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{
"abstract": "Sleep-related eating disorder (SRED) is characterised by eating episodes during the first period of the night sleep with partial loss consciousness, and amnesia. It can rarely be induced by some drugs, including zolpidem. We present a video report of a patient with a 1-year history of SRED caused by zolpidem causing important repercussions in the sleep structure and life quality. The night eating episodes ceased promptly with discontinuation of zolpidem. Upon the follow-up, the sleep structure improved and the daily consequences disappeared. As in few reported cases of zolpidem-induced SRED, our patient was suffering from the parasomnia for a long time before the diagnosis. Active exclusion of symptoms suggestive of SRED in patients under zolpidem treatment can avoid the deleterious effect of the sleep disorder.",
"affiliations": "Department of Neurology, Hospital de Faro, Faro, Portugal. nzwalo@gmail.com",
"authors": "Nzwalo|Hipólito|H|;Ferreira|Ligia|L|;Peralta|Rita|R|;Bentes|Carla|C|",
"chemical_list": "D006993:Hypnotics and Sedatives; D011725:Pyridines; D000077334:Zolpidem",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003937:Diagnosis, Differential; D004435:Eating; D001068:Feeding and Eating Disorders; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D008875:Middle Aged; D017286:Polysomnography; D011725:Pyridines; D012890:Sleep; D007319:Sleep Initiation and Maintenance Disorders; D012893:Sleep Wake Disorders; D000077334:Zolpidem",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23436890",
"pubdate": "2013-02-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21140069;17993047;19961034;8032349;19822330;1759095;16287771;19107832;14592194;18468314;22505857;20965000;10804040",
"title": "Sleep-related eating disorder secondary to zolpidem.",
"title_normalized": "sleep related eating disorder secondary to zolpidem"
} | [
{
"companynumb": "PT-RANBAXY-2012R1-60673",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLPIDEM\\ZOLPIDEM TARTRATE"
},
"drugadditional... |
{
"abstract": "Solitary papilloma is a human papillomavirus (HPV)-induced benign indolent epithelial tumor with limited growth, whereas papillomatosis is an entirely different entity. Papillomatosis requires attention because of its aggressive and recurrent clinical progress with risks of dysplastic and malignant transformation. Recurrent respiratory papillomatosis (RRP) has a high prevalence of dysplasia and reports of transformation to carcinoma-ex-papillomatosis, especially when associated with low-risk HPV type 11. Although papillomatosis seldom occurs in the oral cavity, this report describes 3 cases of oral papillomatosis in immunocompromised patients, with 1 case identified as having HPV type 11. Two cases were kidney transplant recipients and the other case had a history of myelodysplastic syndrome followed by allogeneic bone marrow transplantation and graft-versus-host disease. Oral papillomatosis might be problematic, as in RRP, and periodic oral examination for persistent recurrences and malignant transformation can be beneficial to immunocompromised patients.",
"affiliations": "Clinical Research Assistant Professor, Department of Advanced General Dentistry, Yonsei University College of Dentistry, Seoul, Republic of Korea.;Graduate School Student, Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea.;Professor, Department of Advanced General Dentistry, Yonsei University College of Dentistry, Seoul, Republic of Korea.;Basic Research Assistant Professor, Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea. Electronic address: sandra@yuhs.ac.",
"authors": "Kwak|Eun-Jung|EJ|;Choi|Yun Hee|YH|;Park|Wonse|W|;Cho|Eunae Sandra|ES|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.joms.2017.06.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-2391",
"issue": "76(1)",
"journal": "Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons",
"keywords": null,
"medline_ta": "J Oral Maxillofac Surg",
"mesh_terms": "D016026:Bone Marrow Transplantation; D006086:Graft vs Host Disease; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms; D009190:Myelodysplastic Syndromes; D010212:Papilloma",
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "128-133",
"pmc": null,
"pmid": "28727989",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Oral Papillomatosis in Immunocompromised Patients: A Case Series of Kidney Transplant Recipients and Myelodysplastic Syndrome.",
"title_normalized": "oral papillomatosis in immunocompromised patients a case series of kidney transplant recipients and myelodysplastic syndrome"
} | [
{
"companynumb": "KR-ACCORD-063146",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Although the cause of eosinophilic coronary periarteritis (ECPA) remains unclear, an allergic background is present in fewer patients than expected. A 50-year-old man with no history of allergy or symptoms suggestive of cardiac or respiratory disorders suddenly died shortly after oral administration of loxoprofen sodium. Autopsy showed eosinophilic coronary periarteritis in three main branches of the coronary arteries, characterized by eosinophil-predominant inflammation without fibrinoid necrosis or granulomatous change in the adventitia and its surroundings of the three main branches of the coronary arteries, in addition to the localized sign of bronchial asthma in the lung. Immunohistochemical examination showed that many mast cells positive for human mast cell tryptase were evident in the perivascular tissue containing peripheral nerve trunks. Whereas the blood concentration of loxoprofen sodium was within the therapeutic range, significant elevation of the serum histamine and tryptase levels was found. The present case suggests that eosinophilic coronary periarteritis may be caused by a type I allergic reaction in some patients and that loxoprofen sodium can trigger a life-threatening type I allergic reaction, including eosinophilic coronary periarteritis, leading to sudden unexpected death.",
"affiliations": "Department of Legal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.;Department of Legal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.;Department of Legal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan. Electronic address: nishida@med.u-toyama.ac.jp.",
"authors": "Ichimata|Shojiro|S|;Hata|Yukiko|Y|;Nishida|Naoki|N|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D010666:Phenylpropionates; C040656:loxoprofen",
"country": "United States",
"delete": false,
"doi": "10.1016/j.carpath.2019.107154",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1054-8807",
"issue": "44()",
"journal": "Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology",
"keywords": "Allergy; Drug-induced vasculitis; Eosinophilic coronary periarteritis; Histamine; Loxoprofen sodium; Mast cell",
"medline_ta": "Cardiovasc Pathol",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D001344:Autopsy; D002423:Cause of Death; D003324:Coronary Artery Disease; D003331:Coronary Vessels; D016757:Death, Sudden, Cardiac; D004342:Drug Hypersensitivity; D004802:Eosinophilia; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008407:Mast Cells; D008875:Middle Aged; D010666:Phenylpropionates; D020069:Shoulder Pain",
"nlm_unique_id": "9212060",
"other_id": null,
"pages": "107154",
"pmc": null,
"pmid": "31760242",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "An autopsy case of sudden unexpected death with loxoprofen sodium-induced allergic eosinophilic coronary periarteritis.",
"title_normalized": "an autopsy case of sudden unexpected death with loxoprofen sodium induced allergic eosinophilic coronary periarteritis"
} | [
{
"companynumb": "JP-APTAPHARMA INC.-2079118",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
... |
{
"abstract": "Myeloid sarcoma (MS) is a very rare condition, develops both in patients with other hematological neoplasms, and as isolated tumor. MS of the gynecologic tract is extremely rare. An available literature data about diagnosis and management of MS is summarized in the article. The role of chemotherapy, radiation therapy, surgery and bone marrow transplantation in the treatment is discussed. Polychemotherapy and allogeneic bone marrow transplantation were suggested to be the optimal treatment strategy of MS of the gynecological tract. The use of new targeted agents results in promising clinical data.\n\n\n\nWe are presenting a rare clinical case of a MS of the uterine cervix with concomitant bone marrow involvement and describe all the peculiarities of the clinical course, diagnosis, and treatment. The patient received chemotherapy followed by allogeneic bone marrow transplantation. The pre-transplant therapy allowed us to perform allogeneic bone marrow transplantation with the deepest response possible: complete PET-negative and MRD-negative remission of the disease.\n\n\n\nMS remains a subject of discussion regarding its diagnostic and therapeutic aspects. The use of novel targeting agents can be perspective option for patient with extramedullary disease.",
