidence of pneumocystis pneumonia utilizing pcr based diagnosis in patients with b cell lymphoma receiving rituximab containing combination chemotherapy"
} | [
{
"companynumb": "US-JNJFOC-20161119118",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "Fatal pulmonary hemorrhages and rapidly progressive glomerulonephritis occurred in three patients with Wilson's disease (hepatolenticular degeneration) who had been treated with penicillamine for 2 to 31/2 years. Light microscopic studies of the kidneys showed severe glomerulonephritis with crescent formation, and the lungs showed intraalveolar hemorrhages. Although the clinical and pathologic abnormalities were those of Goodpasture's syndrome, immunofluorescence microscopic studies in the one case tested showed an interrupted, rather than linear, fluorescence pattern.",
"affiliations": null,
"authors": "Sternlieb|I|I|;Bennett|B|B|;Scheinberg|I H|IH|",
"chemical_list": "D010396:Penicillamine; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.7326/0003-4819-82-5-673",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4819",
"issue": "82(5)",
"journal": "Annals of internal medicine",
"keywords": null,
"medline_ta": "Ann Intern Med",
"mesh_terms": "D000328:Adult; D019867:Anti-Glomerular Basement Membrane Disease; D002648:Child; D005260:Female; D005455:Fluorescent Antibody Technique; D005921:Glomerulonephritis; D006469:Hemoptysis; D006470:Hemorrhage; D006527:Hepatolenticular Degeneration; D006801:Humans; D008168:Lung; D008171:Lung Diseases; D008297:Male; D008853:Microscopy; D010396:Penicillamine; D011241:Prednisone",
"nlm_unique_id": "0372351",
"other_id": null,
"pages": "673-6",
"pmc": null,
"pmid": "1094875",
"pubdate": "1975-05",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "D-penicillamine induced Goodpasture's syndrome in Wilson's disease.",
"title_normalized": "d penicillamine induced goodpasture s syndrome in wilson s disease"
} | [
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"companynumb": "US-BAUSCH-BL-2019-007545",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "PENICILLAMINE"
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"abstract": "The incidence of treatment related mortality in children with acute lymphoblastic leukemia (ALL) is reported to be between 2% and 4% with infections being the leading cause.\n\n\n\nTo establish a relationship between body mass index at diagnosis (BMI 0), after protocol I therapy completion (BMI I) and the incidence rate ratio (IRR) of infectious/febrile episodes in children with ALL intermediate risk.\n\n\n\nThirty one consecutive patients (2-18 years old, with a male to female ratio of 19/12) with newly diagnosed ALL that were treated uniformly according to ALL IC 2009 protocol were included in this analysis.\n\n\n\nA BMI decrease of at least 5% during protocol I therapy and BMI 1 under 15th percentile score corresponds significantly with higher IRR (with P-values 0.04 and 0.006 respectively) during the whole intensive therapy.\n\n\n\nSome relationships between BMI reduction and higher IRR in ALL patients were found, but their significance is limited by the size of the group analyzed.",
"affiliations": "a Clinic of Paediatric Oncology and Haematology, Faculty of Medicine , University of Rzeszow , Rzeszow , Poland.;b Department of Paediatric Bone Marrow Transplantation, Oncology and Hematology , Wroclaw Medical University , Wroclaw , Poland.;c Institute of Informatics , University of Warsaw , Warsaw , Poland.;a Clinic of Paediatric Oncology and Haematology, Faculty of Medicine , University of Rzeszow , Rzeszow , Poland.;b Department of Paediatric Bone Marrow Transplantation, Oncology and Hematology , Wroclaw Medical University , Wroclaw , Poland.;d Center for Innovation and Transfer of Natural Sciences and Engineering Knowledge, University of Rzeszow , Rzeszow , Poland.;a Clinic of Paediatric Oncology and Haematology, Faculty of Medicine , University of Rzeszow , Rzeszow , Poland.;e Clinic of Paediatric Endocrinology, Faculty of Medicine , University of Rzeszow , Rzeszow , Poland.",
"authors": "Chaber|Radosław|R|;Latos-Grażyńska|Elżbieta|E|;Ciebiera|Krzysztof|K|;Łach|Kornelia|K|;Tokar|Barbara|B|;Cebulski|Józef|J|;Trybucka|Katarzyna|K|;Mazur|Artur|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/01635581.2018.1516792",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-5581",
"issue": "71(4)",
"journal": "Nutrition and cancer",
"keywords": null,
"medline_ta": "Nutr Cancer",
"mesh_terms": "D000293:Adolescent; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D005260:Female; D005334:Fever; D006801:Humans; D007239:Infections; D008297:Male; D044342:Malnutrition; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D013851:Thinness",
"nlm_unique_id": "7905040",
"other_id": null,
"pages": "701-707",
"pmc": null,
"pmid": "30407874",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D059040:Video-Audio Media",
"references": null,
"title": "Body Mass Index (BMI) and Infectious/Febrile Episodes in Children with Intermediate Risk Acute Lymphoblastic Leukemia (IR ALL).",
"title_normalized": "body mass index bmi and infectious febrile episodes in children with intermediate risk acute lymphoblastic leukemia ir all"
} | [
{
"companynumb": "PL-JNJFOC-20190529536",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
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"drugadditional": "3",
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{
"abstract": "Parkinsonian symptoms are common adverse effects of antipsychotics. Older adults are particularly vulnerable to drug-induced parkinsonism. Nonetheless, parkinsonian symptoms in seniors treated with antipsychotics cannot be straightforwardly attributed to antipsychotic medication. A comprehensive diagnostic workup is necessary in many cases in order to shed light on the cause of such symptoms in this patient population.\n\n\n\nEight cases of hospitalized depressed older adults with parkinsonian symptoms, who were treated for at least one year with antipsychotics, are reported. Based on neurological consultation, structural brain imaging and Ioflupane (I-123) dopamine transporter (DAT) single photon emission computerized tomography (SPECT), Parkinson's disease was diagnosed in one case, idiopathic tremor in another, vascular parkinsonism in another one, while in another individual parkinsonian symptoms persisted at 12-month post-discharge follow-up even though his/her symptoms were classified as drug-induced on discharge. In four patients, parkinsonian symptoms were definitely drug-induced and no movement disturbances were reported at follow-up.\n\n\n\nDifferences in the cause and outcome of parkinsonian symptoms in seniors treated with antipsychotics merit systematic and in-depth study considering the therapeutic and prognostic implications of an accurate detection of the cause of such symptoms. Familiarizing clinical psychiatrists with these differences could pave the way towards approaching seniors with severe, atypical and/or persistent parkinsonian symptoms in a more individualized diagnostic and therapeutic manner, and towards more cautious prescribing of antipsychotics in this age group.",
"affiliations": "Charing Cross Hospital, Department of Neurosurgery, Imperial College London, London, UK.;First Department of Psychiatry, Eginition Hospital; Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;Nuclear Medicine Division, Radiology First Department, \"Aretaieion\" Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;First Department of Psychiatry, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;Research Unit of Radiology, Second Department of Radiology, National and Kapodistrian University of Athens and Bioiatriki, Athens, Greece.;First Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;Department of Nuclear Medicine, Metropolitan Hospital, Neo Faliro, Pireas, Greece.;Nuclear Medicine Division, Radiology First Department, \"Aretaieion\" Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;Department of Psychiatry, Patras University Hospital, Faculty of Medicine, School of Health Sciences, University of Patras, 26504 Rion, Patras, Greece. panos.alexopoulos@upatras.gr.",
"authors": "Politis|Anastasios|A|;Kokras|Nikolaos|N|;Souvatzoglou|Michael|M|;Siarkos|Kostas|K|;Toulas|Panagiotis|P|;Potagas|Constantin|C|;Hatzipanagiotou|Theodoros|T|;Limouris|Georgios|G|;Alexopoulos|Panagiotis|P|0000-0002-9047-6365",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s12888-021-03298-9",
"fulltext": "\n==== Front\nBMC Psychiatry\nBMC Psychiatry\nBMC Psychiatry\n1471-244X\nBioMed Central London\n\n3298\n10.1186/s12888-021-03298-9\nCase Report\nDifferences in cause and 12-month follow-up outcome of parkinsonian symptoms in depressed older adults treated with antipsychotics: a case series\nPolitis Anastasios anastasios.politis@nhs.net\n\n1\nKokras Nikolaos nkokras@icloud.com\n\n2\nSouvatzoglou Michael msouvatz@yahoo.de\n\n3\nSiarkos Kostas kosia2006@yahoo.co.uk\n\n4\nToulas Panagiotis ptoulas@yahoo.gr\n\n5\nPotagas Constantin cpotagas@med.uoa.gr\n\n6\nHatzipanagiotou Theodoros xatzipanagiotou.theodoros@gmail.com\n\n7\nLimouris Georgios nucleard@aretaieio.uoa.gr\n\n3\nhttp://orcid.org/0000-0002-9047-6365\nAlexopoulos Panagiotis panos.alexopoulos@upatras.gr\n\n89\n1 grid.7445.2 0000 0001 2113 8111 Charing Cross Hospital, Department of Neurosurgery, Imperial College London, London, UK\n2 grid.5216.0 0000 0001 2155 0800 First Department of Psychiatry, Eginition Hospital; Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece\n3 grid.5216.0 0000 0001 2155 0800 Nuclear Medicine Division, Radiology First Department, “Aretaieion” Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece\n4 grid.5216.0 0000 0001 2155 0800 First Department of Psychiatry, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece\n5 grid.5216.0 0000 0001 2155 0800 Research Unit of Radiology, Second Department of Radiology, National and Kapodistrian University of Athens and Bioiatriki, Athens, Greece\n6 grid.5216.0 0000 0001 2155 0800 First Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece\n7 grid.415451.0 0000 0004 0622 6078 Department of Nuclear Medicine, Metropolitan Hospital, Neo Faliro, Pireas, Greece\n8 grid.412458.e Department of Psychiatry, Patras University Hospital, Faculty of Medicine, School of Health Sciences, University of Patras, 26504 Rion, Patras, Greece\n9 grid.6936.a 0000000123222966 Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Faculty of Medicine, Technical University of Munich, Munich, Germany\n3 6 2021\n3 6 2021\n2021\n21 28926 1 2021\n20 5 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\nParkinsonian symptoms are common adverse effects of antipsychotics. Older adults are particularly vulnerable to drug-induced parkinsonism. Nonetheless, parkinsonian symptoms in seniors treated with antipsychotics cannot be straightforwardly attributed to antipsychotic medication. A comprehensive diagnostic workup is necessary in many cases in order to shed light on the cause of such symptoms in this patient population.\n\nCase series\n\nEight cases of hospitalized depressed older adults with parkinsonian symptoms, who were treated for at least one year with antipsychotics, are reported. Based on neurological consultation, structural brain imaging and Ioflupane (I-123) dopamine transporter (DAT) single photon emission computerized tomography (SPECT), Parkinson’s disease was diagnosed in one case, idiopathic tremor in another, vascular parkinsonism in another one, while in another individual parkinsonian symptoms persisted at 12-month post-discharge follow-up even though his/her symptoms were classified as drug-induced on discharge. In four patients, parkinsonian symptoms were definitely drug-induced and no movement disturbances were reported at follow-up.\n\nConclusions\n\nDifferences in the cause and outcome of parkinsonian symptoms in seniors treated with antipsychotics merit systematic and in-depth study considering the therapeutic and prognostic implications of an accurate detection of the cause of such symptoms. Familiarizing clinical psychiatrists with these differences could pave the way towards approaching seniors with severe, atypical and/or persistent parkinsonian symptoms in a more individualized diagnostic and therapeutic manner, and towards more cautious prescribing of antipsychotics in this age group.\n\nKeywords\n\nDrug induced parkinsonism\nParkinson’s disease\nVascular parkinsonism\nIdiopathic tremor\nCase series\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nAntipsychotic augmentation is not a rare strategy in the pharmacological treatment of depression in older adults. Τhe prevalence of clinically relevant depressive symptoms in seniors is higher than 15%, while the prevalence of major depression exceeds 5% [1, 2]. Antipsychotics augment antidepressants in 12–32% of older adults with depression [3–6], albeit in most cases in an off-label manner [7]. Antipsychotics contribute not only to treating psychotic symptoms in severe depression with psychotic features [8], but also to depressive symptom improvement, since they enhance monoaminergic neurotransmission [9].\n\nSeniors are particularly vulnerable to side effects of antipsychotic agents, such as parkinsonian symptoms. Both typical antipsychotics, which mainly block D2 receptors, and to a lesser degree atypical ones, blocking both D2 and serotonin 5-HT2A receptors, can lead to parkinsonian symptoms [10, 11]. The annual prevalence of drug-induced parkinsonian symptoms approximates 3% and the annual incidence rate is higher than 3 per 100,00 person-years [12, 13]. Seniors are more vulnerable to parkinsonian symptoms compared to younger patients due to age- related changes in the brain’s response to antipsychotics, diminished drug metabolizing capacity, alterations in blood-brain barrier, as well as drug-drug interactions in an age group burdened by polypharmacy [14]. In addition, age- related, still presymptomatic, neurodegenerative (e.g. Lewy-bodies, nigral cell degeneration) [12, 15] and/or vascular brain changes [16] should be considered as factors crucially implicated in the high susceptibility of seniors treated with antipsychotics to develop severe and persistent parkinsonian symptoms which cannot be unambiguously classified into diagnostic categories. Structural imaging and Ioflupane (I-123) dopamine transporter (DAT) single photon emission computerized tomography (DaTSAN) are useful tools in shedding light on such brain changes and assisting the differential diagnosis [17, 18]. Normal DaTSCAN-imaging supports diagnosis of a condition not involving nigrostriatal neurodegeneration such as Alzheimer’s disease, essential tremor or drug-induced parkinsonism and hence a different therapeutic approach [19]. DaTSCAN sensitivity is estimated to be 78–100% and specificity 70–100% for differentiating neurodegenerative versus non-neurodegenerative parkinsonism [20].\n\nHere, we report on eight hospitalized depressed older adults with parkinsonian symptoms who were treated for at least 12 months prior to their hospital admission with antipsychotics. The presented case series highlights the different causes and 12-month post-discharge follow-up outcomes of such symptoms, despite the initial assessment on admission that they were drug-induced.