"affiliations": "Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341. alexina-96@list.ru.;Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.;Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.;Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.;Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.;Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.;Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.;Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.;Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.;Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.;Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.;Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.;Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.;Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.;Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.;Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation, 197341.",
"authors": "Shatilova|Aleksina|A|http://orcid.org/0000-0002-4799-9398;Girshova|Larisa|L|;Zaytsev|Daniil|D|;Budaeva|Irina|I|;Mirolyubova|Yuliya|Y|;Ryzhkova|Darya|D|;Grozov|Roman|R|;Bogdanov|Konstantin|K|;Nikulina|Tatiana|T|;Motorin|Dmitriy|D|;Zammoeva|Darina|D|;Efremova|Svetlana|S|;Ivanov|Vladimir|V|;Petukhov|Alexey|A|;Alekseeva|Yuliya|Y|;Zaritskey|Andrey|A|",
"chemical_list": "D019086:Bridged Bicyclo Compounds, Heterocyclic; D013449:Sulfonamides; C579720:venetoclax",
"country": "England",
"delete": false,
"doi": "10.1186/s12905-021-01328-y",
"fulltext": "\n==== Front\nBMC Womens Health\nBMC Womens Health\nBMC Women's Health\n1472-6874\nBioMed Central London\n\n1328\n10.1186/s12905-021-01328-y\nCase Report\nThe myeloid sarcoma treated by Venetoclax with hypomethylating agent followed by stem cell transplantation: rare case report\nhttp://orcid.org/0000-0002-4799-9398\nShatilova Aleksina alexina-96@list.ru\n\n1\nGirshova Larisa 1\nZaytsev Daniil 1\nBudaeva Irina 1\nMirolyubova Yuliya 1\nRyzhkova Darya 1\nGrozov Roman 1\nBogdanov Konstantin 1\nNikulina Tatiana 2\nMotorin Dmitriy 1\nZammoeva Darina 1\nEfremova Svetlana 2\nIvanov Vladimir 2\nPetukhov Alexey 1\nAlekseeva Yuliya 2\nZaritskey Andrey 2\n1 Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., Saint Petersburg, Russian Federation 197341\n2 Almazov National Medical Research Center, 2 Akkuratova Str., Saint Petersburg, Russian Federation 197341\n1 5 2021\n1 5 2021\n2021\n21 18416 11 2020\n22 4 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nMyeloid sarcoma (MS) is a very rare condition, develops both in patients with other hematological neoplasms, and as isolated tumor. MS of the gynecologic tract is extremely rare. An available literature data about diagnosis and management of MS is summarized in the article. The role of chemotherapy, radiation therapy, surgery and bone marrow transplantation in the treatment is discussed. Polychemotherapy and allogeneic bone marrow transplantation were suggested to be the optimal treatment strategy of MS of the gynecological tract. The use of new targeted agents results in promising clinical data.\n\nCase presentation\n\nWe are presenting a rare clinical case of a MS of the uterine cervix with concomitant bone marrow involvement and describe all the peculiarities of the clinical course, diagnosis, and treatment. The patient received chemotherapy followed by allogeneic bone marrow transplantation. The pre-transplant therapy allowed us to perform allogeneic bone marrow transplantation with the deepest response possible: complete PET-negative and MRD-negative remission of the disease.\n\nConclusions\n\nMS remains a subject of discussion regarding its diagnostic and therapeutic aspects. The use of novel targeting agents can be perspective option for patient with extramedullary disease.\n\nKeywords\n\nMyeloid sarcoma of the uterine cervix\nVenetoclax\nHypomethylating agent\nStem cell transplantation\nAcute myeloid leukemia\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nMS (also known as chloroma or granulocytic sarcoma) is a very rare condition characterized by proliferation of immature myeloid cells in extramedullary sites [1]. Chloroma most often develops in patients with acute myeloid leukemia (AML), other myeloproliferative neoplasms, or myelodysplastic syndromes, but it can be also presented as an isolated mass. MS, associated with AML, may precede it, develop during the onset or relapse of disease [2–4]. Untreated isolated MS usually leads to AML at a median of 7 months (range of 1 to 2) [5]. Although MS has been reported in various parts of the body, the most common sites are lymph nodes, soft tissues, and bones [5]. MS of the gynecologic tract, in particular the cervix, is rare (up to 5.8–22.7% of all localizations). Vaginal bleeding is a very common presenting symptom of MS of the cervix or uterus [6, 7]. Diagnosis of MS is difficult, especially in the absence of bone marrow involvement, and is based on a combination of clinical features, radiological investigations, and tissue biopsy [1, 8, 9]. Immunohistochemical analysis is an important part of MS diagnostics, which allows establishing the correct diagnosis in 96% of cases [5, 8]. FDG-PET/CT is a useful tool to estimate the extent of the lesion [10]. Treatment of MS with AML (Cytarabine-based) protocols (regardless of bone marrow involvement) is the most reasonable approach [1]. Successful use of targeted agents such as Gemtuzumab ozogamicin, hypomethylating agents (Decitabine and 5-azacitidine), and BCL-2 inhibitors (Venetoclax) has also been described [11–14]. Surgical and radiation therapies are accepted treatment methods, but their roles in the treatment algorithm are not well-defined. Surgical intervention should be considered before the systemic treatment in patients with symptoms of mass effect or when excision biopsy was necessary to establish the diagnosis [1]. Radiation is used in addition to chemotherapy in patients with isolated MS, who do not achieve complete regression of the tumor mass after polychemotherapy, as well as palliative option when compression symptoms (superior vena cava syndrome, spinal cord roots compression) are present [1, 11, 15, 16]. The hematopoietic stem cell transplantation, is an important therapeutic option which can be used in patients with and without bone marrow involvement [1, 8, 17]. In this article, we present a rare clinical case of an MS of the uterine cervix with concomitant bone marrow involvement.\n\nCase presentation\n\nA 49-year-old female with ECOG Performance Score of 0 presented with complaints of profuse metrorrhagia following period of amenorrhea. There was no history of weight loss, fever, or night sweats. A speculum examination showed an exophytic tumor originating from the uterine cervix with contact bleeding. The histological and immunohistochemical study of the biopsy showed that the biopsied tissue was diffuse infiltrated by polymorphous cells with positivity for MPO, LCA, CD99, CD4, CD117, CD15, BCL-2, and negativity for lymphoid, epithelial, and neuroendocrine markers (MCК, CК7, ALK, CD10, CD20, CD3, CD30, CD34, chromogranin A, synaptophysin, desmin, Fli-1, S-100, PAX-4, CD56, CD7) (Fig. 1). The Ki67 was expressed in 40% of the cells.Fig. 1 Immunohistochemical study of MS. a Expression of CD15; b expression of CD45; c expression of CD99; d expression of CD117; e expression of myeloperoxidase, f expression of BCL-2\n\nLaboratory studies revealed the following values: hemoglobin 10.9 g/dL, platelet—177 × 109/l, and white-cell count 3500 per cubic millimeter without pathological findings at leucogram. A bone marrow biopsy showed the presence of 16.2% positive MPO pathological blasts. The immunophenotypic analysis showed the expression of CD117, CD13, CD33, CD64, CD4, and MPO. Karyotype was normal—46, XX (20 metaphases were analyzed), while FISH demonstrated inversion 3 (identified the separation of the fusion signal from region 3q26 at 76 out of 200 analyzed interphase nuclei). A mutation in NPM1B was detected by quantitative PCR (737.8% copies). Lumbar puncture with prophylactic intrathecal chemotherapy was made and there was no evidence of CNS involvement. A pelvic magnetic resonance imaging (MRI) with contrast revealed an intrapelvic lymph nodes lesion and 43 × 75 × 76 mm tumor originating from the uterine cervix with invasion of the uterine corpus, parametrium, and pelvic peritoneum. A FDG-PET/CT showed a 71 × 48 mm lesion at the cervix with a standard uptake value maximum (SUVlbm max) of 5.5 (Fig. 2). Other hypermetabolic focuses were noted at intrapelvic lymphatic nodes: along the common iliac vessels (up to 8 mm with SUVlbm max = 2.16 on the right and up to 7 mm with SUVlbm max = 2.2 on the left), and the external iliac vessels (up to 15 × 11 mm with SUVlbm max = 2.6 on the right and 19 × 14 mm with SUVlbm max = 2.9 on the left). These findings were compatible with the diagnosis of MS involving the cervix and corpus of the uterus, parametrium, pelvic lymph nodes, and bone marrow.Fig. 2 Dynamics of tumor by FDG-PET/CT. a Study at the onset of the disease; b study after course of induction therapy; c study after course of consolidation therapy; d study after course of specific therapy with Venetoclax and 5-azacitidine\n\nThe patient received AML type induction chemotherapy with cytosine arabinoside (200 mg/m2/day for 7 days) and daunorubicin (60 mg/m2 for 3 days). The course was complicated by febrile neutropenia and probable invasive mycosis which was successfully treated. The patient achieved complete clinical and hematologic remission (platelet—373 × 109/l, absolute neutrophil count—1360 per cubic millimeter, bone marrow blasts—1%, independence of red cell transfusions) and partial metabolic response (decrease of tumor mass by 80.3%). The consolidation chemotherapy included high-dose cytosine arabinoside (3 g/m2/day). The control PET/CT showed the decrease in tumor mass (by 93% comparing to the initial size), and we were unable to achieve complete remission due to extramedullary lesion. Considering the data available in the literature about the successful use of BCL-2 inhibitors in combination with hypomethylating agents in AML, including extramedullary lesions [13, 14, 18], the patient underwent a course of chemotherapy with Venetoclax and 5-azacitidine (75 mg/m2). Post-chemotherapy examination demonstrated that the patient achieved complete MRD-negative remission (Fig. 2).\n\nThe patient underwent allogeneic hematopoietic stem cell transplantation from human leukocyte antigens (HLA)-matched related donor (sister) with myeloablative conditioning regimen (Fludarabine 150 mg/m2, Busulfan 12 mg/kg). Posttransplant period was complicated by sepsis, associated with Klebsiella pneumoniae, and systemic invasive mycosis involving the liver, spleen, and lungs, which were successfully treated. The patient achieved complete donor chimerism (100%) in 6 weeks after bone marrow transplantation. There was no evidence of graft-versus-host disease. The patient remains in complete MRD-negative and PET-negative remission for 4 months after bone marrow transplantation.\n\nDiscussion\n\nMS involving the female reproductive system occurs rather rarely. We were able to identify 57 cases of leukemic cervical tumors in published articles from 2002 to 2019 (Table 1). Patients often complain of vaginal bleeding at the onset of disease [6, 7], it was the first symptom in the above case. FDG-PET/CT appears to be the best imaging option to assess the presence of extramedullary AML and effectively used to both search for other possible lesions and monitoring the response to therapy [19–21]. MS may often be misdiagnosed for malignant lymphoma, small cell carcinoma, and undifferentiated tumor, so performing immunohistochemistry study with epithelial, neuroendocrine, myeloid, and lymphoid markers it is highly recommended [1, 2, 8, 21, 22]. Determining the markers, characteristic for myeloid cells (MPO, LCA) and the absence of lymphoid (CD20, CD10, CD3, CD30, CD7), epithelial (MCK, CK7), neuroendocrine (chromogranin A, synaptophysin), and other (ALK, desmin, Fli-1, S-100) markers allowed us to decide on the diagnosis. Additionally, the high expression of BCL-2 was found in the biopsy sampling.Table 1 Literature review of myeloid sarcoma involving the gynecologic tract\n\nNo\tAuthors, country, year of study\tNumber of cases (n)\tAffected region\tConcurrent AML\tTreatment\t% (n)\tDuration of observation (months)\t\n1 [6]\tB. Pathak et al., Canada, 2005\t25\tCervix—76% (n = 19)\n\nUterine corpus—8% (n = 2)\n\nExternal genital organs—4% (n = 1)\n\n ≥ 2 gynecologic sites—4% (n = 1)\n\nNot stated—8% (n = 2)\n\n\t48% (n = 12)\tCT\t28 (7)\t7.7\t\nRT\t8 (2)\t5\t\nSI\t8 (2)\t3\t\nCT + RT\t24 (6)\t13.75\t\nCT + SI\t8 (2)\t20.5\t\nRT + SI\t4 (1)\t1.75\t\nWithout treatment\t16 (4)\t < 1\t\n2 [40]\tR.M. Kahn et al., USA, 2019\t1\t ≥ 2 gynecologic sites (uterine corpus, fallopian tubes, left ovary)\tYes\tCT + SI\t3\t\n3 [12]\tG.Modi et al., India, 2004\t1\tExternal genital organs (vagina)\tNo\tHypomethylating therapy with decitabine\t> 4\t\n4 [41]\tJ.-A. Hernández et al., Spain, 2002\t2\tCervix, left mesosalpinx, ovaries\t100% (n = 2)\tCT + SI + autoBMT\t10\t\nExternal genital organs (vagina)\tCT + autoBMT\t10\t\n5 [42]\tM. Ucar, M. Guryildirim, Turkey, 2014\t1\tBreast, cervix, uterus\tYes\tCT\t> 2\t\n6 [43]\tM.G. Garcia et al., USA, Spain, 2006\t11\tCervix—27.3% (n = 3)\n\nOvary—18.2% (n = 2)\n\nUterine corpus—9% (n = 1)\n\nExternal genital organs—9% (n = 1)\n\n ≥ 2 gynecologic sites—36.5% (n = 4)\n\n\t36.5% (n = 4)\tCT\t64 (7)\t40\t\nRT\t9 (1)\t5\t\nCT + alloBMT\t9 (1)\t> 6\t\nSI\t73 (8)\t-\t\n9\tCervix—11% (n = 1)\n\nOvary—89% (n = 8)\n\n\t22% (n = 2)\tCT\t33 (3)\t15\t\nCT + alloBMT\t11 (1)\t10\t\n7 [44]\tS.C.H. Kim et al., France, 2010\t1\tCervix\tNo\tCT + RT\t> 72\t\n8 [45]\tH. Gill et al., China, 2012\t1\tCervix, left pelvic cavity\tNo\tCT\t16\t\n9 [7]\tW. Gui et al., China, 2019\t2\tCervix, external genital organs (vagina), intrapelvic lymph nodes\tNo\tSI + CT\t21\t\nCervix, uterus, intrapelvic lymph nodes\tYes\tCT\t26\t\n10 [46]\tA.S. Weingertner et al., France, 2009\t1\tCervix, intrapelvic lymph nodes\tYes\tCT\t> 3\t\n11 [47]\tY. Yu et al., China, 2015\t1\tExternal genital organs (vulva, vagina), cervix\tNo\tCT\t4\t\n12 [48]\tH. Bao et al., China, 2019\t1\tExternal genital organs\tYes\tSI + CT + alloBMT\t> 6\t\nCT chemotherapy, RT radiotherapy, SI surgical intervention, autoBMT autologous bone marrow transplantation, alloBMT allogeneic bone marrow transplantation\n\nCertain AML genetic abnormalities, like t(8;21), inv(16) and t(9;11), mutations in NPM1, NRAS, and DNMT3A, are associated with a higher incidence of extramedullary disease [1, 3, 5, 23]. Apart from a mutation in NPM1B, we also identified inversion of chromosome 3, which is strongly associated with poor prognosis in AML patients [24]. No association of chromosome 3 inversion with the extramedullary lesion was found in the literature.\n\nThe genetic assessment of extramedullary tumor is indeed, especially in a case of isolated disease [21], although these data are lacking in our case as in the majority of others, presented in Table 1.\n\nMS is a systemic disease and AML-type regimens are most often recommended as initial therapy as stated in National Comprehensive Cancer Network and European Leukemia Net (2017) guidelines [19, 24]. Earlier studies suggested, MS had had the worse prognosis, in comparison to AML without extramedullary disease [25, 26]. Currently, the majority of authors consider that extramedullary AML is not per se associated with poor prognosis [16, 21].\n\nStandard cytarabine-containing regimens, such as «7 + 3», HDAC (high doses of cytarabine), are used for eligible patients [15, 16, 19, 24]. This regimen was applied to our patient. Bone marrow MRD-negative response was obtained, that looked surprising: usually patients with chromosome 3 abnormality are resistant to chemotherapy: CR—31%, 5-year OS—5.7% ± 3%; EFS—0%; RFS-4.3% ± 4% [27]. Nevertheless, failure of metabolic response in extramedullary disease was registered according to the control PET/CT. Reasons for this discordant are unclear. Cunningham et al. attribute them to gene or microenvironmental deregulations [20, 28, 29], but that is continued to be studied.\n\nIn patients with chemotherapy resistant MS, radiation therapy is standardly recommended as second line of treatment [1, 11, 15, 16, 21]. Delay in systemic therapy often results to early relapse in patient with chromosome 3 inversion [27, 30, 31]. Thus, we thought about alternative regimens that could be used instead of or as an addition to irradiation.\n\nRecently registered medicines such as anti-CD33 monoclonal antibody [32, 33], tyrosine kinase inhibitors (for FIP1L1-PDGFR [34, 35], and FLT3-ITD [36]), and DNA methyltransferase inhibitors [12] offer the possibility to continue systemic therapy for patients with MS.\n\nThe expression of CD33 was not studied in the biopsied tissue, targets for FLT-3 inhibitors were lacking in our patient. Targeting of BCL-2, involving mitochondrial pathway of apoptosis, has emerged as an efficacious and well-tolerated clinical strategy. It is based on founded on myeloblast function rather than on genetics [37, 38]. Regarding MS, overexpression of BCL-2 was found by Wang et al. [39]. Worth mentioning, that the tumor tissue of our patient was revealed to hyperexpression of BCL-2.\n\nCombination of Venetoclax with 5-azacytidine was described as a very promising regimen in several case reports as well as the retrospective study of the small number of patients [13, 14]. This therapeutic option resulted in complete metabolic response and MRD-negative complete remission. Regimen was well tolerable without unusual toxicities. The prompt response of the extramedullary tumor to the combination of Venetoclax with 5-azacytidine allowed us to proceed to allogeneic hematopoietic SCT.\n\nAllogeneic SCT is believed to improve OS in patients both with isolated MS and concurrent AML [8, 17]. Transplantation is usually recommended as consolidative strategy of extramedullary AML based on the disease risk (by cytogenetics or molecular data) and in case of resistance [16, 21]. Patient has been in complete remission until the present.\n\nWe report for the first-time successful treatment of uterine cervix MS with Venetoclax-based regimen is described. Of note, this is the first description MS of the uterine cervix with concurrent bone marrow involvement with chromosome 3 inversion.\n\nConclusion\n\nMS of the gynecologic tract is a very rare and often misdiagnosed hematologic malignancy, whose diagnostics and therapeutic aspects remain a subject of discussion. MS treatment standard is AML-type chemotherapy. Postremission therapy is dependent upon a number of factors: extent of disease, risk profile, and performance status. The use of Venetoclax with hypomethylating agent has shown good results in our clinical case. Adding this combination to standard treatment regimens in patients with extramedullary AML might become a promising clinical option. The pre-transplant therapy allowed us to perform allogeneic bone marrow transplantation with the deepest response possible: complete PET-negative and MRD-negative remission of the disease.