\n\nCase series presentation\n\nThe case series consists of five women and three men older than 59 years who were admitted between 2012 and 2017 to the old age psychiatry division of the Eginition Hospital in Athens because of severe depressive symptoms and consecutively agreed to undergo brain SPECT with 123I-FP-CIT (DaTSCAN, GE Healthcare). The brief, focused neurological examination on admission revealed parkinsonian symptoms, which had been developed during exposure to antipsychotic treatment (Table 1). On admission, each patient was on antipsychotic medication that had not been changed in the twelve months prior to his/her hospital admission (Table 1). Five patients were on atypical and three on typical antipsychotics; four were on serotonin and norepinephrine reuptake inhibitors, two on selective serotonin reuptake inhibitor and four were treated with mirtazapine. Except for one patient, who had received the diagnosis of bipolar disorder many years before current hospital admission, all others had been diagnosed with unipolar depression. Of note, depression had occurred among four patients for the first time at an age greater than or equal to 65 years with no previous history of depression. Table 1 Demographic and clinical data, mental disorder history and medication of older adults with depression and parkinsonian symptoms on hospital admission\n\nCase No\tAge range\tEducation (in years)\tNeuropsychological assessment at admission\tDuration of current depressive syndrome (in years)\tPast mental disorder diagnoses\tAge of onset of the first mental disorder episode\tMedication on admission (in mg/day)\tComorbidities\t\n\t\t\tGeriatric depression scale score\tMini mental state examination score\t\t\t\t\t\t\n1\t71–85\t12\t12\t21\t1\tΜajor depression\t69\tAmisulpiride (100), venlafaxine (75), mirtazapine (30), ferrous sulfate, nifedipine (40)\tAnaemia, hypertension\t\n2\t71–85\t14\t14\t27\t1\tSevere depressive episode with psychotic symptoms\t72\tRisperidone (3), sertraline (200 mg), mirtazapine (30), lorazepam (2.5), irbesartan (150), metoprolol (100)\tHypertension, hypothyreroidism\t\n3\t56–70\t14\t14\t28\t1\tSevere depressive episode with psychotic symptoms\t57\tOlanzapine (5), mirtazapine (45), alprazolam (3), flunitrazepam (1), biperiden (4)\tNone\t\n4\t56–70\t14\t15\t20\t1\tModerate to severe depressive episode\t36\tHaloperidol (10), venlafaxine (150), lorazepam (7.5), biperiden (6), pindolol (5), rosuvastatin (10), atorvastatin (10)\tHypertension, dislipidemia\t\n5\t71–85\t8\t12\t27\t1\tModerate to severe depressive episode with psychotic symptoms\t77\tHaloperidol (10), sertraline (100), bromazepam (3), amiloride hydrochloride/hydrochlorothiazide (5/50)\tHypertension\t\n6\t71–85\t12\t14\t23\t1\tBipolar disorder\t54\tRisperidone (3), mirtazapine (45), gabapentin (600), clonazepam (2), baclofen (20), metformin (2000), rosuvastin (20), bisoprolol fumarate (5), Levothyroxine sodium (125 μg)\tHypertension, diabetes mellitus, coronary heart disease, dyslipidemia, hypothyroidism\t\n7\t71–85\t6\t15\t27\t1\tSevere depressive episode with psychotic symptoms\t76\tHaloperidol (20), venlafaxine (150), pramipexol (0.18), quinapril (20), rabeprazole (10)\tHypertension\t\n8\t56–70\t12\t13\t19\t1\tModerate to severe depressive episodes\t55\tQuetiapine (100), duloxetine (30), pregabalin (75), levodopa/benserazide (200/50)\tHypertension\t\n\nThe diagnostic workup of depressive symptoms included a history from the patient and from an informant; psychiatric examination; laboratory screening and the administration of the 30-point Mini-Mental State Examination (MMSE) [21] and the Geriatric depression scale-15 [22]. Geriatric depression scale score was in all cases higher than 11, highlighting the severity of depressive symptoms (Table 1). In four patients MMSE score was lower than 24 points, pointing to major neurocognitive disorder [21], even though the magnitude of the detected cognitive deficits was supposed to be at least partially potentiated by the depressive syndrome [23].\n\nPatients were diagnosed with antipsychotic- induced parkinsonism according to the International Statistical Classification of Diseases and Related Health Problems version 10 (ICD-10) diagnostic criteria [24]. Severity of parkinsonian symptoms was graded with the Simpson-Angus scale (SAS), being an established instrument of neuroleptic-induced parkinsonism [25]. The instrument is a 10-item rating scale that measures gait (hypokinesia) with one item, rigidity with six items, whilst three additional items assess glabella tap, tremor and salivation, respectively. Items are rated from 0 to 4 points, yielding a total body score divided by 10, and considered normal up to 0.3. It was performed in all cases by the same psychiatrist (KS). Apart from one case, in all other patients total scores on SAS exceeded 0.5 (Table 2). Table 2 Parkinsonian symptoms of depressed older adults\n\nCase No\tDetected movement disturbances on admission\tSimpson-Angus Scale\t\n\t\tTotal score\tGait\tArm dropping\tShoulder shaking\tElbow rigidity\tWrist rigidity\tLeg pendulousness\tHead dropping\tGlabella tap\tTremor\tSalivation\t\n1\tParkinsonism\t0.7\t1\t1\t0\t1\t2\t0\t1\t0\t1\t0\t\n2\tParkinsonism\t0.9\t2\t1\t0\t0\t2\t1\t0\t1\t2\t0\t\n3\tParkinsonism\t0.6\t1\t1\t1\t0\t1\t1\t0\t0\t1\t0\t\n4\tParkinsonism\t1.4\t1\t1\t1\t1\t2\t1\t1\t1\t3\t1\t\n5\tParkinsonism\t1.6\t2\t2\t2\t2\t1\t2\t1\t1\t3\t0\t\n6\tParkinsonism\t1.3\t2\t2\t1\t2\t2\t1\t1\t1\t1\t0\t\n7\tParkinsonism\t0.3\t0\t1\t0\t0\t1\t0\t0\t0\t1\t0\t\n8\tParkinsonism\t1.1\t1\t1\t1\t1\t2\t1\t1\t1\t2\t0\t\n\nBrain MRI (3 T) was performed during the hospitalization period. It included T1 weighted sequences on coronal, sagittal and axial planes (or isotropic T1 images), T2 weighted sequences, T2 Fluid Attenuation Inversion Recovery (FLAIR) images and Diffusion Weighted Imaging (DWI). All MRI scans were evaluated by an experienced neuroradiologist (PT). White matter lesions and vascular disease were evaluated using the Fazekas scale on T2-FLAIR sequences [26]. This scale ranges from 0 (no white matter lesions) to 3 (large confluent areas of white matter lesions) [27]. Based on the Medial Temporal Lobe Atrophy (MTA) -Scheltens Score, MTA was classified using a scale from 0 (no atrophy) to 4 (maximum atrophy) [28]. Unfortunately, MRI imaging was not conducted in two cases due to MRI contraindications (Table 3). Slightly increased signal in T2-weighted images in white matter was observed in four cases and beginning confluent lesions were detected in one case, while in case 8 basal ganglia ischemic lesions were bilaterally observed in addition to large confluent white matter lesions (Fig. 1). Mild or moderate MTA was detected in all cases with available MRI data (Table 3). Table 3 Brain imaging findings of older adults with depression and parkinsonian symptoms\n\nCase No\tStructural brain MR imaging\tDaT scan*\t\n\tMTA-Scheltens Score**\tWhite matter lesions/Fazekas Score***\tSpecific Binding Index right\tBenamer’s criteria****\t\n\t\t\tRight\tLeft\tRater 1\tRater 2\t\n1\t2\t1\t2.17\t2.10\t0\t0\t\n2\t1\t2\t2.05\t2.12\t1\t1\t\n3\t1\t0\t2.04\t2.03\t0\t0\t\n4\tNo atrophy / Computerized tomography (CT) scan\t2.03\t2.02\t0\t1\t\n5\t2\t1\t2.02\t2.06\t0\t0\t\n6\tNo atrophy / Computerized tomography (CT) scan\t2.00\t1.88\t2\t3\t\n7\t2\t1\t1.85\t2.07\t1\t1\t\n8\t2\tBilateral basal ganglia ischemic lesions/3\t1.51\t1.67\t1\t1\t\n* iofluropane iodine-123 (DAT) single-photon emission computed tomography imaging (SPECT)\n\n**Medial Temporal Lobe Atrophy (MTA) -Scheltens Score ranging from 0 (no atrophy) to 4 (severe atrophy)\n\n***The 4-point Fazekas score is a whole brain scale: 0: No lesion or a single punctuate white matter lesion; 1: multiple punctuate lesions; 2: Beginning confluent lesions; 3: large confluent lesions\n\n**** Benamer’s criteria: 0: preserved and largely symmetrical striatal tracer uptake; 1: asymmetric uptake with normal or almost normal putamen activity in one hemisphere, and with a more marked reduction in the contralateral putamen; 2: significant bilateral reduction in putamen uptake with activity confined to the caudate nuclei; 3: virtually absent uptake bilaterally affecting both putamen and caudate nuclei\n\nFig. 1 Brain MRI (3 T) of case 8. Lacunar lesions in superior-anterior-medial surface of right thalamus in the proximity inferior surface of caudal nucleus (arrows) (A: coronal T2* weighted image and B: axial T2 weighted image). Microvascular leukoencephalopathy (Fazekas grade 3). No hemosiderin accumulation in basal ganglia in T2* weighted images. No medial temporal lobe atrophy (C and D: coronal and axial T1 weighted images)\n\nDue to the severity and persistence of parkinsonian symptoms, despite cessation of antipsychotic medication in four cases or switching to other antipsychotic agents in the rest of cases, the assessment of the basal ganglia’s presynaptic dopamine function was recommended. Patients agreed and underwent DaTSCAN. DaTSCAN scintigraphy acquisition and processing methodology as well as the analysis method of the striatal uptake ratios of DaTSCAN images have been previously depicted in detail [29, 30]. Visual analysis of the data was performed by two nuclear medicine specialists who were blind to patients’ clinical status. Tracer uptake patterns were classified according to the Benamer’s criteria [31] as normal (preserved and largely symmetrical striatal tracer uptake), or abnormal grade 1 in case of asymmetric uptake with normal or almost normal putamen activity in one hemisphere, and with a more marked reduction in the contralateral putamen, or abnormal grade 2, if significant bilateral reduction in putamen uptake with activity confined to the caudate nuclei was detected, or abnormal grade 3 in cases with virtually absent uptake bilaterally affecting both putamen and caudate nuclei [32]. The semi-quantitative analysis and calculation (cnts/pixel) of striatal uptake was based on manually drawn, irregular (almost ellipsoid) regions of interest (ROIs), encompassing the entire corpus striatum, and square ROIs in areas corresponding to the occipital cortex in the three consecutive ‘best’ subsets of a transaxial slice through the central striatum of the DaTSCAN image. The specific radiotracer binding ratios of the striatum were calculated from its mean counts per pixel vs those of the occipital cortex as reference [specific binding index in the striatum (S.B.I. ≥ 2.0)] = value for the striatum divided to the value for the occipital cortex reference [29]. According to the visual analysis three patients had a normal study; οne had a marginally asymmetrical tracer uptake; three patients had an abnormal tracer uptake with moderately asymmetric dopaminergic loss and one patient exhibited a significant bilateral reduction in tracer uptake. Consistent with previous reports, the clinical agreement between the two raters was 75% [33, 34]. The specific radiotracer binding indexes point to one case with symmetrically abnormal radiotracer uptake and to two cases with unilateral abnormal uptake, whilst in all other patients the uptake was within the normal range (Table 3) (Fig. 2). For the sake of clarity of presentation, the eight cases are presented in all tables in a descending order regarding the semi-quantitative calculation of tracer uptake in right striatum. Fig. 2 123I-Ioflupane SPECT imaging, a measure of dopamine transporter density, demonstrates in case 2 normal radiotracer uptake or very mild hypoactivity in right caudate (A); in case 3 normal radiotracer uptake bilaterally (B); in case 6 bilateral striatal hypoactivity (C) and in case 8 bilateral hypoactivity with a more marked reduction in right striatum(D)\n\nBased on clinical data, GDS- and MMSE results and imaging findings and in accordance with ICD-10 diagnostic criteria mental disorder- and neurological diagnoses were established [24]. Depressive syndromes were classified as organic mood disorder in four cases and as severe depressive episode of recurrent depressive disorder in the other four. Based on neurological consultation, the diagnosis of Parkinson’s disease was established only in one case, whilst one patient with normal striatal tracer uptake was diagnosed with idiopathic tremor and case 8 with vascular parkinsonism. In all other cases parkinsonian symptoms were attributed to the administration of antipsychotics. Mild cognitive impairment due to Alzheimer’s disease was diagnosed in two cases. On discharge, no patient was treated with typical antipsychotics, while in four cases no antipsychotics were administered at all. Antiparkinsonian drugs were initiated during hospitalization or continued in six patients (Table 4). Interestingly, apart from one case, the number of prescribed drugs on discharge was lower in five cases or in two cases equal to that of agents with which patients were treated on admission. Table 4 Neurological and mental disorder diagnoses and medication on discharge and 12-month post-discharge follow-up outcome regarding movement disturbances and mental disorder- and neurological diagnoses\n\nCase No\tHospitalization duration (in days)\tDischarge neurological diagnosis\tDischarge mental disorder diagnosis\tMedication at discharge\t12-month post-discharge follow-up outcome\t\n1\t45\tDrug-induced parkinsonism\n\nMild Cognitive Impairment due to Alzheimer’s disease\n\n\tOrganic mood disorder\tDuloxetine (90), donepezil (5)\tNo movement disturbances\n\nDementia due to Alzheimer’s disease\n\n\t\n2\t40\tIdiopathic tremor\tSevere depressive episode of recurrent depressive disorder\tQuetapine (25), duloxetine (60),\n\nclonazepam (2),\n\nlevothyroxine sodium (100 μg)\n\n\tIdiopathic tremor\t\n3\t90\tDrug-induced parkinsonism\tSevere depressive episode of recurrent depressive disorder\tRisperidone (4),\n\nparoxetine (20), mirtazapine (60), alprazolam (4), biperiden (4)\n\n\tNo movement disturbances\t\n4\t120\tDrug-induced parkinsonism\n\nTardive dyskinesia\n\nMild Cognitive Impairment due to Alzheimer’s disease\n\n\tSevere depressive episode of recurrent depressive disorder\tQuetiapine (150), trazodone (50), mirtazapine (45), lorazepam (7.5), biperiden (2), pindolol (5)\tTardive dyskinesia\n\nDementia due to Alzheimer’s disease\n\n\t\n5\t60\tDrug-induced parkinsonism\tOrganic mood disorder\tQuetiapine (50), duloxetine (90), lorazepam (0.5),\n\nlevodopa/benserazide (100/25),\n\namiloride, hydrochloride/hydrochlorothiazide (5/50)\n\n\tParkinsonism\n\nPersistent psychotic symptoms\n\n\t\n6\t35\tParkinson’s disease\tOrganic mood disorder\tEscitalopram (40), lorazepam (1),\n\nlevodopa/benserazide (600/150), amantadine (100)\n\n\tParkinsonism\t\n7\t100\tDrug-induced parkinsonism\tSevere depressive episode of recurrent depressive disorder\tDuloxetine (60),\n\nmirtazapine (45),\n\nlorazepam (1),\n\nlevodopa/benserazide (200/50)\n\n\tNo movement disturbances\n\nDementia due to Alzheimer’s disease\n\n\t\n8\t40\tVascular parkinsonism\n\nMicrovascular ischemic brain disease\n\n\tOrganic mood disorder\tDuloxetine (30), rivastigmine (4.6), levodopa/benserazide (200/50), ilbesartan (150)\tParkinsonism\n\nVascular dementia\n\n\t\n\nFor the 12-month post-discharge follow-up outcome assessment, a caregiver-based telephone interview format was employed. The interview was based on questions about movement disturbances and mental disorder- and neurological diagnoses. The individuals diagnosed on discharge with Parkinson’s disease, idiopathic tremor and vascular parkinsonism, respectively, still suffered from movement disturbances, as expected. In a patient who had been diagnosed on discharge with drug-induced parkinsonism, persistent movement disturbances were reported, despite the discontinuation of antipsychotic agents during hospitalization. In all other patients no parkinsonian symptoms were reported, in line with the discharge diagnosis of drug- induced parkinsonism. The two patients who received on discharge the diagnosis of mild cognitive impairment due to Alzheimer’s disease progressed to dementia and faced at follow-up difficulties with both complex and basic activities of daily living.\n\nDiscussion and conclusions\n\nThe development of parkinsonian symptoms while being on antipsychotic medication does not straightforwardly substantiate the presence of drug-induced parkinsonism, especially in seniors. The presented case series, which in contrast to the heterogeneity of study samples of most past reports [35–37], focuses exclusively on older adults with depression treated with antidepressants and antipsychotics, clearly points to a diagnostic riddle in this patient population.\n\nTreatment with antipsychotics can induce parkinsonian symptoms, uncover subclinical degenerative and/or vascular striatal brain pathologies, or lead to the exacerbation of previously mildly manifest parkinsonian symptoms [38]. Drug-induced parkinsonism is conceptualized as parkinsonism that occurs during drug exposure and resolves within six months after the withdrawal of the implicated agent [12], even though symptoms can persist beyond six to nine months cessation of the drug without evidence of impaired striatal dopamine transporter density [18]. Drug-induced parkinsonism may be distinguished from Parkinson’s disease, since contrary to the latter, drug-induced parkinsonism is characterized by bilateral and symmetric parkinsonism, with more prominent bradykinesia and rigidity. Nonetheless, relying exclusively on the clinical manifestation of parkinsonian symptoms in order to differentiate between drug-induced parkinsonism and other causes is not a reliable and feasible strategy particularly in seniors who commonly develop atypical symptom phenotypes [12]. Ιndeed, more than 30% of patients with drug-induced parkinsonism show asymmetric parkinsonism and tremor at rest [12, 38].\n\nIn older adults treated with antipsychotics, the puzzle of the genesis and clinical manifestation of parkinsonian symptoms are further perplexed by the heavy burden of coexisting brain pathologies (e.g. amyloidosis, cerebrovascular alterations, mitochondrial abnormalities) [39, 40]. The clinical expression of such brain pathologies may be potentiated or masked by a complex, dynamic interplay between the interacting co-pathologies and harmful and protective environmental factors (e.g. diet and lifestyle parameters, motor reserve) [41, 42]. Exposure to antipsychotic agents influences this interplay and may trigger the development of clinically evident parkinsonian symptoms. This dynamic equilibrium is mirrored in the complex relationships between DaTSCAN- and MRI- findings, clinical diagnoses and 12-month follow-up outcome (resolution vs. persistence of parkinsonian symptoms) in the presented eight cases. For instance, bilateral basal ganglia ischemic lesions seem to have increased the vulnerability of case 8 to the development of parkinsonian symptoms, even though he/she was treated with quetiapine, i.e. an atypical antipsychotic with low risk of aggravation of parkinsonism [12].