\n\nHematopoietic stem-cell transplantation remains an important therapeutic option.\n\nAbbreviations\n\nAML Acute myeloid leukemia\n\nBCL-2 B-cell lymphoma 2\n\nCD Cluster of differentiation\n\nCNS Central nervous system\n\nCR Complete remission\n\nDNA Deoxyribonucleic acid\n\nECOG Eastern Cooperative Oncology Group\n\nEFS Event-free survival\n\nFDG-PET/CT Fluorodeoxyglucose positron emission tomography/computed tomography\n\nFISH Fluorescence in situ hybridization\n\nFLT3 FMS-like tyrosine kinase 3\n\nHLA Human leukocyte antigens\n\nLCA Leucocyte common antigen\n\nMCK Multi-cytokeratin\n\nMPO Myeloperoxidase\n\nMRD Minimal residual disease\n\nMRI Magnetic resonance imaging\n\nMS Myeloid sarcoma\n\nNPM1B Nucleophosmin 1B\n\nOS Overall survival\n\nPCR Polymerase chain reaction\n\nFDG-PET/CT Positron emission tomography–computed tomography\n\nRFS Relapse-free survival\n\nSCT Stem cell transplantation\n\nSUVlbm max Standard uptake value maximum\n\nAcknowledgements\n\nNot applicable.\n\nAuthors' contributions\n\nAS managed the patient, analyzed this case report, literature findings and prepared the manuscript. LG was attending doctor of this patient, took part in writing the Case Presentation and Discussion section. DZ, IB, VI, YA and SE were hematologists involved in the management of the patient, worked on writing the Case Presentation and analyzing the literature. DM and Darina Z were hematologists who performing the allogeneic transplantation and wrote the section describing the course and results of transplantation. YM, KB, TN and AP were doctors involved in the diagnostical part of management of the patient, performed the morphological, cytogenetic and molecular studies and wrote the diagnostic part of Case Presentation and Discussion section. DR was the radiologist, who analyzed the PET/CT-results and prepared images with PET/CT results with commentaries. RG was the pathologist, analyzing biopsy and prepared histologic images with commentaries for this article. AZ contributed in critical revision of the manuscript. All listed authors meet the ICMJE criteria. We attest that all authors contributed significantly to the creation of this manuscript, each having fulfilled criteria as established by the ICMJE. All authors read and approved the manuscript.\n\nFunding\n\nNo funding was received for this work. This work was financially supported by the Ministry of Science and Higher Education of the Russian Federation (Agreement No. 075-15-2020-901).\n\nAvailability of data and materials\n\nAll data related to this case report are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nCompeting interests\n\nWe wish to confirm that there are no known conflicts of interest associated with this publication and 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. 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Gui W Li J Zhang Z Primary hematological malignancy of the uterine cervix: a case report Oncol Lett 2019 18 3 3337 3341 31516559\n8. Pileri SA Ascani S Cox MC Myeloid sarcoma: clinico-pathologic, phenotypic and cytogenetic analysis of 92 adult patients Leukemia 2007 21 2 340 350 17170724\n9. Sharma V Dora T Patel M Case report of diffuse large B cell lymphoma of uterine cervix treated at a semiurban cancer centre in North India Case Rep Hematol 2016 2016 3042531 27597906\n10. Aschoff P Häntschel M Oksüz M Integrated FDG-PET/CT for detection, therapy monitoring and follow-up of granulocytic sarcoma Initial Results Nuklearmedizin 2009 48 5 185 191 19710955\n11. Avni B Koren-Michowitz M Myeloid sarcoma: current approach and therapeutic options Ther Adv Hematol 2011 2 5 309 316 23556098\n12. Modi G Madabhavi I Panchal H Primary vaginal myeloid sarcoma: a rare case report and review of the literature Case Rep Obstet Gynecol 2015 2015 957490 25685570\n13. Otoukesh S, Zhang J, Nakamura R, et al. The efficacy of venetoclax and hypomethylating agents in acute myeloid leukemia with extramedullary involvement [published online ahead of print, 2020 Mar 19]. Leuk Lymphoma. 2020;1–4. 10.1080/10428194.2020.1742908\n14. Kanate AS Vos J Chargualaf MJ Venetoclax for refractory myeloid sarcoma J Oncol Pract 2019 15 7 413 415 31291562\n15. Bakst RL Tallman MS Douer D How I treat extramedullary acute myeloid leukemia Blood 2011 118 14 3785 3793 21795742\n16. Shahin O Ravandi F Myeloid sarcoma Curr Opin Hematol 2020 27 2 88 94 31904666\n17. Chevallier P Labopin M Cornelissen J Allogeneic hematopoietic stem cell transplantation for isolated and leukemic myeloid sarcoma in adults: a report from the Acute Leukemia Working Party of the European group for Blood and Marrow Transplantation Haematologica 2011 96 9 1391 1394 21685467\n18. Lachowiez C DiNardo CD Konopleva M Venetoclax in acute myeloid leukemia—current and future directions Leuk Lymphoma 2020 61 6 1313 1322 32031033\n19. Pollyea DA, Bixby D, Perl A, et al. NCCN guidelines insights: acute myeloid leukemia, version 2.2021: featured updates to the NCCN guidelines. J Natl Compr Cancer Netw 2021;19(1):14, 45, 64.\n20. Cunningham I Post-transplant leukemia relapse in organs: biology and behavior in 585 reports Crit Rev Oncol/Hematol 2021 157 103170\n21. Shallis RM Gale RP Lazarus HM Myeloid sarcoma, chloroma, or extramedullary acute myeloid leukemia tumor: a tale of misnomers, controversy and the unresolved Blood Rev 2020\n22. Neiman RS Barcos M Berard C Granulocytic sarcoma: a clinicopathologic study of 61 biopsied cases Cancer 1981 48 6 1426 1437 7023656\n23. Kashofer K Gornicec M Lind K Detection of prognostically relevant mutations and translocations in myeloid sarcoma by next generation sequencing Leuk Lymphoma 2018 59 2 501 504 28633614\n24. Döhner H Estey E Grimwade D Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel Blood 2017 129 4 424 447 27895058\n25. Paydas S Zorludemir S Ergin M Granulocytic sarcoma: 32 cases and review of the literature Leuk Lymphoma 2006 47 12 2527 2541 17169797\n26. Byrd JC Weiss RB Arthur DC Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461 J Clin Oncol 1997 15 2 466 475 9053467\n27. Lugthart S Gröschel S Beverloo HB Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia J Clin Oncol 2010 28 24 3890 3898 20660833\n28. Cunningham I A basis for updating our approach to resistant acute leukemia Am J Hematol 2012 87 251 257 22287495\n29. Cunningham I Hamele-Bena D Guo Y Extramedullary leukemia behaving as solid cancer: clinical, histologic, and genetic clues to chemoresistance in organ sites Am J Hematol 2019 94 1200 1207 31353508\n30. Sitges M Boluda B Garrido A Acute myeloid leukemia with inv(3)(q21.3q26.2)/t(3;3)(q21.3;q26.2): Study of 61 patients treated with intensive protocols Eur J Haematol. 2020 105 2 138 147 32243655\n31. Rogers HJ Hsi ED Myeloid Neoplasms with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) Surg Pathol Clin 2013 6 4 677 692 26839193\n32. Piccaluga PP Martinelli G Rondoni M Gemtuzumab ozogamicin for relapsed and refractory acute myeloid leukemia and myeloid sarcomas Leuk Lymphoma 2004 45 9 1791 1795 15223637\n33. Zaytsev D Girshova L Ivanov V Rapid efficacy of Gemtuzumab Ozogamicin in refractory AML patients with pulmonary and kidney failure Biology (Basel) 2020 9 2 28\n34. Tang TC Chang H Chuang WY Complete response of myeloid sarcoma with FIP1L1-PDGFRA-associated myeloproliferative neoplasms to imatinib mesylate monotherapy Acta Haematol 2012 128 2 83 87 22722648\n35. Mandelker D Dal Cin P Jacene HA Refractory myeloid sarcoma with a FIP1L1-PDGFRA rearrangement detected by clinical high throughput somatic sequencing Exp Hematol Oncol 2015 4 30 26457233\n36. Grillo G Zucchetti E Forno B Lotesoriere I Inzoli E Cairoli R Targeted therapy in FLT3-ITD positive myeloid sarcoma: proof of principle Blood 2017 130 Supplement 1 5061\n37. Pollyea DA Amaya M Strati P Venetoclax for AML: changing the treatment paradigm Blood Adv 2019 3 24 4326 4335 31869416\n38. Konopleva M Letai A BCL-2 inhibition in AML: an unexpected bonus? Blood 2018 132 10 1007 1012 30037885\n39. Wang HQ Li J Clinicopathological features of myeloid sarcoma: Report of 39 cases and literature review Pathol Res Pract 2016 212 9 817 824 27515547\n40. Kahn RM Gordhandas S Chapman-Davis E Acute myeloid leukemia presenting as myeloid sarcoma with a predisposition to the gynecologic tract Case Rep Oncol Med 2019 2019 1 5\n41. Hernandez J-A Navarro J-T Rozman M Primary myeloid sarcoma of the gynecologic tract: a report of two cases progressing to acute myeloid leukemia Leuk Lymphoma 2002 43 11 2151 2153 12533040\n42. Ucar M Guryildirim M Granulocytic sarcoma of the uterus: a rare presentation of extramedullary relapse of AML and importance of MRI Case Rep Radiol 2014 2014 1 4\n43. Garcia MG Deavers MT Knoblock RJ Myeloid sarcoma involving the gynecologic tract: a report of 11 cases and review of the literature Am J Clin Pathol 2006 125 5 783 790 16707383\n44. Kim SCH Natarajan-Ame S Lioure B Successful treatment of a granulocytic sarcoma of the uterine cervix in complete remission at six-year follow-up J Oncol 2010 2010 1 3\n45. Gill H Loong F Mak V Myeloid sarcoma of the uterine cervix presenting as missed abortion Arch Gynecol Obstet 2012 286 5 1339 1341 22791383\n46. Weingertner AS Wilt M Atallah I Myeloid sarcoma of the uterine cervix as presentation of acute myeloid leukaemia after treatment with low-dose radioiodine for thyroid cancer: a case report and review of the literature Case Rep Oncol 2009 2 1 1 6 20844570\n47. Yu Y Qin X Yan S Non-leukemic myeloid sarcoma involving the vulva, vagina, and cervix: a case report and literature review Oncol Targets Ther 2015 8 3707 3713\n48. Bao H Gao J Chen YH Rare myeloid sarcoma with KMT2A (MLL)-ELL fusion presenting as a vaginal wall mass Diagn Pathol 2019 14 1 26 30922345\n\n",
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"keywords": "Acute myeloid leukemia; Hypomethylating agent; Myeloid sarcoma of the uterine cervix; Stem cell transplantation; Venetoclax",
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"title": "The myeloid sarcoma treated by Venetoclax with hypomethylating agent followed by stem cell transplantation: rare case report.",
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"abstract": "BACKGROUND\nTransjugular intrahepatic portosystemic shunt (TIPS) alters portal blood flow and may impact drug metabolism and bioavailability. However, little evidence has been published to provide guidance on medication alterations after TIPS procedures.\n\n\nMETHODS\nWe report a patient who developed phenytoin toxicity requiring a prolonged readmission after a TIPS procedure. It is likely that the TIPS procedure altered phenytoin metabolism and led to toxicity in this patient. Phenytoin is an antiepileptic drug that is primarily eliminated by hepatic metabolism. It is possible that phenytoin toxicity may occur after TIPS, and that decreased dose requirements may be a durable effect of the procedure. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: TIPS is now the most common portal hypertension decompressive procedure performed by interventional radiologists and has become the primary portosystemic shunt (surgical or percutaneous) performed in the United States. Patients with a history of TIPS procedures commonly present to tertiary- and quaternary-care emergency departments with complex clinical presentations. Greater familiarity with the potential effects of TIPS on drug metabolism may help emergency physicians prevent adverse drug effects and optimize clinical outcomes.",
"affiliations": "Department of Pharmacy, University of California (UC) San Diego Health System, San Diego, California.;Department of Emergency Medicine, UC San Diego School of Medicine, San Diego, California; Division of Ultrasound, UC San Diego Health, San Diego, California.;Department of Emergency Medicine, UC San Diego School of Medicine, San Diego, California; Division of Hyperbaric Medicine, UC San Diego Health, San Diego, California.;Department of Pharmacy, University of California (UC) San Diego Health System, San Diego, California.;Department of Emergency Medicine, UC San Diego School of Medicine, San Diego, California; Division of Medical Toxicology, UC San Diego Health, San Diego, California.",
"authors": "Bassell|Timothy|T|;Aminlari|Amir|A|;Hayden|Stephen|S|;Del Rosso|Jake|J|;Ly|Binh T|BT|",
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"title": "Phenytoin Toxicity After Transjugular Intrahepatic Portosystemic Shunt (TIPS).",
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"abstract": "BACKGROUND\nSinus bradycardia has been reported after administration of pulse dose steroids, although most cases have occurred in children and are asymptomatic. We report a case of acute symptomatic sinus bradycardia due to pulse dose steroids in a woman with multiple sclerosis. Interestingly, this patient also suffered from inappropriate sinus tachycardia due to autonomic involvement of multiple sclerosis.\n\n\nMETHODS\nA 48-year-old Caucasian woman with multiple sclerosis and chronic palpitations due to inappropriate sinus tachycardia was prescribed a 5-day course of intravenous methylprednisolone for treatment of an acute flare. Immediately following the fourth dose of intravenous methylprednisolone, she developed dyspnea, chest heaviness, and lightheadedness. She was referred to the emergency department where an electrocardiogram showed marked sinus bradycardia (40 beats per minute). Initial laboratory test results, including a complete blood count, basic metabolic profile and cardiac biomarkers, were normal. She was admitted for observation on telemetry monitoring. Her heart rate gradually increased and her symptoms resolved. Her outpatient dose of atenolol, taken for symptomatic inappropriate sinus tachycardia, was resumed.\n\n\nCONCLUSIONS\nOur patient's acute symptoms were attributed to symptomatic sinus bradycardia due to pulse dose steroid treatment. Although several theories have been suggested to explain this phenomenon, the exact mechanism still remains unknown. It does not warrant any specific treatment, as it is a self-limiting side effect that resolves after discontinuing steroid infusion. Young patients who are free of any active cardiac conditions can safely be administered pulse dose steroids without monitoring. However, older patients with active cardiac conditions should have heart rate and blood pressure monitoring during infusion. Our patient also suffered from inappropriate sinus tachycardia, a manifestation of autonomic involvement of multiple sclerosis that has not been previously described. This case has implications for the pathogenesis and treatment of dysautonomia in patients with multiple sclerosis.",
"affiliations": "Department of Medicine, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA. Amartya.Kundu@umassmemorial.org.;Department of Medicine, Cardiovascular Division, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA. timothy.fitzgibbons@umassmemorial.org.",
"authors": "Kundu|Amartya|A|;Fitzgibbons|Timothy P|TP|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 70110.1186/s13256-015-0701-xCase ReportAcute symptomatic sinus bradycardia in a woman treated with pulse dose steroids for multiple sclerosis: a case report Kundu Amartya Amartya.Kundu@umassmemorial.org Fitzgibbons Timothy P. 508-856-6573timothy.fitzgibbons@umassmemorial.org Department of Medicine, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655 USA Department of Medicine, Cardiovascular Division, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655 USA 24 9 2015 24 9 2015 2015 9 21630 1 2015 31 8 2015 © Kundu and Fitzgibbons. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nSinus bradycardia has been reported after administration of pulse dose steroids, although most cases have occurred in children and are asymptomatic. We report a case of acute symptomatic sinus bradycardia due to pulse dose steroids in a woman with multiple sclerosis. Interestingly, this patient also suffered from inappropriate sinus tachycardia due to autonomic involvement of multiple sclerosis.\n\nCase presentation\nA 48-year-old Caucasian woman with multiple sclerosis and chronic palpitations due to inappropriate sinus tachycardia was prescribed a 5-day course of intravenous methylprednisolone for treatment of an acute flare. Immediately following the fourth dose of intravenous methylprednisolone, she developed dyspnea, chest heaviness, and lightheadedness. She was referred to the emergency department where an electrocardiogram showed marked sinus bradycardia (40 beats per minute). Initial laboratory test results, including a complete blood count, basic metabolic profile and cardiac biomarkers, were normal. She was admitted for observation on telemetry monitoring. Her heart rate gradually increased and her symptoms resolved. Her outpatient dose of atenolol, taken for symptomatic inappropriate sinus tachycardia, was resumed.\n\nConclusions\nOur patient’s acute symptoms were attributed to symptomatic sinus bradycardia due to pulse dose steroid treatment. Although several theories have been suggested to explain this phenomenon, the exact mechanism still remains unknown. It does not warrant any specific treatment, as it is a self-limiting side effect that resolves after discontinuing steroid infusion. Young patients who are free of any active cardiac conditions can safely be administered pulse dose steroids without monitoring. However, older patients with active cardiac conditions should have heart rate and blood pressure monitoring during infusion. Our patient also suffered from inappropriate sinus tachycardia, a manifestation of autonomic involvement of multiple sclerosis that has not been previously described. This case has implications for the pathogenesis and treatment of dysautonomia in patients with multiple sclerosis.\n\nKeywords\nSinus BradycardiaIntravenous MethylprednisolonePulse Steroid TherapyMultiple SclerosisInappropriate sinus tachycardia.issue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nMultiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system that frequently manifests with a waxing and waning course, characterized by lesions disseminated in both time and location. High-dose intravenous corticosteroid therapy, also known as pulse steroid therapy (PST), is commonly used to treat a wide range of autoimmune disorders because of its rapid anti-inflammatory effect and is considered to be standard therapy for treatment of acute flares of MS [1].