\n\nDeciphering the cause of parkinsonian symptoms in seniors treated with antipsychotics is crucial for designing the proper, individualized therapeutic plan. Prescribing antiparkinsonian drugs without an established diagnosis of Parkinson’s disease or even of a Parkinson-plus syndrome, which albeit responds in most cases poorly to current therapies compared to Parkinson’s disease [43], is not justifiable. Antiparkinsonian agents can lead to further exacerbation of psychotic symptoms (dopaminergic agents) or induce cognitive impairment or delirium (anticholinergic agents), whilst polypharmacy is related to adverse outcomes, including adverse drug events and disability in this age group [44, 45]. On the other hand, cessation of the assumed causative agent in order to shed light on the cause of the parkinsonian symptoms and distinguish between drug-induced parkinsonian symptoms and a movement disorder may not be practical in many cases, since depression in late life tends to be a persistent or recurrent and not rarely a therapy resistant condition [23], while persistence or paradoxical progressive deterioration of parkinsonism upon antipsychotic withdrawal have been described [30, 46]. Thus, a rigorous and comprehensive diagnostic workup of parkinsonian symptoms, including structural brain imaging and DaTSCAN, seems to be in cases with atypical, severe and/or persistent parkinsonian symptoms inevitable, in order to design justifiable, individualized treatment plans. In addition, such a diagnostic workup can be prospectively conducted in patients thought to be at high risk for parkinsonism because of age, family history or subthreshold parkinsonian symptoms [30], so that a vulnerable degenerated nigrostriatal tract is identified and considered in decision making about the treatment plan.\n\nDespite the phenotypic homogeneity and the thorough and rigorous diagnostic workup of the considered patients, the presented case series has a number of limitations. Even though all patients suffered from severe depressive symptoms on admission, four were diagnosed at discharge with recurrent depressive disorder and four with organic mood disorder, while in one case the diagnosis of bipolar disorder had been established prior hospital admission. Moreover, the age of onset of the first mood disorder episode as well as performance on MMSE varied across the cases. Only four cases can be classified as suffering from late-onset depression. In four cases MMSE scores pointed to clinically significant abnormalities in cognitive function [21]. Taking into account the differences in symptoms and pathogenesis of late-onset depression compared to other forms of depression [23], the complex relationship between depression and cognitive impairment in seniors [47], as well as the higher vulnerability of older adults to side effects of antipsychotics, studies on parkinsonian symptoms with homogenous samples with regard to mental disorder diagnosis, age at symptom onset, cognitive status and antipsychotic medication are needed. In the present cases series, the follow-up assessment was conducted twelve months after hospital discharge, although drug-induced parkinsonian symptoms can persist longer than twelve months after cessation of the offending drug [12]. However, in general they resolve in six to nine months and 70% of patients usually recover within a few months after withdrawal of the causative drug [12, 36]. In addition, the diagnostic tools employed in the eight presented cases are characterized by shortcomings. For instance, the SAS has been criticized for overemphasizing body rigidity [48] and DaTSCAN interrater variability and inconsistencies between visual interpretation and classification based on quantitative radiotracer uptake calculation [49], which were also observed in cases presented here (Table 3), are further sources of uncertainty. Regarding the impact of DaTSCAN, the diagnosis itself is not exclusively driven by imaging findings, although physicians reported previously that DaTSCAN influences their final diagnosis, confidence in their diagnosis and management of the patient [50]. Of note, a case series including eight individuals does not suffice to generalize conclusions. Nonetheless, the observed differences in cause and 12-month follow-up outcome in this limited number of depressed older adults treated with antipsychotics point to the uncertainties related to the pathogenesis and development of parkinsonian symptoms in this clinical phenotype and age group and may fuel future research aiming to shed more light on a diagnostic riddle with therapeutic and prognostic implications.\n\nIn conclusion, detecting the cause of parkinsonian symptoms in seniors who are exposed to antipsychotics and subsequently taking appropriate action is a challenging task. Indeed, parkinsonian symptoms cannot be straightforwardly classified as drug-induced in older adults treated with antipsychotics. Age-related neurodegenerative and vascular brain changes may underlie parkinsonism and shape a terrain of unreliable clinical characteristics, ambiguous exam findings and in many cases hardly justifiable therapeutic choices. Comprehensive diagnostic workup is in cases with atypical, severe and/or persistent parkinsonian symptoms the only feasible strategy for developing proper treatment plans. The field of deciphering the cause of parkinsonian symptoms in seniors treated with antipsychotics merits a systematic and thorough study of possible clinical, imaging and outcome endophenotypes of such symptoms, so that in the future personalized and efficient therapeutic strategies can be designed. Familiarizing clinical psychiatrists with effective ways to cope with inconsistent and/or ambiguous imaging and clinical data and make good diagnostic and therapeutic decisions is another step towards this direction.\n\nAbbreviations\n\n5-HT2A receptor 5-hydroxy-tryptamin-type 2A receptor\n\nGDS Geriatric depression scale\n\nMMSE Mini-mental state examination\n\nSAS Simpson-Angus scale\n\nMRI Magnetic resonance imaging\n\nFLAIR Fluid Attenuation Inversion Recovery\n\nDWI Diffusion weighted imaging\n\nMTA Medial temporal lobe atrophy\n\nDaTSCAN Ioflupane (I-123) dopamine transporter (DAT) single photon emission computerized tomography (SPECT)\n\nSBI specific binding index\n\nICD-10 International Statistical Classification of Diseases and Related Health Problems version 10\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nAP and PA designed this study. NK, KS, GL collected this data. AP, MS, PT, CP, TH, GL, PA analyzed data. AP and PA mainly wrote this manuscript. NK, KS, GL, MS, PT, CP, TH helped in writing the manuscript. All authors have read and approved the final manuscript.\n\nFunding\n\nNot applicable.\n\nAvailability of data and materials\n\nAll data analyzed during this study are included in this published article in tables or text.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe study has been approved by the Bioethics Committee of the Medical School of the National and Kapodistrian University of Athens and was conducted in accordance with the 1964 Helsinki declaration and its later amendments. The authors state that the patients have given their written informed consent for participation in the study. They were deemed by the head psychogeriatrician capable of ethically and medically consenting for their participation.\n\nConsent for publication\n\nWritten informed consent for publication of their clinical details and diagnostic workup findings was obtained from patients, who were deemed by the head psychogeriatrician capable of ethically and medically consenting for publication of these data.\n\nCompeting interests\n\nPA is a member of the editorial board of BMC psychiatry. There has been no significant financial support for this work that could have influenced its outcome.\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. Forlani C Morri M Ferrari B Dalmonte E Menchetti M de Ronchi D Atti AR Prevalence and gender differences in late-life depression: a population-based study Am J Geriatr Psychiatry 2014 22 4 370 380 10.1016/j.jagp.2012.08.015 23567427\n2. 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"keywords": "Case series; Drug induced parkinsonism; Idiopathic tremor; Parkinson’s disease; Vascular parkinsonism",
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"title": "Differences in cause and 12-month follow-up outcome of parkinsonian symptoms in depressed older adults treated with antipsychotics: a case series.",
"title_normalized": "differences in cause and 12 month follow up outcome of parkinsonian symptoms in depressed older adults treated with antipsychotics a case series"
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"abstract": "Chronic granulomatous disease (CGD) is an autosomal recessive or X-linked disorder caused by NADPH oxidase deficiency leading to an impaired ability of reactive superoxide anion and metabolite formation and recurring severe bacterial and fungal infections, with a high mortality rate. Diarrhea, colitis, ileus, perirectal abscess formation and anal fissures are reported gastrointestinal findings in these patients. We report a case of intractable colitis associated with CGD in a young girl.",
"affiliations": "Division of Pediatric Gastroenterology, Department of Pediatrics, Ankara University Faculty of Medicine, Ankara, Turkey. aytacyaman@gmail.com.",
"authors": "Yaman|Aytaç|A|;Kuloğlu|Zarife|Z|;Doğu|Figen|F|;İkincioğulları|Aydan|A|;Ensari|Arzu|A|;Çiftçi|Ergin|E|;Kansu|Aydan|A|",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Intractable colitis associated with chronic granulomatous disease in a young girl.",
"title_normalized": "intractable colitis associated with chronic granulomatous disease in a young girl"
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"companynumb": "TR-PFIZER INC-2016003539",
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"abstract": "The authors report two cases of patients with advanced gastroenteric carcinoma, which developed different cardiotoxicity patterns after the administration of cytotoxic drugs. The first patient showed a picture of dilatative cardiomyopathy with associated symptoms of angina pectoris and congestive heart failure; the second patient presented a cardiac arrhythmia after several administrations of 5-fluorouracil. The possible mechanisms of these toxic effects, as well as the drug interactions are briefly discussed. Cardiotoxicity of cytotoxic drugs should be considered by oncologists even in patients with no previous history of cardiac disease.",
"affiliations": "Ospedale Sesto S. Giovanni, Centro Studi e Ricerche, A. Oldrini, Sesto S. Giovanni, Milano, Italia.",
"authors": "Raina|A|A|;Ferrante|F|F|;Bisol|A|A|;Fiori|G|G|;Galeone|M|M|",
"chemical_list": "D000970:Antineoplastic Agents; D008937:Mitomycins; D004317:Doxorubicin; D005472:Fluorouracil",
"country": "United States",
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"issn_linking": "0300-8916",
"issue": "73(4)",
"journal": "Tumori",
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"medline_ta": "Tumori",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D004317:Doxorubicin; D005260:Female; D005472:Fluorouracil; D006321:Heart; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D008937:Mitomycins; D013274:Stomach Neoplasms",
"nlm_unique_id": "0111356",
"other_id": null,
"pages": "359-61",
"pmc": null,
"pmid": "3660474",
"pubdate": "1987-08-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cardiotoxicity during chemotherapy for advanced gastroenteric tumors.",
"title_normalized": "cardiotoxicity during chemotherapy for advanced gastroenteric tumors"
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"companynumb": "IT-BAXTER-2020BAX021253",
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"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
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"abstract": "Metronidazole is an antimicrobial agent mainly used in the treatment of several protozoal and anaerobic infections, additionally, is often used in hepatic encephalopathy and Crohn disease. Apart from peripheral neuropathy, metronidazole can also cause symptoms of central nervous system dysfunction like ataxic gait, dysarthria, seizures, and encephalopathy which may result from both short term and chronic use of this drug and is collectively termed as \"metronidazole induced encephalopathy\"(MIE). Neuroimaging forms the backbone in clinching the diagnosis of this uncommon entity, especially in cases where there is high index of suspicion of intoxication. Although typical sites of involvement include cerebellum, brain stem and corpus callosum, however, lesions of other sites have also been reported. Once diagnosed, resolution of findings on Magnetic Resonance Imaging (MRI) of the Brain along with clinical improvement remains the mainstay of monitoring. Here we review the key clinical features and MRI findings of MIE as reported in medical literature. We also analyze implication of use of this drug in special situations like hepatic encephalopathy and brain abscess and discuss our experience regarding this entity.",
"affiliations": "Resident, Department of Neurology, Bangur Institute of Neurosciences, IPGMER , Kolkata, India .;Senior Resident, Department of Neurology, Vardhman Mahavir Medical College and Safdarjung Hospital , New Delhi, India .;Associate Professor, Department of Neurology, Bangur institute of Neurosciences, IPGMER , Kolkata, India .;Resident, Department of Neurology, Bangur Institute of Neurosciences, IPGMER , Kolkata, India .;Resident, Department of Neurology, Bangur Institute of Neurosciences, IPGMER, Kolkata, India.",
"authors": "Roy|Ujjawal|U|;Panwar|Ajay|A|;Pandit|Alak|A|;Das|Susanta Kumar|SK|;Joshi|Bhushan|B|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2016/19032.8054",
"fulltext": null,
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"issn_linking": "0973-709X",
"issue": "10(6)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Cerebellum; Corpus callosum; Magnetic resonance imaging; Nitroimidazoles; Toxicity",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "OE01-9",
"pmc": null,
"pmid": "27504340",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "24277041;26710409;17368540;19752101;7898724;11098341;2768064;22566735;7396319;17885234;19346865;24198899;22879116;12488741;8554259;19560788;842719;21763942;24339581;21874144;11778010;10474673;20171413;13679281;19452566;14676060;4130856;20703237;2887562;12774970;15778547;24401329;22019662;25865108;23650235;11818607;629500;25596288;15824365;15358960;15765436;21042443;198056;4727731;8412602;21996645;23115678;21757988;21082066;22870180;15855780;21339674;25561434;25374704;12736767;26157659;15450780;11790239;10588115",
"title": "Clinical and Neuroradiological Spectrum of Metronidazole Induced Encephalopathy: Our Experience and the Review of Literature.",
"title_normalized": "clinical and neuroradiological spectrum of metronidazole induced encephalopathy our experience and the review of literature"
} | [
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"companynumb": "IN-VIVIMED-2018SP006086",
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"abstract": "Candida species are infrequently grown in bile cultures. An association between biliary candidiasis and regional malignancy may exist. The role of fungus membranes in frequent biliary stent occlusion is also presented in this case series.\nWe retrospectively identified patients who underwent percutaneous trans-hepatic cholangiogram (PTC) for obstructive jaundice between January 2014 and January 2019. The results of bile cultures - obtained by PTC - for all patients were analyzed, and patients with fungus growth were determined; their medical records were reviewed.\nA total of 71 patients with obstructive jaundice underwent PTC between January 2015 and January 2019. Five patients (all male; mean age 55.8 years) had candida species growth in bile cultures. Two patients were diagnosed with cholangiocarcinoma, one with adenocarcinoma of the head of the pancreas, one with gallbladder cancer, and one with locally advanced gastric adenocarcinoma. Formation of fungal balls predisposed to frequent PTC drain clogging. Eradication of Candida was achieved in 4 patients after 10 days to 3 weeks of antifungal therapy.\nWe present a case series of biliary candidiasis in patients with obstructive jaundice and regional malignancy. We suggest that patients with obstructive jaundice and regional malignancy should be screened for biliary candidiasis. Persistent cholestasis may be caused by the recurrent formation of fungal membranes (balls).",
"affiliations": "Department of General Surgery, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan.;Department of Internal Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan.;Department of General Surgery, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan.;Department of Radiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan.;Department of Radiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan.;Department of General Surgery, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan.;Department of Radiology, Faculty of Medicine, The Hashemite University, Zarqa, Jordan.;Department of General Surgery, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan.",
"authors": "Al Manasra|Abdel Rahman A|ARA|0000-0003-4556-6000;Jadallah|Khaled|K|0000-0001-9177-0980;Aleshawi|Abdelwahab|A|;Al-Omari|Mamoon|M|0000-0002-3166-0939;Elheis|Mwaffaq|M|0000-0003-3829-8191;Reyad|Ahmad|A|;Fataftah|Jehad|J|0000-0003-0812-5695;Al-Domaidat|Hamzeh|H|0000-0001-5688-3744",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/CEG.S301340",
"fulltext": "\n==== Front\nClin Exp Gastroenterol\nClin Exp Gastroenterol\nceg\nceg\nClinical and Experimental Gastroenterology\n1178-7023\nDove\n\n301340\n10.2147/CEG.S301340\nOriginal Research\nIntractable Biliary Candidiasis in Patients with Obstructive Jaundice and Regional Malignancy: A Retrospective Case Series\nAl manasra et al\nAl manasra et al\nhttp://orcid.org/0000-0003-4556-6000\nAl manasra Abdel rahman A 1\nhttp://orcid.org/0000-0001-9177-0980\nJadallah Khaled 2\nAleshawi Abdelwahab 1\nhttp://orcid.org/0000-0002-3166-0939\nAl-Omari Mamoon 3\nhttp://orcid.org/0000-0003-3829-8191\nElheis Mwaffaq 3\nReyad Ahmad 1\nhttp://orcid.org/0000-0003-0812-5695\nFataftah Jehad 4\nhttp://orcid.org/0000-0001-5688-3744\nAl-Domaidat Hamzeh 1\n1 Department of General Surgery, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan\n2 Department of Internal Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan\n3 Department of Radiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan\n4 Department of Radiology, Faculty of Medicine, The Hashemite University, Zarqa, Jordan\nCorrespondence: Abdel rahman A Al manasra Department of General Surgery, Faculty of Medicine, Jordan University of Science and Technology, P.O. Box 3030, Irbid, JordanTel +962 796453510 Email abdjust@yahoo.com\n04 3 2021\n2021\n14 8389\n10 1 2021\n24 2 2021\n© 2021 Al manasra et al.\n2021\nAl manasra et al.\nThis work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nBackground\n\nCandida species are infrequently grown in bile cultures. An association between biliary candidiasis and regional malignancy may exist. The role of fungus membranes in frequent biliary stent occlusion is also presented in this case series.\n\nMethods\n\nWe retrospectively identified patients who underwent percutaneous trans-hepatic cholangiogram (PTC) for obstructive jaundice between January 2014 and January 2019. The results of bile cultures – obtained by PTC – for all patients were analyzed, and patients with fungus growth were determined; their medical records were reviewed.\n\nResults\n\nA total of 71 patients with obstructive jaundice underwent PTC between January 2015 and January 2019. Five patients (all male; mean age 55.8 years) had candida species growth in bile cultures. Two patients were diagnosed with cholangiocarcinoma, one with adenocarcinoma of the head of the pancreas, one with gallbladder cancer, and one with locally advanced gastric adenocarcinoma. Formation of fungal balls predisposed to frequent PTC drain clogging. Eradication of Candida was achieved in 4 patients after 10 days to 3 weeks of antifungal therapy.\n\nConclusion\n\nWe present a case series of biliary candidiasis in patients with obstructive jaundice and regional malignancy. We suggest that patients with obstructive jaundice and regional malignancy should be screened for biliary candidiasis. Persistent cholestasis may be caused by the recurrent formation of fungal membranes (balls).\n\nKeywords\n\nCandida\nobstructive jaundice\ncholangiocarcinoma\nbiliary\nPTC\n==== Body\nIntroduction\n\nFungi represent an important cause of infection to human being. Candida albicans is the most pathogenic yeast species.1 Candida parapsilosis, Candida glabrata, Candida tropicalis and the newly identified (1995) species of Candida dubliniensis (Dublin, Ireland)2 have also been associated with most forms of candidiasis. Fungal infections are frequently recognized, especially in patients with risk factors including cystic fibrosis, long term antibiotic therapy, prolonged critical care admission, and immunosuppression.3 Fungal involvement of the biliary tract seems to occur more often nowadays, probably due to the greater use of biliary interventions, both endoscopic and percutaneous.4 Data concerning the microbiological flora of the biliary tract are scarce, probably due to methodological limitations.4 Although bile analysis is useful to guide the therapeutic procedures in patients with biliary infections, few studies performed a microbiological analysis of bile in patients with different biliary diseases (Figure 1).Figure 1 Light microscopy for histopathology smears of infected bile (400×), (A) budding yeast (B) Candida albicans demonstrating chlamydospores (arrow 1), blastospores (arrow 2) and pseudohyphae (arrow 3).\n\nTable 1 Clinical Course, Management and Outcome of Patients\n\n\tPatient No.1\tPatient No.2\tPatient No.3\tPatient No.4\tPatient No.5\t\nFungus species\tCandida albicans\tCandida glabrata\tCandida albicans\tCandida albicans\tCandida albicans\t\nAntifungal treatment\tFluconazole “systemic” 200mg/day\nTwice -daily drain flush with 100mg fluconazole\tFluconazole,systemic 200mg/day\nTwice -daily drain flush with 100mg fluconazole\tFluconazole,systemic 200mg/day\nSystemic Caspofungin\nTwice -daily drain flush with 100mg fluconazole\tSystemic,Fluconazole\tFluconazole “systemic” 200mg/day\nTwice -daily drain flush with 100mg fluconazole\t\nFungal eradication\tYes, after 10 days\tYes, after 2 months\tNo eradication after 6 months.\tYes, after 2 weeks\tYes after 5 weeks\t\nInterventions\t- ERCP* attempted and failed.\n-PTC**: internal external drainage\n- PTC: metallic stent with external drainage.\n-PTC: removal of drainage.\t- ERCP: failed and complicated by duodenal perforation.\n- PTC: internal external drainage for persistent jaundice.\n- PTC: metallic stent deployed, drainage kept in place.\n- Whipple’s surgery\n- PTC: stent with external drainage due to postoperative bile leak and anastomotic stricture.\n- PTC: stent removed\t- ERCP: insertion of rubber stent at another hospital before presenting to us.\n- PTC: internal external drainage.\n- multiple PTC procedures for replacement and repositioning of drains.\t-ERCP attempted and failed.\n-PTC: internal external drainage.\n- PTC: metallic stent deployed, drain removed.\t-ERCP failed.\n-PTC: internal external drainage.\n- multiple PTC procedures for replacement and repositioning of drains.\n- PTC: metallic stent deployed, drain removed.\t\nFollowing interventions\tChemotherapy\tChemotherapy\tNone\tChemotherapy\tChemotherapy\t\nSurvival after presentation\tAlive after 5 months\tDeath after 15 months\tDeath after 6 months\tDeath after 6 months\tDeath after 7 months\t\nAbbreviations: *ERCP, endoscopic retrograde cholangiopancreatography; **PTC, percutaneous transhepatic cholangiogram.\n\nTable 2 Clinical and Demographic Features of Patients\n\nPatient No.\tAge\tGender\tClinical Presentation\tPrimary Diagnosis\tDisease Stage (Radiologic)\tComorbidities\t\n1\t71\tMale\tObstructive jaundice\tGallbladder Cancer\tExtensive distant lymph node involvement and mesenteric deposits\tPrevious History of urinary bladder Cancer\t\n2\t51\tMale\tObstructive jaundice\tAdenocarcinoma of the head of the pancreas\tNo evidence of metastasis Stage 1b\tSmoker, FAP mutation with history of colectomy\t\n3\t54\tMale\tObstructive jaundice, abdominal pain\tDistal cholangiocarcinoma\tPleural and lungs metastasis\tDiabetes Mellitus\t\n4\t40\tMale\tObstructive jaundice, epigastric pain\tAdvanced gastric cancer\tLiver metastasis and extensive Lymph node involvement\tSmoker\t\n5\t63\tMale\tObstructive jaundice, epigastric pain\tAdenocarcinoma of the head of the pancreas\tMultiple liver metastatic lesions\tHypertension\t\nAbbreviation: FAP, familial adenomatous polyposis.\n\nDespite the emerging awareness of biliary candidiasis, its clinical relevance and potential risk factors remain debatable The terms “Biliary candidiasis” or “Biliary mycosis” are alternatively used when candida species is detected in microbiological bile fluid analysis, with or without cholangitis. However, it is still controversial whether positive bile analysis represents fungal infection or colonization, and how the results should impact the therapeutic approach. In this study, we review cases of biliary candidiasis in the setting of biliary or regional malignancy, highlighting the potential correlation between biliary candidiasis and malignancy. Additionally, we describe the role of fungus balls in frequent biliary stent occlusion.\n\nPatients and Methods\n\nStudy Design\n\nThis is a retrospective study in which we identified patients who underwent percutaneous trans-hepatic cholangiogram (PTC) for obstructive jaundice between January 2015 and January 2019. The results of bile cultures for all patients were examined.\n\nInclusion Criteria\n\nOnly patients with fungus growth in bile cultures were included. The medical records of these patients were reviewed, and definitive diagnosis, management protocols, and outcomes were described.\n\nEthics\n\nThe study protocol was reviewed and approved by the Institutional Review Board at King Abdullah University Hospital and by the Committee of Research on Human Subjects at the Jordan University of Science and Technology. (Non-funded research No: 20200438). We protected Patients’ confidentiality in accordance with declaration of Helsinki provisions. Written informed consent was obtained from the patients for the inclusion of their clinical data within this work.\n\nProcedures\n\nEndoscopic retrograde cholangiopancreatography (ERCP), as the intervention of choice, was attempted by an experienced gastroenterologist in those 5 patients. Inability to achieve biliary access in those patients through ERCP was attributed to the high-grade blockage of the distal portion of the common bile duct.5\n\nTherefore, PTC was performed next, in which the level of obstruction was demonstrated, bypassed, and balloon-dilated. Bile samples for cultures for bacteria and fungi were obtained, and biopsies and/or brush cytology were taken. Occasionally, Candida pseudohyphae were directly observed on bile smears. We submitted samples for fungal culture in patients with a high-grade obstruction or prolonged jaundice. The specimens were cultivated both on Kimmig agar plates and in Sabouraud bouillons and additional delineation was performed by micromorphological and biochemical methods.\n\nDuring initial PTC, internal plastic stents were placed without the routine use of external drainage, given that distal contrast runoff was smooth and free. After stent placement, an initial drop in cholestatic indices (direct bilirubin, alkaline phosphatase, gamma-GT) level was observed in nearly all patients, but then it spiked again in 48 to 72hrs. A repeat PTC confirmed partial or complete blockage of the stent with filling defects (fungus balls) in the common bile duct (Figure 2). Therefore, bile samples were resubmitted and an internal-external biliary drain was left in place. The daily drainage through the external catheter ranged from one to two liters, indicating persistent or recurrent occlusion. Multiple PTC stent revisions were necessary for several patients as shown in Table 1.Figure 2 Common bile duct stent partial occlusion with filling defects (fungus balls) at the tip of the black arrow.\n\nFollowing the diagnosis of fungal cholangitis with direct visualization of pseudohyphae in smears or positive culture growth, we started systemic antifungals with fluconazole 200mg/day and twice-daily drain flush with 100mg of fluconazole until repeat culture showed no growth.\n\nResults\n\nA total of 71 patients (mean age: 55.8, M: F 5:0) with obstructive jaundice underwent PTC between January 2015 and January 2019. Only 5 patients (7%) had candida growth on PTC-obtained bile cultures (4 Candida albicans, 1 Candida glabrata). Two patients were diagnosed with cholangiocarcinoma, one with adenocarcinoma of the head of the pancreas, one with gallbladder cancer, and one with gastric adenocarcinoma. The patient with pancreatic adenocarcinoma experienced fungal cholangitis, which was successfully eradicated, and then he underwent a pancreaticoduodenectomy (Whipple’s procedure). The rest of the patients had metastatic disease at the time of diagnosis and were referred -after fungus eradication- for chemotherapy. Table 2 summarizes the clinical and demographic features of our cases. Patients’ comorbidities, disease staging, treatment options, and outcomes are illustrated in Table 1. Formation of fungal membranes predisposed to frequent drain clogging. Eradication was achieved in 4 patients after 10 days, 2 months, 2 weeks, and 3 weeks. One patient died after 6 months with persistent candida growth and frequent stent occlusion. Concerning the other 4 patients, chemotherapy delay intervals correlated with the aforementioned eradication periods.\n\nDiscussion\n\nIn this series, although we cultured candida species in 7% of patients undergoing PTC, we demonstrated that all patients with biliary candidiasis are found to have biliary or regional malignancy. In spite of the fact that other predisposing factors –including immunodeficiency, biliary instrumentation, and prolonged stagnation due to stricture- contribute to fungus overgrowth inside bile ducts, this rare infection was alarming for the presence of cancer.\n\nFungal cholangitis, as a form of Invasive candidiasis, is a leading cause of sepsis (candidemia) in this population, ie; patients with locoregional malignancies. Given the high cost of antifungal drugs, the potential for toxicity with prolonged use, and the poorer outcomes associated with delayed therapy; it is highly recommended that clinical microbiology as well as infectious diseases services are incorporated in the diagnosis and management of invasive candidiasis. The guidelines published by National Institute for Health and Care Excellence (NICE)6 along with 2019 updates on the core elements of hospital antibiotic Stewardship programs, both emphasized the importance of tracking, monitoring, and reporting of antimicrobial impact and outcomes.7\n\nWelch has first described microbial presence in bile more than 130 years ago when Bacteria implication in gallstone pathogenesis was revealed.8,9 Pathogens may enter the biliary tree by a retrograde ascent from the duodenum -where 100–1000 bacteria live in each 1 milliliter of its’ lining mucosa- or from portal venous blood or during instrumentation of CBD.10\n\nBecause of the existence of biliary sphincter, bile flow, and some bile components that have antibacterial features, such as bile acids and immunoglobulin A (IgA), many authors suggest that bile in the biliary tract would be normally sterile unless the bile ducts are obstructed, or stones are present.11 On the contrary, multiple bacterial strains that can grow in bile (bile-tolerant) have been recently identified with the application of next-generation sequencing.12 These strains may induce chronic infection with possible malignant transformation (eg Helicobacter species, Hemophilus influenzae, E. coli).13\n\nMoreover, in a study of 19 bile samples obtained during surgery from patients with a normal biliary tree (no stones or obstruction), there was positive growth in 16/19 samples for bacteria which led to a conclusion that human bile is not, as first thought, sterile.14\n\nMost studies were conducted on abnormal biliary systems or unhealthy individuals. To make more reliable conclusions on the normal flora of the biliary system we believe that further studies of the normal biliary system of healthy individuals are warranted. However, this type of study may face technical challenges or ethical barriers. Therefore, we recommend obtaining bile cultures in all cases of biliary obstruction, and we believe that fungus growth in bile cultures obtained by PTC is of clinical significance.\n\nIn patients with obstructive jaundice, ERCP is usually attempted first. According to the American Society for Gastrointestinal Endoscopy (ASGE) guidelines,15 ERCP is the intervention of choice due to its advantage of drainage without the need for an external catheter. However, ERCP has a failure rate of 10–15%.16 Common reported causes of ERCP failure include duodenal diverticula, which increases with age, adhesions due to previous upper abdominal surgery or gastrointestinal diversions, or to a less extent obstruction due to tumors.17 The failure rate increases by 78-fold in patients with periampullary tumors that infiltrate the ampulla of Vater. Hence, PTC is a suitable alternative, especially in patients with a hilar obstruction or surgically-altered anatomy.18\n\nSince bile samples from PTC are less prone to contamination by intestinal flora than ERCP samples, cultures from PTC samples are more reliable for an accurate diagnosis and antimicrobial selection.19\n\nSeveral studies10,20,21 have investigated biliary candidiasis in terms of clinical presentation, diagnosis, and treatment modalities. However, only a few studies have analyzed its correlation with malignancy22 and the impact on patient outcomes, including survival rates. In a study by Kim and colleagues,18 Candida species were found in 23% of bile samples collected during PTC from patients with cholangiocarcinoma; Patients with biliary candidiasis had reduced survival compared to those without, the authors suggested that biliary candidiasis is a factor of poor prognosis. Reduced survival is probably attributed to factors such as sepsis, poor oral intake, complications of frequent invasive interventions, and delayed surgery or chemotherapy.