\n\nAlthough many side effects of intravenous steroid infusion are well established in the medical literature, PST is generally considered to have a good safety profile. Some of the commonly reported adverse effects following high-dose intravenous steroid infusion are hyperglycemia, gastrointestinal intolerance, and psychiatric manifestations such as euphoria or depression. Minor transient side effects include facial flushing, fluid retention, weight gain and parasthesias [1].\n\nSinus bradycardia is an uncommon adverse effect following steroid infusion and is very rarely symptomatic. Herein we report a case of symptomatic sinus bradycardia in a patient following PST with intravenous methylprednisolone given for treatment of an acute flare of MS.\n\nCase presentation\nA 48-year-old Caucasian woman with a history of MS, smoking, and palpitations was prescribed a 5-day course of intravenous methylprednisolone (1 gram per day administered intravenously) as part of ongoing intensive therapy for a flare of MS. Her predominant symptoms were pain and numbness in her legs. One year prior, she had had a course of PST for similar symptoms. On this occasion, she noticed that her heart rate felt slow on days 2 and 3 following steroid infusions, but this was transient, and she felt normal soon afterward. Her documented heart rate during infusion on those days ranged from 81 to 96 beats per minute (bpm). However, during the infusion on day 4, she noticed that her chest started to feel heavy, she felt slightly lightheaded, and had difficulty breathing. She was transferred to the emergency department for evaluation of these symptoms. Prior to the infusion, she had only pain and numbness in her legs; the chest pain and dyspnea started after the infusion. On subsequent questioning, she denied any recent changes in her list of home medications. She had been taking atenolol for inappropriate sinus tachycardia (IST) for several years, and had taken her usual dose of 25mg that morning. Her usual resting heart ranged from 100 to 120bpm prior to starting atenolol, and 80 to 100bpm after starting atenolol.\n\nOn presentation to the emergency department, her blood pressure was 124/72mmHg, her pulse was 40bpm, and her oxygen saturation was 88% on room air. Results of the physical examination and laboratory tests were within normal limits. A 12-lead electrocardiogram (ECG) showed marked sinus bradycardia with a heart rate of 42bpm and normal PR (120msec), QRS (88msec) and QTc (402msec) intervals (Fig. 1). A prior ECG, done 1 year earlier, had shown normal sinus rhythm with a rate of 78bpm (Fig. 2). Cardiac biomarkers were normal and pulmonary embolism was excluded by a computed tomography (CT) pulmonary angiogram. She was admitted for observation on telemetry monitoring with supplemental oxygen therapy. With time, her oxygen saturation improved to normal on room air.Fig. 1 Electrocardiogram obtained upon admission showing sinus bradycardia at 42 beats per minute\n\nFig. 2 Electrocardiogram done 1-year prior demonstrating normal sinus rhythm at 78 beats per minute\n\n\n\nTelemetry monitoring showed persistence of sinus bradycardia for 8 hours without atrioventricular block or ventricular arrhythmias. Our patient denied any further chest tightness or lightheadedness. The next day, her heart rate increased to normal sinus rhythm at 80bpm. An echocardiogram was performed and showed normal biventricular size and function without valvular abnormalities. Her fifth (and final) dose of intravenous methylprednisolone was withheld. As our patient remained asymptomatic with a normal heart rate, she was discharged from the hospital soon after on her usual home dose of atenolol.\n\nDiscussion\nAlthough symptomatic sinus bradycardia following high-dose steroid infusion has been previously reported, it is an uncommon occurrence, and relatively underappreciated in the cardiovascular literature. Most of the prior reported cases have been asymptomatic, and all have recovered spontaneously over a variable period of time after stopping the steroid infusion [2–4].\n\nMiura et al. reported sinus bradycardia occurring between 1 and 82% of children receiving intravenous methylprednisolone therapy for Kawasaki disease [5]. In a prospective study in adults by Tvede et al., five patients received high-dose intravenous methylprednisolone for treatment of rheumatoid arthritis [6]. All five patients experienced sinus bradycardia, although it was symptomatic in only one patient who reported chest tightness. It was self-limiting in all the patients, but it took as long as 7 days for the heart rate to return to normal.\n\nVasheghani-Farahani et al. conducted a study on 52 patients who were admitted to the hospital for PST for treatment of an acute flare of MS [7]. The purpose was to determine the effect of high-dose intravenous methylprednisolone on cardiac rhythms in patients with MS. All patients underwent continuous cardiac monitoring and a total of 167 sessions of PST were monitored. Patients with a history of cardiac disease and those receiving antiarrhythmic drugs or beta blockers were excluded from the study. The most common cardiac arrhythmia observed was sinus tachycardia, occurring in 83.8% of patients after steroid therapy. Sinus bradycardia was observed in 41.9% of the recorded rhythms after steroid infusion. Sinus bradycardia was found to be more common in patients who were male, smokers and those with autonomic disorders such as bladder and/or bowel sphincter disturbance [7].\n\nSeveral hypotheses have been suggested to explain the pathophysiology of bradycardia following high-dose steroid infusion, but the exact mechanism still remains unknown. Both the rates of infusion, and the presence of underlying heart disease, are thought to increase the risk of occurrence [8]. Fujimoto et al. monitored ECG tracings, serum electrolyte levels as well as fractional excretion of sodium and potassium in 25 patients undergoing treatment with intravenous methylprednisolone for nephrotic syndrome [9]. Arrhythmias were observed in four of these patients. Serum potassium levels and fractional excretion of potassium significantly increased from baseline after PST. This suggests that abnormal cardiac rhythms may be caused due to sudden changes in potassium flux across the cell membrane [10, 11]. Another possible mechanism could be alterations in ionized calcium levels caused by formation of calcium phosphate complexes, which may be induced by the sodium phosphate contained in some commercially available preparations of methylprednisolone [12]. However our patient’s serum calcium and other electrolyte levels were normal on admission and prior to discharge.\n\nPudil et al. reported two patients who developed bradycardia following intravenous methylprednisolone where technetium-99m pyrophosphate myocardial scanning showed diffusely increased radionuclide accumulation in the myocardium that resolved on follow-up a few weeks later, suggesting that transient direct damage to the myocardium as a possible mechanism [13]. Our patient did not have a pharmacologic perfusion study, but echocardiography showed normal left ventricular function, making this explanation less likely. Although sinus bradycardia has most commonly been associated with high-dose PST, cases have also been reported following low-dose methylprednisolone infusion as well as oral prednisone therapy [14, 15]. Corticosteroids cause sodium retention and hypertension due to their intrinsic mineralocorticoid activity. Baroreceptor-mediated reflex bradycardia in response to hypertension caused by steroids is another potential explanation for bradycardia seen in patients treated with intravenous steroids [3]. Of note, our patient had no previous history of hypertension and her blood pressure level was normal throughout the course of observation. Finally, it has been suggested that bradycardia may simply be an idiosyncratic reaction to high-dose steroid infusion in a certain population of patients [16].\n\nIt is debatable whether routine cardiac monitoring is necessary for all patients receiving high-dose steroid therapy for treatment of MS, especially as a lot of PST sessions take place in the outpatient setting. Moreover, most cases of sinus bradycardia are self-limiting, asymptomatic, and do not require any treatment. White et al. recommended cardiac monitoring during PST for dermatologic patients who may have compromised skin integrity predisposing to electrolyte shifts, and in those with cardiac and renal disease [17]. It is probably prudent to proceed with a slow rate of steroid infusion and monitor select patients who have a history of cardiac disease or those who have experienced adverse effects following PST in the past. Interestingly, fingolimod, a recently approved sphingosine-1-phosphate inhibitor for use in relapsing-remitting MS, also causes sinus bradycardia and even second-degree atrioventricular block [18]. It is recommended that patients receive 6 hours of continuous ECG and blood pressure monitoring after the first dose of this oral disease-modifying agent [18].