\n\nIn another study by Lenz and colleagues,4 in which bile samples were collected during ERCP, Candida was isolated in 30% of patients. However, all patients suffered from severe chronic diseases and required frequent intervention; the authors found in a multivariate analysis that previous endoscopic sphincterotomy -which eliminates an important protective mechanism- was a significant risk factor for biliary candidiasis.\n\nOther studies have demonstrated that fungus balls could be responsible for frequent CBD and stent occlusion. Story and Gluck23 described the soft filling defects within the bile duct. They also outlined the treatment approach, which consisted of daily oral antifungal and daily antifungal flushing through PTC external drain or cholecystostomy tube. In that study, the proposed treatment succeeded in the eradication of the infection in about 75% of cases.\n\nIn the present study, the diagnosis of fungal cholangitis preceded that of malignancy, suggesting that biliary candidiasis could be a warning sign of an underlying malignancy. We also highlight the role of fungus balls in frequent stent occlusion after PTC or ERCP, which is a rare but potentially treatable condition. Additionally, we emphasize the role of combined (systemic and intra-biliary) antifungal therapy in eradicating the pathogen. Our results suggest that biliary candidiasis could be associated with a worse prognosis.\n\nThis study has some limitations. Firstly, it is a retrospective study. Secondly, the sample size of patients with biliary candidiasis was too small to evaluate risk factors with statistical significance. Thirdly, many patients who did not have their bile cultures obtained may still have the infection, leading to some false-negative cases. Despite these limitations, the findings in this study contribute to the understanding of cancer association with biliary candidiasis and the importance of the implementation of an appropriate treatment approach.\n\nIn Conclusion, sampling bile for culture is recommended in patients with obstructive jaundice. Biliary candidiasis should raise concerns of underlying biliary or regional malignancy, in particular in the absence of other risk factors. Persistent cholestasis after biliary drainage may be attributed to fungus growth in the form of fungal balls, which may delay treatment by chemotherapy or surgery. Future prospective studies are warranted to investigate the putative association between biliary candidiasis and malignancy.\n\nDisclosure\n\nThe authors report no conflicts of interest for this work.\n==== Refs\nReferences\n\n1. Moran GP, Coleman DC, Sullivan DJ. Candida albicans versus Candida dubliniensis: why is Calbicans more pathogenic? Int J Microbiol. 2012;2012 :205921. doi:10.1155/2012/205921 21904553\n2. Krcmery V, Barnes AJ. Non-albicans Candida spp. causing fungaemia: pathogenicity and antifungal resistance. J Hosp Infect. 2002;50 (4 ):243–260. doi:10.1053/jhin.2001.1151 12014897\n3. Lenz P, Eckelskemper F, Erichsen T, et al. Prospective observational multicenter study to define a diagnostic algorithm for biliary candidiasis. World J Gastroenterol. 2014;20 (34 ):12260–12268. doi:10.3748/wjg.v20.i34.12260 25232260\n4. Lenz P, Conrad B, Kucharzik T, et al. Prevalence, associations, and trends of biliary-tract candidiasis: a prospective observational study. Gastrointest Endosc. 2009;70 (3 ):480–487. doi:10.1016/j.gie.2009.01.038 19555935\n5. Swan MP, Bourke MJ, Williams SJ, et al. Failed biliary cannulation: clinical and technical outcomes after tertiary referral endoscopic retrograde cholangiopancreatography. World J Gastroenterol. 2011;17 (45 ):4993–4998. doi:10.3748/wjg.v17.i45.4993 22174549\n6. National Institute for Health and Care Excellence. Guideline NG15. Antimicrobial stewardship: systems and processes for effective antimicrobial medicine use. Available from: https://www.nice.org.uk/guidance/ng15/resources/antimicrobial-stewardship-systemsand-processes-for-effective-antimicrobial-medicine-use-1837273110469. Accessed 8, 2021.\n7. CDC. Core elements of hospital antibiotic Stewardship programs. Atlanta, GA: US Department of Health and Human Services, CDC; 2019. Available from: https://www.cdc.gov/antibiotic-use/core-elements/hospital.html. Accessed 28, 2021.\n8. Keighley MR. Micro-organisms in the bile. A preventable cause of sepsis after biliary surgery. Ann R Coll Surg Engl. 1977;59 (4 ):328–334.879637\n9. Wetter LA, Hamadeh RM, Griffis JM, et al. Differences in outer membrane characteristics between gallstone-associated bacteria and normal bacterial flora. Lancet. 1994;343 (8895 ):444–448. doi:10.1016/S0140-6736(94)92691-3 7905954\n10. Shenoy SM, Shenoy S, Gopal S, Tantry BV, Baliga S, Jain A. Clinicomicrobiological analysis of patients with cholangitis. Indian J Med Microbiol. 2014;32 :157–160. doi:10.4103/0255-0857.129802 24713902\n11. Suna N, Yıldız H, Yüksel M, et al. The change in microorganisms reproducing in bile and blood culture and antibiotic susceptibility over the years. Turk J Gastroenterol. 2014;25 :284–290. doi:10.5152/tjg.2014.6253\n12. Ye F, Shen H, Li Z, et al. Influence of the biliary system on biliary bacteria revealed by bacterial communities of the human biliary and upper digestive tracts. PLoS One. 2016;11 (3 ):e0150519. doi:10.1371/journal.pone.0150519 26930491\n13. Ljungh Å, Wadström T. The role of microorganisms in biliary tract disease. Curr Gastroenterol Rep. 2002;4 :167–171. doi:10.1007/s11894-002-0055-6 11900683\n14. Warburton RC, Gelson W, Harper S, et al. Human bile retrieved from the normal biliary system is not sterile. J Hepatol. 2017;1 (66 ):S63–S94.\n15. Buxbaum JL, Abbas Fehmi SM, Sultan S, Fishman DS, Qumseya BJ, Cortessis VK. ASGE guideline on the role of endoscopy in the evaluation and management of choledocholithiasis. Gastrointest Endosc. 2019;89 (6 ):1075–1105.e15. doi:10.1016/j.gie.2018.10.001 30979521\n16. Collins C, Maguire D, Ireland A, Fitzgerald E, O’Sullivan GC. A prospective study of common bile duct calculi in patients undergoing laparoscopic cholecystectomy. Ann Surg. 2014;239 :28–33. doi:10.1097/01.sla.0000103069.00170.9c\n17. Balik E, Eren T, Keskin M, et al. Parameters that may be used for predicting failure during endoscopic retrograde cholangiopancreatography. J Oncol. 2013;2013 :201681. doi:10.1155/2013/201681 23861683\n18. Kim IH, Choi JK, Lee DG, et al. Clinical significance of isolated biliary candidiasis in patients with unresectable cholangiocarcinoma. Hepatobiliary Pancreat Dis Int. 2016;15 :533–539. doi:10.1016/S1499-3872(16)60109-1 27733324\n19. Negm AA, Schott A, Vonberg RP, et al. Routine bile collection for microbiological analysis during cholangiography and its impact on the management of cholangitis. Gastrointest Endosc. 2010;72 (2 ):284–291. doi:10.1016/j.gie.2010.02.043 20541201\n20. Neve RA, Biswas S, Dhir V, Mohandas KM, Kelkar R, Shukla P. Bile cultures and sensitivity patterns in malignant obstructive jaundice. Indian J Gastroenterol. 2003;22 (1 ):16–18.12617446\n21. Diebel LN, Raafat AM, Dulchavsky SA, Brown WJ. Gallbladder and biliary tract candidiasis. Surgery. 1996;120 (4 ):760–764. doi:10.1016/S0039-6060(96)80028-6 8862389\n22. Yu H, Guo Z, Xing W, Guo X, Liu F, Li B. Bile culture and susceptibility testing of malignant biliary obstruction via PTBD. Cardiovasc Intervent Radiol. 2012;35 :1136–1144. doi:10.1007/s00270-011-0263-2 21904809\n23. Story B, Gluck M. Obstructing fungal cholangitis complicating metal biliary stent placement in pancreatic cancer. World J Gastroenterol. 2010;16 (24 ):3083–3086. doi:10.3748/wjg.v16.i24.3083 20572314\n\n",
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"abstract": "BACKGROUND Cancer in pregnancy is extremely rare, and gastric cancers are rarer still. Diagnosis is difficult in pregnancy due to overlapping symptoms with pregnancy such as nausea, pain, anemia, and fatigue. CASE REPORT A 26-year-old G1 woman at 32 weeks gestation with a past medical history of systemic lupus erythematosus presented with new-onset chest pain and shortness of breath. Computed tomography of the chest, electrocardiogram, and echocardiogram were normal. Laboratory evaluation revealed thrombocytopenia, proteinuria of 480 milligrams, and normal complement. She delivered on hospital day 3 due to worsening chest pain. During cesarean delivery, the patient became hypotensive and hypoxic and required intensive care unit admission after a cesarean hysterectomy. On postoperative day 2 she had a pulmonary embolus and was started on therapeutic anticoagulation. She clinically improved until postoperative day 4, when she was found unresponsive with pulseless electrical activity. After 38 minutes of Advanced Cardiac Life Support, death was pronounced. An autopsy was performed and the cause of death found to be complications of multi-organ system involvement of adenocarcinoma with signet ring cell features. Lymphangitic carcinomatosis was noted throughout the lungs. CONCLUSIONS This patient had adenocarcinoma with signet ring cell features and associated lymphangitic carcinomatosis, which led to her postpartum death. Lymphangitic carcinomatosis is associated with an exceedingly poor prognosis, especially in pregnancy.",
"affiliations": "Department of Obstetrics and Gynecology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Department of Obstetrics and Gynecology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Department of Obstetrics and Gynecology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Department of Obstetrics and Gynecology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Department of Obstetrics and Gynecology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.",
"authors": "Whittington|Julie R|JR|;Whitcombe|Dayna D|DD|;Eads|Lauren E|LE|;Jeffus|Susanne K|SK|;Quick|Charles M|CM|;Wendel|Paul J|PJ|;Magann|Everett F|EF|",
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"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3184403610.12659/AJCR.919412919412ArticlesSignet Ring Cell Carcinoma with Lymphangitic Carcinomatosis in Pregnancy: A Case Report of an Unexpected Maternal Death and Review of the Literature Whittington Julie R. ABCDEF1Whitcombe Dayna D. ACEF1Eads Lauren E. BDE1Jeffus Susanne K. DE2Quick Charles M. D2Wendel Paul J. ABCD1Magann Everett F. ABCDE1\n1 Department of Obstetrics and Gynecology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A.\n2 Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Julie R. Whittington, e-mail: Julie.whittington09@gmail.com2019 17 12 2019 20 1888 1891 14 8 2019 17 10 2019 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 26-year-old\n\nFinal Diagnosis: Adenocarcinoma with signet-ring cell features\n\nSymptoms: 32 week gestation with new onset chest pain and shortness of breath\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Obstetrics and Gynecology\n\nObjective:\nRare co-existance of disease or pathology\n\nBackground:\nCancer in pregnancy is extremely rare, and gastric cancers are rarer still. Diagnosis is difficult in pregnancy due to overlapping symptoms with pregnancy such as nausea, pain, anemia, and fatigue.\n\nCase Report:\nA 26-year-old G1 woman at 32 weeks gestation with a past medical history of systemic lupus erythematosus presented with new-onset chest pain and shortness of breath. Computed tomography of the chest, electrocardiogram, and echocardiogram were normal. Laboratory evaluation revealed thrombocytopenia, proteinuria of 480 milligrams, and normal complement. She delivered on hospital day 3 due to worsening chest pain. During cesarean delivery, the patient became hypotensive and hypoxic and required intensive care unit admission after a cesarean hysterectomy. On postoperative day 2 she had a pulmonary embolus and was started on therapeutic anticoagulation. She clinically improved until postoperative day 4, when she was found unresponsive with pulseless electrical activity. After 38 minutes of Advanced Cardiac Life Support, death was pronounced. An autopsy was performed and the cause of death found to be complications of multi-organ system involvement of adenocarcinoma with signet ring cell features. Lymphangitic carcinomatosis was noted throughout the lungs.\n\nConclusions:\nThis patient had adenocarcinoma with signet ring cell features and associated lymphangitic carcinomatosis, which led to her postpartum death. Lymphangitic carcinomatosis is associated with an exceedingly poor prognosis, especially in pregnancy.\n\nMeSH Keywords:\nCarcinoma, Signet Ring CellMaternal MortalityNeoplasm MetastasisPregnancy Complications, Neoplastic\n==== Body\nBackground\nCancer in pregnancy is extremely rare, with 0.001–0.09% of pregnancies being affected [1,2]. Rarer still is gastric carcinoma, which has an incidence of 0.2/100 000 pregnancies [2]. Diagnosis of cancer in pregnancy is difficult and can be delayed due to comparable symptoms such as nausea, abdominal pain, anemia, and fatigue [3]. We present a case of metastatic signet ring cell carcinoma with lymphangitic carcinomatosis that was diagnosed at autopsy after maternal death on postpartum/postoperative day 4. Overall, the maternal mortality rate in the United States is estimated to be 18 per 100 000 births [4]. In approximately 6.5% of all maternal deaths, the cause is unknown [4]. Without autopsy, our case likely would have ended up either wrongly categorized or without a known cause.\n\nCase Report\nA 26-year-old female gravida 1 was referred to our institution at 14 weeks’ gestation by last menstrual period, consistent with a 9-week ultrasound for supervision of high-risk pregnancy secondary to maternal history of systemic lupus erythematosus (SLE). Outside records revealed positive ANA with elevated SSA >8 and SSB of 1.6 (normal SSA and SSB <1). Physical examination at time of initial presentation to our institution was consistent with a normally developed young woman, normotensive, with a BMI of 26. Physical examination at that time was unre-markable. Baseline pregnancy-induced hypertension lab work at 15 weeks’ gestation was within normal limits and 24-hour urine collection was 150 mg of protein. An echocardiogram demonstrated normal cardiac structure and function, with an ejection fraction of 60%. Targeted ultrasound evaluation at 22 weeks’ gestation revealed a normal fetal anatomic survey, growth, and amniotic fluid volume. A fetal echocardiogram was normal.\n\nAt 32 weeks’ gestation the patient presented to a clinic with complaints of new-onset chest pain and shortness of breath with palpitations and new-onset proteinuria. She was admitted to the hospital for further evaluation, with a leading differential diagnosis of preeclampsia versus lupus flare. Lab work revealed thrombocytopenia (69 000), 24-hour urine protein of 480 milligrams, and normal C3/C4 complement levels. She was normotensive, but required supplemental oxygen to maintain oxygen saturations >95%. Computed tomography (CT) protocol to diagnose pulmonary embolus was performed, with no central segmental pulmonary embolus demonstrated. Bilateral ground-glass changes with peri-bronchovascular nodularity and mediastinal hilar lymphadenopathy were noted (Figure 1). Echocardiography was repeated and again demonstrated normal cardiac structure and function, with an ejection fraction of 60%. Azithromycin and ceftriaxone were initiated for possible community-acquired pneumonia.\n\nIn the setting of normal complement and no other signs of lupus on exam, the leading diagnosis was atypical preeclampsia and the decision was made to proceed with delivery on hospital day 3 due to worsening symptoms and lab results. She underwent primary low transverse cesarean section and delivered a viable female infant with Apgar scores of 7 and 8 and weight of 2020 grams. Immediately following delivery, the patient clinically decompensated, becoming hypotensive and hypoxic, requiring resuscitative measures with vasopressors, transfusion of blood products, and intubation. The immediate postpartum course was also complicated by uterine atony, and she subsequently underwent supra-cervical hysterectomy after no improvement with conservative management, including bimanual uterine massage, utero-tonic medication (carboprost), and B-lynch suture placement. On postoperative day 1, her course was complicated by continued postpartum hemorrhage requiring bilateral uterine artery embolization. Resuscitative efforts beginning intra-operatively and extending through postoperative day 2 were guided by serial rotational thromboelastometry (ROTEM) and included a total of 5 units packed red blood cells, 7 units of fresh frozen plasma, 3 units of cryoprecipitate, and 3 units of platelets. A CT pulmonary embolus protocol was performed on postoperative day 2 due to complaint of sudden-onset shortness of breath with associated tachypnea and hypoxia. The CT demonstrated bilateral pulmonary emboli with right heart strain (significant right ventricular enlargement) (Figure 2). She was transferred to the surgical intensive care unit for closer monitoring and management with continuous pulse oximetry and initiation of heparin drip while bridging to therapeutic warfarin dosing. On postoperative day 4, the patient was found unresponsive with pulseless electrical activity (PEA). Advanced cardiac life support was immediately initiated. After 38 minutes of resuscitation, compressions were discontinued and death was pronounced.\n\nAutopsy was performed, revealing the cause of death to be complications of multi-organ system involvement by adenocarcinoma with signet ring cell features (Figure 3). We discovered adenocarcinoma with signet ring cell features involving lymph-vascular spaces (lymphangitic carcinomatosis), as well as multiple small thrombi of all lobes of the lung, and mediastinal/hilar lymphadenopathy involved by metastatic adenocarcinoma (Figure 4). The right ovary was also enlarged at 6.3 cm with a 4-cm right ovarian mass involved with adenocarcinoma with signet ring cell features. The vertebral bone marrow and spleen were also extensively involved. The primary site of cancer could not be definitively identified, although a gastric primary site was thought to be the most likely source given that gastric adenocarcinoma accounts for 96% of signet ring cell carcinomas.\n\nDiscussion\nA literature search was undertaken by our research librarian using the search engines of PubMed and Web of Science. The search terms used included “lymphangitic OR lymphangitis AND carcinomatosis” AND “pregnancy”. The search was limited to articles in English and there was no limit on the years searched. Two authors (DDW and JRW) independently reviewed the abstracts and citations from the literature search. Inclusion criteria included any article that discussed lymphangitic carcinomatosis and its diagnosis or management in pregnancy. Only 1 case of metastatic lymphangitic carcinomatosis in pregnancy was found in the literature search [5].\n\nPulmonary lymphangitic carcinomatosis (PLC), defined as the spread of tumor cells throughout the lymphatic system of the lungs, occurs in 6–8% of patients with pulmonary metastases and is considered a rare end-stage manifestation of malignancy that carries a poor prognosis. The most common primary sites are the stomach, breast, lung, pancreas, colon, and prostate, with 80% being adenocarcinomas. Tumor cells are theorized to invade lymphatic vessels, likely through diaphragm and pleural surfaces, or spread from hilar lymph nodes, leading to obstruction of these vessels. As described in this case, patients with PLC often present with chief complaints of shortness of breath and pleuritic chest pain. Cough is another common presenting symptom. Without early recognition, complications of PLC, including pulmonary emboli, pulmonary hypertension, or cor pulmonale, can result in increased morbidity and mortality. Symptoms characteristic of the primary site of cancer are often absent [6–9].\n\nThis patient’s history of systemic lupus erythematosus (SLE) complicated the clinical picture, making a definitive diagnosis even more challenging, as most patients with SLE show some sign of involvement of the lungs, pulmonary vasculature, pleura, and/or diaphragm during the course of their disease. Pleural involvement is common in SLE and may cause chest pain. Patients also may report cough and/or dyspnea. Respiratory symptoms must also be distinguished from infection, particularly if the patient is on immunosuppressive therapy or in an immunocompromised state, as is the case with pregnancy. Additionally, maternal complications of preeclampsia may include pulmonary edema, acute respiratory distress syndrome, and coagulopathy, which are all more likely to occur in the presence of pre-existing medical disorders such as SLE.\n\nImaging, including chest radiography and computed tomography (CT), in patients with PLC may be normal or have non-specific findings. Grossly, lung parenchyma appear normal on imaging [6]. More subtle findings due to extensive infiltration of lymphatic vessels with tumor cells include bronchovascular and interlobular thickening. Pleural effusions and hilar or mediastinal lymphadenopathy are other possible, although nonspecific, findings [6,9,10]. In this case, the initial CT chest demonstrated mediastinal and hilar lymphadenopathy with bilateral ground-glass changes and bronchovascular nodular changes. Chest radiography was also performed with no acute cardio-pulmonary changes observed. Due to the inability to rule out infection, the patient was started on antibiotics, with no subsequent clinical improvement, making an underlying infection less likely to be the etiology of this patient’s symptomatology.\n\nConfirmatory diagnosis of PLC requires a histopathologic specimen through biopsy and is often not diagnosed until postmortem at the time of autopsy [6,8]. This diagnostic delay is presumptively due to nonspecific symptomatology and radio-graphic findings, as well as a low initial suspicion for malignancy. In this case, there was no personal or family history of malignancy that would have raised the clinical suspicion for PLC and prompting lung biopsy. Due to these factors, along with the extent of metastatic disease seen with lymphangitic carcinomatosis, prognosis is generally poor [6,7]. In a systematic review and meta-analysis of case reports by Klimek, PLC can be the first manifestation of primary occult neoplasm, occurring at any age, with approximately half of patients dying within 2 months of their first respiratory symptoms [11]. This is consistent with findings by Dennstedt et al., who reported that the diagnosis of primary gastric tumor with PLC was only made at autopsy in 4 of 6 patients; the patients included in this study had an average age of 26 and mean survival time of 22 days after initial hospital admission [12]. Additionally, gastric adenocarcinoma with signet ring cell histology is considered a poor prognostic indicator [6,7].\n\nConclusions\nDiagnosis of cancer in pregnancy is often delayed as many symptoms of malignancy are nonspecific and common during pregnancy, including nausea/vomiting, dyspepsia, epigastric pain, abdominal pain, shortness of breath, breast changes, and fatigue [3]. In summary, the differential diagnosis for this patient was broad and included infection, lupus flair, heart failure, pulmonary embolism, preeclampsia, and malignancy. This may be one of the few cases of maternal death in which death was both unpredictable, unpreventable, and unavoidable.\n\nWe would like to thank Donna Eastham, BA for her assistance with editing and submission and Sheila L. Thomas, MA(LS), M.Ed., librarian at UAMS, for her valuable assistance with the literature search.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Computed tomography of chest with mediastinal hilar lymphadenopathy. The largest lymph node measured 1.5 cm in the subcarinal space.\n\nFigure 2. CT chest with prominence of the right ventricle when compared to the left ventricle, measuring 4.9 cm and 4.3 cm, respectively\n\nFigure 3. Higher magnification demonstrates the signet ring cell appearance of the tumor cells. Necrosis is also present (right side of the image) (H&E, 200×).\n\nFigure 4. Lymphangitic spread of signet ring cell carcinoma in the lung (H&E stain, 20×).\n==== Refs\nReferences:\n1. Parazzini F Franchi M Tavani A Frequency of pregnancy related cancer: A population based linkage study in Lombardy, Italy Int J Gynecol Cancer 2017 27 3 613 19 28107260 \n2. Kobayashi Y Tabata T Omori M A Japanese survey of malignant disease in pregnancy Int J Clin Oncol 2019 24 3 328 33 30368627 \n3. Botha MH Rajaram S Karunaratne K Cancer in pregnancy. Int J Gynaecol Obstet 2018 143 Suppl. 2 137 42 \n4. Center for Disease Control and Prevention Pregnancy mortality surveillance system. 2018 \n5. Shi AW Shen XF Ding HJ Pancreatic carcinoma underlying a complex presentation in late pregnancy: A case report J Med Case Rep 2018 12 1 369 30551739 \n6. Khachekian A Shargh S Arabian S Pulmonary lymphangitic carcinomatosis from metastatic gastric adenocarcinoma: Case report J Am Osteopath Assoc 2015 115 5 332 37 25938528 \n7. Bruce DM Heys SD Eremin O Lymphangitis carcinomatosa: A literature review J R Coll Surg Edinb 1996 41 1 7 13 8930034 \n8. Moubax K Wuyts W Vandecaveye V Pulmonary lymphangitic carcinomatosis as a primary manifestation of gastric carcinoma in a young adult: A case report and review of the literature BMC Res Notes 2012 5 638 23158653 \n9. Hauser TE Steer A Lymphangitic carcinomatosis of the lungs: Six case reports and a review of the literature Ann Intern Med 1951 34 4 881 98 14830071 \n10. Thomas A Lenox R Pulmonary lymphangitic carcinomatosis as a primary manifestation of colon cancer in a young adult CMAJ 2008 179 4 338 40 18695182 \n11. Klimek M Pulmonary lymphangitis caricintomatosis: Systematic review and meta-analysis of case reports, 1970–2018 Postgrad Med 2019 131 5 309 18 30900501 \n12. Dennstedt FE Greenberg SD Kim HS Pulmonary lymphangitic carcinomatosis from occult stomach carcinoma in young adults: An unusual cause of dyspnea Chest 1983 84 6 787 88 6641323\n\n",
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"abstract": "Variations in the activity, up to absolute deficiency, of the enzyme dihydropyrimidine dehydrogenase (DPD), result in the occurrence of adverse reactions to chemotherapy, and have been included among the pharmacogenetic factors underlying inter-individual variability in response to fluoropyrimidines. The study of single-nucleotide polymorphisms of the DPYD gene, which encodes the DPD enzyme, is one of the main parameters capable of predicting reduced enzymatic activity and the consequent influence on fluoropyrimidine treatment, in terms of reduction of both adverse reactions and therapeutic efficacy in disease control. In this paper, we describe a patient with metastatic breast cancer showing signs of increased toxicity following capecitabine therapy. The DPD enzyme activity analysis revealed a partial deficiency. The study of the most frequent polymorphisms of the DPYD gene suggested a wild-type genotype but indicated a novel variant c.1903A>G (p.Asn635Asp), not previously described, proximal to the splice donor site of exon 14. After excluding the potential pathogenic feature of the newly-identified variant, we performed cDNA sequencing of the entire DPYD coding sequence. This analysis identified the variants c.85T>C and c.496A>G, which were previously described as pivotal components of the haplotype associated with decreased enzyme activity and suggested that both variant alleles are related to DPD deficiency. The clinical case findings described in this study emphasize the importance of performing complete genetic analysis of the DPYD gene in order to identify rare and low frequency variants potentially responsible for toxic reactions to fluoropyrimidine treatment.",
"affiliations": "Section of Clinical and Molecular Oncology, Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari, Bari, Italy.;Section of Clinical and Molecular Oncology, Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari, Bari, Italy.;Department of Biology, Military Training Hospital Begin, Saint Mandé, France.;Department of Oncology, Military Training Hospital Begin, Saint Mandé, France.;Val-de-Grâce Military School, Paris, France.;Section of Clinical and Molecular Oncology, Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari, Bari, Italy.",
"authors": "Palmirotta|Raffaele|R|;Lovero|Domenica|D|;Delacour|Hervé|H|;Le Roy|Audrey|A|;Cremades|Serge|S|;Silvestris|Franco|F|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2019.00139",
"fulltext": "\n==== Front\nFront OncolFront OncolFront. Oncol.Frontiers in Oncology2234-943XFrontiers Media S.A. 10.3389/fonc.2019.00139OncologyCase ReportRare Dihydropyrimidine Dehydrogenase Variants and Toxicity by Floropyrimidines: A Case Report Palmirotta Raffaele 1*Lovero Domenica 1Delacour Hervé 23Le Roy Audrey 4Cremades Serge 34Silvestris Franco 11Section of Clinical and Molecular Oncology, Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari, Bari, Italy2Department of Biology, Military Training Hospital Begin, Saint Mandé, France3Val-de-Grâce Military School, Paris, France4Department of Oncology, Military Training Hospital Begin, Saint Mandé, FranceEdited by: Christian Celia, Università degli Studi G. d'Annunzio Chieti e Pescara, Italy\n\nReviewed by: Todd Skaar, Indiana University Hospital, United States; Andrea Lapucci, Università degli Studi di Firenze, Italy\n\n*Correspondence: Raffaele Palmirotta raffaelepalmirotta@gmail.comThis article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology\n\n11 3 2019 2019 9 13924 11 2018 18 2 2019 Copyright © 2019 Palmirotta, Lovero, Delacour, Le Roy, Cremades and Silvestris.2019Palmirotta, Lovero, Delacour, Le Roy, Cremades and SilvestrisThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Variations in the activity, up to absolute deficiency, of the enzyme dihydropyrimidine dehydrogenase (DPD), result in the occurrence of adverse reactions to chemotherapy, and have been included among the pharmacogenetic factors underlying inter-individual variability in response to fluoropyrimidines. The study of single-nucleotide polymorphisms of the DPYD gene, which encodes the DPD enzyme, is one of the main parameters capable of predicting reduced enzymatic activity and the consequent influence on fluoropyrimidine treatment, in terms of reduction of both adverse reactions and therapeutic efficacy in disease control. In this paper, we describe a patient with metastatic breast cancer showing signs of increased toxicity following capecitabine therapy. The DPD enzyme activity analysis revealed a partial deficiency. The study of the most frequent polymorphisms of the DPYD gene suggested a wild-type genotype but indicated a novel variant c.1903A>G (p.Asn635Asp), not previously described, proximal to the splice donor site of exon 14. After excluding the potential pathogenic feature of the newly-identified variant, we performed cDNA sequencing of the entire DPYD coding sequence. This analysis identified the variants c.85T>C and c.496A>G, which were previously described as pivotal components of the haplotype associated with decreased enzyme activity and suggested that both variant alleles are related to DPD deficiency. The clinical case findings described in this study emphasize the importance of performing complete genetic analysis of the DPYD gene in order to identify rare and low frequency variants potentially responsible for toxic reactions to fluoropyrimidine treatment.\n\npharmacogenomicscapecitabinefluoropyrimidinedihydropyrimidine dehydrogenasegene variationtoxicityAssociazione Italiana per la Ricerca sul Cancro10.13039/501100005010\n==== Body\nBackground\nFluoropyrimidines, as fluorouracil, capecitabine and tegafur, are chemotherapeutic agents commonly used in the treatment of many solid tumors, including gastrointestinal, head and neck, and breast cancers (1). Up to 90% of the administered dose is physiologically inactivated in the liver by dihydropyrimidine dehydrogenase (DPD), an enzyme involved in the catabolism of the drug (2).\n\nThe DPYD gene (OMIM * 612779) which extends for 4,399 nucleotides and includes 23 coding exons on chromosome 1p22, usually presents a number of polymorphisms, transmitted in an autosomal recessive manner, which may result in a partial or absolute enzyme deficiency associated with an increased risk of toxicity (3, 4). Carriers of some of these allelic variants, even if heterozygous, are exposed to a high risk of developing severe toxicity such as neutropenia, nausea, vomiting, diarrhea, stomatitis, mucositis, hand-foot syndrome, and peripheral neuropathy with sometimes even fatal outcomes following fluoropyrimidine-based chemotherapy (3–5).\n\nAmong around 450 missense DPYD single-nucleotide polymorphisms (SNPs) reported in NCBI dbSNP (6) to date, only approximately twenty of them acquire a functional significance. Four of these variants are considered to be of clinical relevance for recognized effects on the protein, their identified toxic effects, and for their population frequency (7, 8): c.1905G >A (rs3918290, also IVS14 +1G >A), c.1679T >G (rs55886062), c.2846A>T (rs67376798) and c.1129–5923C>G (rs75017182, HapB3). This last variant is in linkage disequilibrium with the synonymous variant c.1236G> A (rs56038477) in Europeans (7) and is often employed during mutational screening analysis.