\n\nAlthough involvement of the autonomic nervous system is common in MS, cardiovascular side effects are not. Autonomic symptoms usually include bowel, bladder, or sexual dysfunction. Postural orthostatic tachycardia syndrome (POTS) has been reported in MS, but IST has not. The latter can be difficult to diagnose as patients usually suffer from concomitant anxiety and/or pain [19]. Treatment is typically conservative, including beta blockers and anxiolytics, with electrophysiologic testing reserved for more severe cases [19]. Our patient has been managed effectively with the same conservative regimen.\n\nWe believe that this case highlights two unique features of MS that are not widely appreciated in the adult cardiovascular literature. One, pulse dose steroid treatment in patients with MS can cause acute asymptomatic and, more rarely, symptomatic sinus bradycardia. Newer disease-modifying agents, such as fingolimod, also cause bradyarrythmias, which can be more frequent and severe. Patient-specific factors such as active cardiac disease, smoking status or concomitant medications (that is, beta blockers) should be considered when administering these agents [7]. Second, autonomic involvement of MS can affect the cardiovascular system, and may cause POTS or IST. Care of patients with MS should be longitudinal and collaborative, involving primary care, neurology, cardiology and mental health professionals to consider all these factors.\n\nConclusions\nIn conclusion, our patients’ symptoms of dyspnea, chest heaviness and lightheadedness were attributed to sinus bradycardia due to high-dose intravenous methylprednisolone therapy. The majority of prior reported cases have been asymptomatic and thus, symptomatic sinus bradycardia remains an extremely rare adverse effect of PST. It does not warrant any treatment as most cases are self-limiting and resolve after discontinuing steroid infusion. Cardiac monitoring is generally not needed if patients are young and free of active cardiac conditions, however patient-specific factors, such as the use of concomitant medications (that is, beta blockers) and smoking status should be considered when making this decision. Finally, chronic symptoms such as palpitations, syncope, or orthostatic intolerance in MS patients, should raise suspicion for cardiovascular effects of MS, which can include IST or POTS.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nbpmbeats per minute\n\nCTcomputed tomography\n\nECGelectrocardiogram\n\nISTinappropriate sinus tachycardia\n\nMSmultiple sclerosis\n\nPSTpulse steroid therapy\n\nPOTSpostural orthostatic tachycardia syndrome\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAK drafted the manuscript. TF made significant editorial modifications. Both authors read and approved the final manuscript.\n\nAcknowledgements\nDr. Fitzgibbons’ research is supported by a Fellow-to-Faculty Transition Award from the National Affiliate of the American Heart Association (number 12FTF1126090) and the Harold S. Geneen Charitable Trust.\n==== Refs\nReferences\n1. Lyons PR Newman PK Saunders M Methylprednisolone therapy in multiple sclerosis: a profile of adverse effects J Neurol Neurosurg Psychiatry. 1988 51 285 7 10.1136/jnnp.51.2.285 3346696 \n2. van der Gugten A Bierings M Frenkel J Glucocorticoid-associated bradycardia J Pediatr Hematol Oncol. 2008 30 172 5 10.1097/MPH.0b013e31815dcfeb 18376273 \n3. Akikusa JD Feldman BM Gross GJ Silverman ED Schneider R Sinus bradycardia after intravenous pulse methylprednisolone Pediatrics. 2007 119 e778 82 10.1542/peds.2006-0029 17308245 \n4. Hsu DT Steroids and bradycardia: how slow can you go? J Pediatr Hematol Oncol. 2008 30 119 20 10.1097/MPH.0b013e31815f8906 18376262 \n5. Miura M Ohki H Yoshiba S Ueda H Sugaya A Satoh M Adverse effects of methylprednisolone pulse therapy in refractory Kawasaki disease Arch Dis Child. 2005 90 1096 7 10.1136/adc.2004.062299 16177169 \n6. Tvede N Nielsen LP Andersen V Bradycardia after high-dose intravenous methylprednisolone therapy Scand J Rheumatol. 1986 15 302 4 10.3109/03009748609092597 3798047 \n7. Vasheghani-Farahani A Sahraian MA Darabi L Aghsaie A Minagar A Incidence of various cardiac arrhythmias and conduction disturbances due to high dose intravenous methylprednisolone in patients with multiple sclerosis J Neurol Sci. 2011 309 75 8 10.1016/j.jns.2011.07.018 21831398 \n8. Guillén EL Ruíz AM Bugallo JB Hypotension, bradycardia, and asystole after high-dose intravenous methylprednisolone in a monitored patient Am J Kidney Dis. 1998 32 10.1053/ajkd.1998.v32.pm10074612 10074612 \n9. Fujimoto S Kondoh H Yamamoto Y Hisanaga S Tanaka K Holter electrocardiogram monitoring in nephrotic patients during methylprednisolone pulse therapy Am J Nephrol. 1990 10 231 6 10.1159/000168087 1696428 \n10. Parham WA Mehdirad AA Biermann KM Fredman CS Hyperkalemia revisited Texas Heart Inst J. 2006 33 40 7 \n11. Dananberg J Schwartz GR Electrolyte abnormalities affecting the heart Principles and practice of emergency medicine 1999 4 Baltimore Williams & Wilkins 425 7 \n12. Moses RE McCormick A Nickey W Fatal arrhythmia after pulse methylprednisolone therapy Ann Intern Med. 1981 95 781 2 10.7326/0003-4819-95-6-781_3 7305165 \n13. Pudil R Hrncir Z Severe bradycardia after a methylprednisolone minipulse treatment Arch Intern Med. 2001 161 1778 9 10.1001/archinte.161.14.1778-a 11485514 \n14. Darling HS Marwah V Rajput AK Varma PP Singh KK Low dose methylprednisolone induced bradycardia J Assoc Physicians India. 2013 61 920 2 24968553 \n15. Al Shibli A Al Attrach I Hamdan MA Bradycardia following oral corticosteroid use: case report and literature review Arab J Nephrol Transplant. 2012 5 47 9 22283866 \n16. Lucas KG Howrie DL Phebus CK Cardiorespiratory decompensation following methylprednisolone administration Pediatr Hematol Oncol. 1993 10 249 55 10.3109/08880019309029492 8217541 \n17. White KP Driscoll MS Rothe MJ Grant-Kels JM Severe adverse cardiovascular effects of pulse steroid therapy: is continuous cardiac monitoring necessary? J Am Acad Dermatol. 1994 30 768 73 10.1016/S0190-9622(08)81508-3 8176017 \n18. Schurmann P Basra S Awar OG Aguilar D Basant A Dragan E Abnormal rhythms in patients without known cardiac disease after a first dose of fingolimod Mult Scler Relat Disord. 2014 3 408 12 10.1016/j.msard.2013.11.001 25876482 \n19. Olshansky B Sullivan RM Inappropriate sinus tachycardia J Am Coll Cardiol. 2013 61 793 801 10.1016/j.jacc.2012.07.074 23265330\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "9()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
"mesh_terms": "D001919:Bradycardia; D004562:Electrocardiography; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007262:Infusions, Intravenous; D008775:Methylprednisolone; D008875:Middle Aged; D009103:Multiple Sclerosis; D020551:Pulse Therapy, Drug",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "216",
"pmc": null,
"pmid": "26400725",
"pubdate": "2015-09-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10074612;23265330;16177169;25876482;8217541;3346696;7305165;18376273;3798047;18376262;11485514;21831398;16572868;24968553;22283866;1696428;8176017;17308245",
"title": "Acute symptomatic sinus bradycardia in a woman treated with pulse dose steroids for multiple sclerosis: a case report.",
"title_normalized": "acute symptomatic sinus bradycardia in a woman treated with pulse dose steroids for multiple sclerosis a case report"
} | [
{
"companynumb": "US-JUBILANT CADISTA PHARMACEUTICALS-2015JUB00343",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
... |
{
"abstract": "Neuroleptic malignant syndrome is considered as a rare but potentially fatal complication of neuroleptic medications e.g.,antipsychotics, sedatives and anti emetics. It is characterized by hyperthermia, muscle rigidity, an elevated creatine kinase level and autonomic instability. The syndrome often develops after the start of antipsychotic or a sudden increase in dosage of the neuroleptic medication or in states of dehydration. Treatment is mainly supportive and includes withdrawal of the neuroleptic medication and, possibly, administration of drugs such as dantrolene and bromocriptine. In rare cases where drugs treatment remains ineffective a trial of electroconvulsive therapy is being given. The case presented is a drug resistant case of Neuroleptic Malignant Syndrome where finally electroconvulsive therapy was effective.",
"affiliations": null,
"authors": "Hashim|Husnain|H|;Zeb-un-Nisa|||;Alrukn|Suhail Abdulla Mohammad|SA|;Al Madani|Abubaker Abdul Rahman Shaffi|AA|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "Pakistan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-9982",
"issue": "64(4)",
"journal": "JPMA. The Journal of the Pakistan Medical Association",
"keywords": null,
"medline_ta": "J Pak Med Assoc",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D018450:Disease Progression; D004351:Drug Resistance; D004565:Electroconvulsive Therapy; D005260:Female; D006801:Humans; D009459:Neuroleptic Malignant Syndrome; D017211:Treatment Failure",
"nlm_unique_id": "7501162",
"other_id": null,
"pages": "471-3",
"pmc": null,
"pmid": "24864649",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug resistant neuroleptic malignant syndrome and the role of electroconvulsive therapy.",
"title_normalized": "drug resistant neuroleptic malignant syndrome and the role of electroconvulsive therapy"