\n\nTherefore, the main scientific consortia and working groups in this field suggest adoption of analysis of DPYD mutations and suggest a reduction in fluoropyrimidine doses, or the adoption of an alternate drug in case of heterozygosity or homozygosity, respectively (4, 7, 8). However, it has been suggested that other DPYD polymorphisms could contribute to the variability in therapeutic responses, while several of the more common DPYD variants to date show conflicting evidence regarding their effects (7). Genotyping methods appear to be a more reliable approach to identify patients at risk of serious adverse reactions, compared to pharmacokinetic analyses and evaluations of enzymatic activity (9). Thus, development of an extensive screening method is a suitable tool for validating the potential pathogenicity of some variants, as well as for the proper management of cancer patients undergoing fluoropyrimidine treatment (10).\n\nCase Report\nAn 81 year-old woman was admitted to our oncology unit (Military Training Hospital Bégin, Unit of Oncology, Paris, France) for the management of grade 3 diarrhea due to fluoropyrimidine-related toxicity. She suffered from an invasive ductal carcinoma of the left breast (Elston-Ellis grade 3, RH+ HER2-) diagnosed in 2007. Medical management was initially based on surgery, radiation therapy and chemotherapy (adriamycine and cyclophosphamide). Hormonal therapy (anastrozole then exemestane) was performed during the following 5 years (2008–2012), and then she entered a regular clinical and radiological follow-up program. As bone and hepatic metastases were diagnosed in 2016 and 2017, respectively, hormonal therapy (exemestane) and chemotherapy (paclitaxel) were reintroduced. In May 2018, given evidence of CNS progression with multiple cerebral metastases, capecitabine (1,500 mg twice a day) was administered. The patient presented signs of major toxicity requiring urgent hospitalization in our department 20 days after capecitabine treatment, and the main symptoms included diarrhea (grade 3) and asthenia (grade 3). She was admitted to our department for close monitoring, with intensive fluid and nutritional support.\n\nBiological investigations performed at admission revealed hematological toxicity with grade 4 neutropenia (absolute neutrophil count: 0.31 × 109/L; reference interval, 1.5–4 × 109/L) and grade 4 thrombocytopenia (platelet count: 35 × 109/L; reference interval, 150–300 × 109/L). The consequences of the severe diarrhea resulted in low blood levels of potassium (2.8 mmol/L; reference interval, 3.5–4.5 mmol/L), phosphate (0.4 mmol/L: reference interval, 0.81–1.45 mmol/L) and magnesium (0.63 mmol/L; reference interval, 0.7–1.05 mmol/L). Moreover, prothrombin time was increased (prothrombin ratio: 41 %; reference interval, >70 %) with a mild elevation of liver transaminase levels (ALT: 60 UI/L; reference interval, <33 UI/L and AST: 106; reference interval, < 32 UI/L) and a marked hypoalbuminemia (albumin level: 22.3 g/L, reference interval, 35–52 g/L). Stool cultures failed to detect bacterial pathogens, including C. difficile strains.\n\nCapecitabine treatment was suspended upon the patient's admission to our service. The clinical evolution was slowly favorable: no diarrhea was observed after 72 h, and cell blood counts were normalized in 1 month.\n\nDPD deficiency was suspected as a potential explanation for the severe toxicity following the first cycle of treatment with capecitabine. DPD phenotype assessment was performed by measurements of plasma uracil (U) and dihydrouracil (UH2) using an LC-MS/MS method (11). Analysis revealed a partial DPD deficiency according to the established criteria (U: 40.4 ng/mL, deficiency cut-off > 16 ng/mL and/or UH2/U ratio: 5.0, deficiency cut-off < 6) (12). The patient signed written informed consent for genotyping and related data for scientific research. The four DPYD SNPs most commonly observed in the Indo-European population were genotyped according to the current recommendations of the Clinical Pharmacogenetics Implementation Consortium (7). The SNPs (c.1905+1G>A, rs3918290; c.2846A>T, rs67376798; c.1679T>G; rs55886062 and c.1236G>A, rs56038477) were genotyped using LAMP Human DPD deficiency kit (LaCAR MDx Technologies, Lièges, Belgium). None of the four variant were detected. However, an atypical profile of the melting curve relative to rs3918290 genotyping was observed (Figure 1). As the presence of an uncommon SNP was suspected, sequencing of DPYD exon 14 was performed which revealed that the patient harbored a SNP in a heterozygous state: c.1903A>G (p.Asn635Asp) (chromosome position 1:97915617, A/G). To the best of our knowledge, this is a novel variant and is not identified in any of the specific Ensembl, dbSNP, ExAC, Alfred, HGMD or LOVD databases.\n\nFigure 1 Melting curve relative to rs3918290 (c.1905+1G>A) genotyping using LAMP Human DPD deficiency kit (LaCAR MDx Technologies, Lièges, Belgium). The melting curve observed with the patient sample (blue line) is clearly different from those associated with the wild-type genotype (green and yellow lines) and the heterozygous genotype (red line). This atypical profile of the melting curve suggested the presence of an uncommon SNP.\n\nIn order to evaluate the impact of the proximity of this variant to the intron 14 mRNA splice donor site, we used the most popular in silico tools to predict potential functional alterations involving splicing sites. SIFT (Scale-Invariant Feature Transform, http://sift.bii.a-star.edu.sg/, accessed 28 September 2018) and MutationTaster (http://www.mutationtaster.org/, accessed 28 September 2018) predictions suggested a deleterious effect for this variant, with scores of 0.002 and 23, respectively, while PolyPhen-2 prediction (http://genetics.bwh.harvard.edu/pph2/index.shtml, accessed 28 September 2018) indicated a benign effect, with a confidence score of 0.371. The PROVEAN (Protein Variation Effect Analyzer—http://provean.jcvi.org/index.php, accessed 28 September 2018) tool indicated a neutral prediction with a score of −1.770, while the Human Splicing Finder (htt://www.umd.be/HSF3/index.html, accessed 28 September 2018) tool referred to an exonic splicing enhancer (ESE) mutation “Alteration of an exonic ESE site. Potential alteration of splicing.” Furthermore, the SwissModel web tools (http://swissmodel.expasy.org/, accessed 28 September 2018) indicated that the missense variant did not affect the final structure of the protein.\n\nTherefore, in order to characterize the potential pathogenic features of the identified variant, a peripheral blood sample stored in PAXgene Blood RNA Tube (Qiagen, Hilden, Germany) was sent to the Oncogenomic Research Center (University of Bari, Italy) for further molecular analysis. Total RNA was extracted from whole blood using the PAXgene Blood RNA Kit (PreAnalytiX GmbH, Hombrechtikon, Switzerland) and reverse transcribed into cDNA with an iScript cDNA Synthesis Kit (BioRad, Hercules, CA, USA). Using a pair of primers spanning exons 13 and 15 of DPYD, the cDNA was amplified and sequenced using a 3500 Genetic Analyzer (Applied Biosystems, 3500 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). Sequence analysis performed on the cDNA tract including exons 13–15 did not indicate exon 14 skipping (Figure 2).\n\nFigure 2 Direct sequence analysis of the DPYD c.1903A>G, p.Asn635Asp variant detected in our patient. The upper panel shows the gDNA sequence of exon 14 and intron–exon border. The lower panel shows the patient cDNA sequence, performed with primers spanning exons 13 and 15, demonstrating the integrity of exon 14.\n\nThe cDNA was then used to perform real-time quantitative PCR assays using the iTaq Universal SYBR Green Supermix (BioRad) in the Step One Plus instrument (Applied Biosystems). The mRNA levels were measured using 3 replicates per sample, with the comparative threshold cycle (Ct) method using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and beta-actin (ACTB) as endogenous controls, and with related values calculated by ΔCt. As controls, equal amounts of RNA extracted from whole blood of 3 subjects, previously genotyped and identified as wild-type for variants in the DPYD gene, were used. DPYD mRNA levels in the patient carrying the variant were reduced by an average of 45% compared to those observed in healthy subjects expressing the wild-type DPYD gene. A potential limitation in this analysis is that it is difficult to normalize across patients in samples containing multiple cell types that have different expression levels of house keeping genes, but normalizing with either a structural gene and a metabolic gene gave similar results, suggesting the effective reduction of gene expression in the patient.\n\nAs a subsequent analytical step, 5 pairs of primers were designed to perform sequencing of a 3296 bp cDNA segment, including the 3078 bp coding sequence of the DPYD gene (Table 1).\n\nTable 1 Primers used in the DPYD cDNA amplification and sequencing (RefSeq: NM_000110, Transcript ID: ENST00000370192.7).\n\nIncluded region\tCode sequence 5′-3′\tTM\tSize (bp)\t\n5′UTR-35–916\tcDNA1 fw\tTTGTCACTGGCAGACTCG\t55\t951\t\n\tcDNA1 rev\tATGTATAAAACCCCTGGTCC\t\t\t\n827–1946\tcDNA2 fw\tTACAAAGCTGCTTTCATTGG\t56\t1,139\t\n\tEX 13-15 rev\tTTGGCAAGTTCCGTCCAG\t\t\t\n1605–2291\tEX 13-15 fw\tTAGAAATGGCCGGATTGAAG\t58\t686\t\n\tcDNA3 rev\tTCCATATGTAGTTCGCTTTGC\t\t\t\n2209–2875\tcDNA4 fw\tACTGTCTCAGGTCTGATGGG\t58\t676\t\n\tA2846T rev\tTCATGTAGCATTTACCACAGTTGA\t\t\t\n2781–3′UTR+182\tA2846T fw\tAAGCACTGCAGTACCTTGGAA\t59\t482\t\n\tcDNA5 rev\tTTGAATGGTCATTGACATGAGAC\t\t\t\nTM, Melting Temperature; bp, base pair.\n\nAnalysis of the results allowed the identification of the variants c.85T>C (Cys29Arg) and c.496A>G (Met166Val) recognized as the reference SNP (refSNP) Cluster Report rs1801265 and rs2297595, described with clinical significance of “Pathogenic” and “With drug-response allele” respectively (http://www.ncbi.nlm.nih.gov/snp/ accessed 28 September 2018).\n\nThe re-introduction of capecitabine at lower doses (1,000 mg twice a day) was associated with recurrence of adverse effects (grade 3 diarrhea and thrombocytopenia—platelet count: 88 × 109/L) and treatment was stopped. Following this, new therapies were adopted (Palbociclib and Fulvestrant) until the patient died 3 weeks later.\n\nDiscussion\nHere, we describe the diagnostic procedure involving a breast cancer patient exhibiting fluoropyrimidine-related toxicity and subjected to DPYD mutational analysis. At first, during the molecular screening carried out to evaluate the variant IVS14 + 1G> A, a never previously described variant, c.1903A> G, was identified at the last codon of DPYD exon 14, encoding the amino acid substitution p.Asn635Asp. Therefore, to assess its potential pathogenic role, we used several Web tools to identify any possible deleterious effects on the protein. The prediction of its potential pathogenicity by several websites led us to perform both qualitative and quantitative mRNA analyses, which in all instances excluded any involvement of the splicing process, but confirmed a reduction in mRNA abundance.\n\nAt the same time, we also performed a complete mutational analysis of the DPYD gene, which revealed the presence of two other rare variants.\n\nThe c.496A>G (Met166Val) transition is referred to as “Damaging” by SIFT (score: 0.004), PolyPhen-2 (score: 1.00) and PROVEAN (score: −3.50). Analysis of the DPYD protein crystalline structure showed that this mutation has the ability to modify the integrity of the dimeric complex of DPYD, resulting in an alteration of a hydrophobic conserved three-dimensional environment determined by the interaction of amino acids L840, W849, Q852, V162, and I168 (13). A study conducted on 89 patients diagnosed with breast, gastroesophageal and colorectal cancer showed a significant G allele association with the phenotype of enhanced toxicity of grade III/IV (1). Other studies did not show a significant correlation between the presence of the variant and 5-FU toxicity (14, 15) and one study even demonstrated that the M166V variant exhibited significantly higher enzyme activity of approximately 120% compared to that of wild-type DPYD (16).\n\nTo date the c.85T>C (Cys29Arg) variant is considered neutral/tolerated by the SIFT algorithms (score: 0.19), PolyPhen-2 (score: 0.00) and PROVEAN (score: 0.08). The first in vitro studies performed on the c.85 T>C variant by analysis of expression in Escherichia coli resulted in a C29R inactive mutant DPD protein without residual enzymatic activity (17), while subsequent studies have shown a significant increase in functionality, exhibiting 13% higher activity than wild-type (18). Ocular side effects manifesting in the course of 5-FU-based chemotherapy have also been described in a subject carrying this mutation (19).\n\nMore recently the two mutations were included in a panel of 10 DPYD genetic variants for fluoropyrimidine-related adverse events (FAEs) retrospectively evaluated in the TOSCA (Three or six colon adjuvant) clinical trial (5). The study included 508 patients with surgically resected, stage III and high-risk stage II colorectal cancer, treated with 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. The rs2297595 variant was one of the mutations that showed a shorter time-to-toxicity (TTT) with a 6.6 and 1.2 month TTT in the heterozygous and homozygous states, respectively. The deleterious effect of this variant is explained by the authors on the basis of the methionine-valine exchange at a site crucial for enzyme function and which is highly conserved through evolution (20). On the contrary, the same study did not show any association regarding the rs1801265 variant (5). Finally, a DPYD multi-SNP analysis performed to investigate the genotype-phenotype correlation involving 5-FU metabolism showed that the presence of minor alleles of the SNPs rs1801265 (C) and rs2297595 (G) determining the formation of a haplotype (Hap4, estimated frequency 8% in the Western population), is associated with a marked reduction in the values of 5-FU degradation rate (5-FUDR) (21).\n\nConclusion\nHere, we describe a diagnostic itinerary in a patient with metastatic breast cancer presenting symptoms of toxicity to capecitabine. In the first instance, during a mutational analysis of the four clearly pathogenic variants suggested by the main current guidelines, we identified a novel mutation at the terminal portion of exon 14. Despite the prediction of its pathogenicity by several computational algorithms, mRNA analysis allowed us to exclude a potential deleterious effect for this variant. However, the detection of reduced mRNA levels and the partial DPYD protein deficiency led us to extend the mutational analysis across the coding region of the entire DPYD gene. Numerous reports suggest today that the discovery of rare or novel mutations in the DPYD gene may account for an appreciable percentage of fluoropyrimidine toxicity in chemotherapy patients (22). Our analytical approach, based on the mutational analysis of the entire transcript of the DPYD gene in our patient, suggests that the rare variants identified may most likely be responsible for a reduction in mRNA levels, as also suggested by the previous scientific literature (1, 5, 17, 19, 20).\n\nWe believe that the solution adopted here, which provides a complete sequence analysis of the mRNA through the use of only 5 amplification reactions, provides a rapid and reliable method to identify rare sequence variants and splice site alterations (22). This can be an effective, inexpensive solution and is also achievable in most diagnostic centers and, in agreement with recent specific studies that identify an ideal screening for the identification of DPYD variants as “feasible and convenient, exceeding screening costs” (9, 23). Therefore, we hope that our experience can help to update specific databases and could be clinically relevant to address diagnostic paths useful for identifying fluoropyrimidine-related toxicity.\n\nEthics Statement\nThe authors state that they have obtained appropriate institutional review board approval with written informed consent from the subject. Informed consent was obtained from the patient in order to publish this case report. The subject gave written informed consent in accordance with the Declaration of Helsinki.\n\nAuthor Contributions\nRP, HD, and FS participated in the study's design and coordination, performed acquisition of data, and drafted the manuscript. DL and HD participated in molecular biology tests, data interpretation, and revised the manuscript. ALR and SC were resident in charge of patients during treatment and revised the manuscript. All authors read and approved the final manuscript.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nFunding. This work was supported by the AIRC Associazione Italiana per la Ricerca sul Cancro [grant number 17536], from the Apulia Region (Oncogenomic Project and Jonico-Salentino Project).\n==== Refs\nReferences\n1. Gross E Busse B Riemenschneider M Neubauer S Seck K Klein HG . Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients . PLoS ONE. (2008 ) 3 :e4003 . 10.1371/journal.pone.0004003 19104657 \n2. Dobritzsch D Schneider G Schnackerz KD Lindqvist Y . Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil . EMBO J. 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"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "9()",
"journal": "Frontiers in oncology",
"keywords": "capecitabine; dihydropyrimidine dehydrogenase; fluoropyrimidine; gene variation; pharmacogenomics; toxicity",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "139",
"pmc": null,
"pmid": "30915274",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "11125122;11179210;11875367;14635116;18299612;19104657;19530960;22760589;23328581;24434920;24648345;26216193;26573078;26644533;27179185;28024938;28427087;28430339;29065426;29152729;29327356;29861877;9439663",
"title": "Rare Dihydropyrimidine Dehydrogenase Variants and Toxicity by Floropyrimidines: A Case Report.",
"title_normalized": "rare dihydropyrimidine dehydrogenase variants and toxicity by floropyrimidines a case report"
} | [
{
"companynumb": "IT-MYLANLABS-2019M1036908",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EXEMESTANE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nToxoplasmosis is a rare but life-threatening infection occurring in immunocompromised hosts, including allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. However, thus far, the clinical features and incidence of toxoplasmosis in autologous HSCT (auto-HSCT) recipients remain unknown. This retrospective survey aimed to analyze 152 patients who received auto-HSCT between 1998 and 2017.\n\n\nMETHODS\nSerological tests for Toxoplasma gondii-specific IgG were performed on 109 (71.7%) recipients, and 12 pre-HSCT recipients (11%) were Toxoplasma seropositive. Among the 12 recipients, three who did not receive trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis developed cerebral, pulmonary or disseminated toxoplasmosis due to reactivation after auto-HSCT and died despite treatment.\n\n\nRESULTS\nThe incidences of toxoplasmosis were 2% and 25% among 152 auto-HSCT recipients (five recipients received auto-HSCT two times) and 12 pre-HSCT Toxoplasma seropositive recipients, respectively. Further, we conducted a literature review and identified 21 cases of toxoplasmosis following auto-HSCT. In these previous cases, the mortality rate was high, especially for pulmonary and disseminated toxoplasmosis. Our findings suggest that, similar to toxoplasmosis after allo-HSCT, toxoplasmosis after auto-HSCT is a fatal complication.\n\n\nCONCLUSIONS\nSerial screening of T. gondii-specific IgG before HSCT could contribute to the detection of Toxoplasma reactivation and allow for prompt diagnosis and treatment. The present study is the first to reveal the incidence of toxoplasmosis after auto-HSCT among seropositive patients in Japan.",
"affiliations": "Department of Hematology, Nagano Red Cross Hospital, Nagano City, Nagano, Japan.;Department of Hematology, Nagano Red Cross Hospital, Nagano City, Nagano, Japan.;Department of Infection and Host Defense, Graduate School of Medicine, Chiba University, Chiba City, Chiba, Japan.;Department of Infection and Host Defense, Graduate School of Medicine, Chiba University, Chiba City, Chiba, Japan.;Department of Hematology, Nagano Red Cross Hospital, Nagano City, Nagano, Japan.;Department of Hematology, Nagano Red Cross Hospital, Nagano City, Nagano, Japan.;Department of Hematology, Nagano Red Cross Hospital, Nagano City, Nagano, Japan.;Department of Hematology, Nagano Red Cross Hospital, Nagano City, Nagano, Japan.;Department of Hematology, Nagano Red Cross Hospital, Nagano City, Nagano, Japan.;Department of Hematology, Nagano Red Cross Hospital, Nagano City, Nagano, Japan.;Department of Hematology, Nagano Red Cross Hospital, Nagano City, Nagano, Japan.;Department of Pathology, Suwa Red Cross Hospital, Suwa City, Nagano, Japan.;Department of Hematology, Nagano Red Cross Hospital, Nagano City, Nagano, Japan.",
"authors": "Kitahara|Mari|M|https://orcid.org/0000-0003-0586-5014;Hiroshima|Yuki|Y|;Norose|Kazumi|K|;Hikosaka|Kenji|K|;Kazumoto|Hiroko|H|;Uematsu|Nozomu|N|;Shishido|Tsutomu|T|;Kaiume|Hiroko|H|;Sato|Keijiro|K|;Ueki|Toshimitsu|T|;Sumi|Masahiko|M|;Watanabe|Masahide|M|;Kobayashi|Hikaru|H|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13726",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": null,
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "anti-Toxoplasma gondii-specific IgG antibody; autologous hematopoietic stem cell transplantation; incidence; infection; toxoplasmosis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13726",
"pmc": null,
"pmid": "34542220",
"pubdate": "2021-09-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical characteristics and incidence of toxoplasmosis after autologous hematopoietic stem cell transplantation: A retrospective study and literature review.",
"title_normalized": "clinical characteristics and incidence of toxoplasmosis after autologous hematopoietic stem cell transplantation a retrospective study and literature review"
} | [
{
"companynumb": "JP-TEVA-2022-JP-2033022",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "4",
... |
{
"abstract": "Hematologic malignances are more common and often higher risk in older patients. Allogeneic hematopoietic cell transplantation (alloHCT) best enables long-term disease control for patients with poor risk or relapsed/refractory hematologic malignancies such as acute myeloid leukemia, myelodysplastic syndromes, or myelofibrosis. Rates of alloHCT among older patients, while still relatively low compared with younger patients, have risen sharply over the past decade. Accumulating evidence supports alloHCT for patients ≥60 years of age relative to non-HCT therapies based on improved overall and disease-free survival. However, a significant proportion of older adults have limitations characterized by geriatric assessment. A systematic process to evaluate and optimize older patients may improve decision making, transplant outcomes, and alloHCT access. We present case-based studies to illustrate a stepwise and rational approach to proper older patient evaluation, pretransplant optimization, and posttransplant care with attention to important geriatric issues and quality of life.",
"affiliations": "Memorial Sloan Kettering Cancer Center, New York, NY.;City of Hope National Medical Center, Duarte, CA.",
"authors": "Lin|Richard J|RJ|;Artz|Andrew S|AS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1182/hematology.2021000257",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1520-4383",
"issue": "2021(1)",
"journal": "Hematology. American Society of Hematology. Education Program",
"keywords": null,
"medline_ta": "Hematology Am Soc Hematol Educ Program",
"mesh_terms": null,
"nlm_unique_id": "100890099",
"other_id": null,
"pages": "254-263",
"pmc": null,
"pmid": "34889392",
"pubdate": "2021-12-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Allogeneic hematopoietic cell transplantation for older patients.",
"title_normalized": "allogeneic hematopoietic cell transplantation for older patients"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK202202813",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "3",
... |
{
"abstract": "Treatment of symptomatic candiduria is notoriously challenging because of the limited repository of antifungals that achieve adequate urinary concentrations. Fluconazole, amphotericin B-based products, and flucytosine are established treatment options for most Candida species. Candida krusei exhibits intrinsic resistance to fluconazole and decreased susceptibility to amphotericin B and flucytosine. In transplant patients, both amphotericin B-based products and flucytosine are less desirable because of their toxicities. Other triazole antifungals are unappealing because they do not achieve adequate urinary concentrations, have multiple toxicities, and interact with transplant-related immunosuppressive medications. Echinocandins are well-tolerated but have been traditionally deferred in the treatment of symptomatic funguria because of their poor urinary concentrations but there is a small but emerging body of literature supporting their use. Here, we present a case of successful eradication of chronic symptomatic C krusei urinary tract infection with micafungin 150 milligrams daily in a liver and kidney transplant recipient, and we review the literature on treatment of symptomatic candiduria.",
"affiliations": "Division of Infectious Diseases & Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California.;Division of Infectious Diseases & Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California.;Division of Infectious Diseases & Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California.",
"authors": "Multani|Ashrit|A|https://orcid.org/0000-0003-4043-4287;Subramanian|Aruna K|AK|;Liu|Anne Y|AY|",
"chemical_list": "D000935:Antifungal Agents; D000077551:Micafungin",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13118",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "21(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nCandida krusei\n; candiduria; echinocandin; funguria; kidney transplant; liver transplant; micafungin; urinary tract infection",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000935:Antifungal Agents; D002175:Candida; D002177:Candidiasis; D006801:Humans; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008297:Male; D000077551:Micafungin; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D066027:Transplant Recipients; D016896:Treatment Outcome; D014552:Urinary Tract Infections",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13118",
"pmc": null,
"pmid": "31111613",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Successful eradication of chronic symptomatic Candida krusei urinary tract infection with increased dose micafungin in a liver and kidney transplant recipient: Case report and review of the literature.",
"title_normalized": "successful eradication of chronic symptomatic candida krusei urinary tract infection with increased dose micafungin in a liver and kidney transplant recipient case report and review of the literature"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP000253",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditiona... |
{
"abstract": "Use of adoptive immunotherapy with virus-specific T cells (VST) in patients with inborn errors of immunity prior to hematopoietic stem cell transplantation (HSCT) has been reported in few patients. We report our experience, reviewing all the cases previously reported.\n\n\n\nWe report four children with inborn errors of immunity who received VST infusion in a pre-HSCT setting in two reference centers in Spain and review all inborn errors of immunity cases previously reported.\n\n\n\nTaking into account our four cases, nine children have been reported to receive VST prior to HSCT to date: 3 severe combined immunodeficiency, 2 CTPS1 deficiency, 1 dyskeratosis congenital, 1 ORAI1 deficiency, 1 Rothmund-Thomson syndrome, and 1 combined immunodeficiency without confirmed genetic defect. In four patients, immunotherapy resulted in clinical improvement, allowing to proceed to HSCT. In these cases, the infusion was started closely to viral diagnosis [mean time 28 days (IQR; 17-52 days)], and the VST was followed shortly thereafter by HSCT [mean time 28 days (IQR; 10-99 days)]. Viremia was controlled after HSCT in two cases (performed 7 and 36 days after the infusion). Multiple infusions were required in many cases. Five out of nine patients died before receiving HSCT. These patients presented with a prolonged and uncontrolled infection before VST administration [mean time from viral diagnosis to VST infusion was 176 days (IQR; 54-1687)].\n\n\n\nIn patients with inborn errors of immunity, the efficacy of VST for treating disseminated viral infections in pre-transplant settings seems to have a limited efficacy. However, this therapy could be used in a pre-emptive setting before severe viral disease occurs or closely to HSCT.",
"affiliations": "HSCT Department, Hospital Vall d'Hebron, Barcelona, Spain.;Paediatric Infectious Diseases Department, La Paz University Hospital, Madrid, Spain. amendezes@yahoo.es.;Immunogenetics and Histocompatibility Laboratory, Banc de Sang i Teixits, Barcelona, Spain.;Paediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain.;Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Paediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain.;Paediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain.;Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Hematology Department, La Paz University Hospital, Madrid, Spain.;Immunology Department, La Paz University Hospital, Madrid, Spain.;Cellular Therapy Unit, Cord Blood Bank, Centre Frederic Duran i Jordà, Barcelona, Spain.;Immunology Department, La Paz University Hospital, Madrid, Spain.;Immunology Department, La Paz University Hospital, Madrid, Spain.;Laboratory of Immunology, Department of Pathology, Hospital del Mar, Barcelona, Spain.;HSCT Department, Hospital Vall d'Hebron, Barcelona, Spain.;Paediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain.",
"authors": "Alonso|Laura|L|;Méndez-Echevarría|Ana|A|0000-0002-7455-9080;Rudilla|Francesc|F|;Mozo|Yasmina|Y|;Soler-Palacin|Pere|P|;Sisinni|Luisa|L|;Bueno|David|D|;Riviere|Jacques|J|;de Paz|Raquel|R|;Sánchez-Zapardiel|Elena|E|;Querol|Sergi|S|;Rodriguez-Pena|Rebeca|R|;López-Granados|Eduardo|E|;Gimeno|Ramón|R|;Díaz de Heredia|Cristina|C|;Pérez-Martínez|Antonio|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10875-020-00961-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-9142",
"issue": "41(4)",
"journal": "Journal of clinical immunology",
"keywords": "Inborn errors of immunity; immunotherapy; primary immunodeficiency diseases; viruses",
"medline_ta": "J Clin Immunol",
"mesh_terms": null,
"nlm_unique_id": "8102137",
"other_id": null,
"pages": "748-755",
"pmc": null,
"pmid": "33462728",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": "29753156;31953710",
"title": "Failure of Viral-Specific T Cells Administered in Pre-transplant Settings in Children with Inborn Errors of Immunity.",
"title_normalized": "failure of viral specific t cells administered in pre transplant settings in children with inborn errors of immunity"
} | [
{
"companynumb": "ES-TEVA-2021-ES-1942252",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEFLUNOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "The authors report a case of intraoperative reversal of apixaban with andexanet alfa in a patient supported with venoarterial extracorporeal membrane oxygenation due to low- cardiac-output immediately after surgery for acute type A aortic dissection and massive intraoperative transfusion with administration of procoagulants. In this patient, andexanet alfa's off-label use was not associated with acute thrombotic complications despite being given during extracorporeal life support and after previous administration of prothrombin complex concentrates.",
"affiliations": "Division of Cardiothoracic and Vascular Anesthesia and Intensive Care Medicine, General Hospital Vienna, Medical University of Vienna, Vienna, Austria.;Division of Cardiothoracic and Vascular Anesthesia and Intensive Care Medicine, General Hospital Vienna, Medical University of Vienna, Vienna, Austria.;Department of Internal Medicine, General Hospital Vienna, Medical University of Vienna, Vienna, Austria.;Division of Cardiothoracic and Vascular Anesthesia and Intensive Care Medicine, General Hospital Vienna, Medical University of Vienna, Vienna, Austria. Electronic address: martin.dworschak@meduniwien.ac.at.",
"authors": "Kainz|Matthias|M|;Bsuchner|Paul|P|;Schellongowski|Peter|P|;Dworschak|Martin|M|",
"chemical_list": "D065427:Factor Xa Inhibitors; C580915:PRT064445; D011720:Pyrazoles; D011728:Pyridones; D011994:Recombinant Proteins; C522181:apixaban; D000069552:Rivaroxaban; D015951:Factor Xa",
"country": "United States",
"delete": false,
"doi": "10.1053/j.jvca.2020.08.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-0770",
"issue": "35(1)",
"journal": "Journal of cardiothoracic and vascular anesthesia",
"keywords": "Andexanet alfa; anti-Xa activity; apixaban; deep hypothermic circulatory arrest; extracorporeal membrane oxygenation; massive transfusion; prothrombin complex concentrate; type A aortic dissection",
"medline_ta": "J Cardiothorac Vasc Anesth",
"mesh_terms": "D000784:Aneurysm, Dissecting; D015199:Extracorporeal Membrane Oxygenation; D015951:Factor Xa; D065427:Factor Xa Inhibitors; D006801:Humans; D056687:Off-Label Use; D011720:Pyrazoles; D011728:Pyridones; D011994:Recombinant Proteins; D000069552:Rivaroxaban",
"nlm_unique_id": "9110208",
"other_id": null,
"pages": "262-264",
"pmc": null,
"pmid": "32868154",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Intraoperative Off-Label Reversal of Apixaban by Andexanet Alfa while on VA-ECMO Immediately After Emergent Surgery for Acute Type A Aortic Dissection.",
"title_normalized": "intraoperative off label reversal of apixaban by andexanet alfa while on va ecmo immediately after emergent surgery for acute type a aortic dissection"
} | [
{
"companynumb": "AT-BION-009036",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
"dr... |
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