} | [
{
"companynumb": "PHHY2014AE145190",
"fulfillexpeditecriteria": "1",
"occurcountry": "AE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
"dru... |
{
"abstract": "Blau syndrome (BS) is a monogenic autoinflammatory disease caused by mutations in nucleotidebinding oligomerization domain containing 2 (NOD2). BS is characterized by the clinical triad of granulomatous dermatitis, arthritis and recurrent uveitis. Due to the low incidence of BS and the lack of treatment studies with large samples, a specific treatment scheme has not been established. We report the case of a patient with BS that was uncontrollable with various immunosuppressive therapies but had a good response to thalidomide. She had the typical triad of rash, arthritis and uveitis. Gene sequencing indicated a NOD2 heterozygous missense variant (c.1759C > T, p.R587C), which has been reported as a pathogenic mutation. The BS diagnosis was confirmed. After treatment with methotrexate, an anti-tumour necrosis factor (TNF)-α inhibitor and corticosteroids, the patient's clinical symptoms and inflammatory indicators remained uncontrolled, and she experienced multiple side effects, such as hypertension and growth retardation attributed to prolonged corticosteroid use. After treatment with thalidomide, her condition was controlled without recurrence or side effects, and corticosteroids were stopped as soon as possible. This report suggests that thalidomide may be effective for BS treatment, but more research is needed to evaluate its long-term efficacy and side effects.",
"affiliations": "Chinese Academy of Medical Sciences, Peking Union Medical College, Peking Union Medical College Hospital Pediatrics, Beijing, China.;Chinese Academy of Medical Sciences, Peking Union Medical College, Peking Union Medical College Hospital Pediatrics, Beijing, China.;Chinese Academy of Medical Sciences, Peking Union Medical College, Peking Union Medical College Hospital Pediatrics, Beijing, China.;Chinese Academy of Medical Sciences, Peking Union Medical College, Peking Union Medical College Hospital Pediatrics, Beijing, China.;Chinese Academy of Medical Sciences, Peking Union Medical College, Peking Union Medical College Hospital Ophthalmology, Beijing, China.;Chinese Academy of Medical Sciences, Peking Union Medical College, Peking Union Medical College Hospital Pediatrics, Beijing, China.",
"authors": "Wang|Wei|W|;Wang|Wei|W|;Zhong|Lin-Qing|LQ|;Li|Wen-Dao|WD|;Wu|Shi-Jing|SJ|;Song|Hong-Mei|HM|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/apm-21-2216",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2224-5820",
"issue": null,
"journal": "Annals of palliative medicine",
"keywords": "Blau syndrome (BS); case report; thalidomide; treatment",
"medline_ta": "Ann Palliat Med",
"mesh_terms": null,
"nlm_unique_id": "101585484",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34775778",
"pubdate": "2021-11-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Thalidomide may be an effective drug for Blau syndrome: a case report.",
"title_normalized": "thalidomide may be an effective drug for blau syndrome a case report"
} | [
{
"companynumb": "CN-LOTUS-2021-LOTUS-048364",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "1",
... |
{
"abstract": "One-third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within 6 months. Treatment options for these patients remain limited. Here we analyse 20 BRAF(V600)-mutant melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2(C125S), but not the synonymous MEK1(C121S) protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (for example, RAC1 and AKT3) that activate the MAPK and PI3K pathways and are thus predicted to diminish response to MAPK inhibitors.",
"affiliations": "1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Mater Hospital, North Sydney, New South Wales 2060, Australia.;1] Precision Cancer Therapy Laboratory, Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales 2109, Australia [2] Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia.;1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales 2145, Australia.;Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia.;1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia [3] Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales 2145, Australia.;1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Departments of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2006, Australia.;1] Precision Cancer Therapy Laboratory, Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales 2109, Australia [2] Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia.;Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia.;1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Departments of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2006, Australia.;1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Departments of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2006, Australia.;1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Department of Surgical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales 2145, Australia.;Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.;Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.;1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Departments of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2006, Australia [3] Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia.;1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Precision Cancer Therapy Laboratory, Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales 2109, Australia [4] Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia.;1] Precision Cancer Therapy Laboratory, Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales 2109, Australia [2] Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia.",
"authors": "Long|Georgina V|GV|;Fung|Carina|C|;Menzies|Alexander M|AM|;Pupo|Gulietta M|GM|;Carlino|Matteo S|MS|;Hyman|Jessica|J|;Shahheydari|Hamideh|H|;Tembe|Varsha|V|;Thompson|John F|JF|;Saw|Robyn P|RP|;Howle|Julie|J|;Hayward|Nicholas K|NK|;Johansson|Peter|P|;Scolyer|Richard A|RA|;Kefford|Richard F|RF|;Rizos|Helen|H|",
"chemical_list": "D007093:Imidazoles; D008565:Membrane Proteins; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C107953:RAC1 protein, human; C560077:trametinib; C482128:MAP2K2 protein, human; D019869:Phosphatidylinositol 3-Kinases; C491754:AKT3 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D020830:rac1 GTP-Binding Protein; C561627:dabrafenib",
"country": "England",
"delete": false,
"doi": "10.1038/ncomms6694",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2041-1723",
"issue": "5()",
"journal": "Nature communications",
"keywords": null,
"medline_ta": "Nat Commun",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D019008:Drug Resistance, Neoplasm; D020558:GTP Phosphohydrolases; D006801:Humans; D007093:Imidazoles; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D008545:Melanoma; D008565:Membrane Proteins; D010091:Oximes; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D011728:Pyridones; D011744:Pyrimidinones; D012878:Skin Neoplasms; D020830:rac1 GTP-Binding Protein",
"nlm_unique_id": "101528555",
"other_id": null,
"pages": "5694",
"pmc": null,
"pmid": "25452114",
"pubdate": "2014-12-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma.",
"title_normalized": "increased mapk reactivation in early resistance to dabrafenib trametinib combination therapy of braf mutant metastatic melanoma"
} | [
{
"companynumb": "PHHY2015AU147814",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABRAFENIB\\TRAMETINIB"
},
"drugadditional": null,
... |
{
"abstract": "Fetal goitrous hypothyroidism is a rare entity and is caused mainly by maternal treatment of Graves' disease (GD). We report a case of a 22-year-old woman referred at 12 weeks of gestation due to hyperthyroidism subsequent to recently diagnosed GD. She started treatment with propylthiouracil and, at 21 weeks of gestation, fetal goitre was detected. A cordocentesis confirmed the diagnosis of fetal goitrous hypothyroidism, and intra-amniotic administration of levothyroxine (LT4) was performed and repeated through the pregnancy due to maintenance of fetal goitre. The pregnancy proceeded without further complications and a healthy female infant was born at 37 weeks of gestation, with visible goitre and thyroid function within the normal range at birth. Although there is no consensus on the optimal dose, the number of injections and the interval between them, intra-amniotic LT4 administration is recommended once fetal goitrous hypothyroidism is suspected, in order to prevent long-term complications of fetal hypothyroidism.",
"affiliations": "Endocrinology, Centro Hospitalar de Vila Nova de Gaia Espinho EPE, Vila Nova de Gaia, Portugal.;Gynecology and Obstetrics, Centro Hospitalar de Vila Nova de Gaia Espinho EPE, Vila Nova de Gaia, Portugal.;Pediatrics, Centro Hospitalar de Vila Nova de Gaia Espinho EPE, Vila Nova de Gaia, Portugal.;Endocrinology, Centro Hospitalar de Vila Nova de Gaia Espinho EPE, Vila Nova de Gaia, Portugal.",
"authors": "Machado|Catarina Martins|CM|;Castro|Jorge Manuel|JM|;Campos|Rosa Arménia|RA|;Oliveira|Maria João|MJ|",
"chemical_list": "D013974:Thyroxine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-230457",
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"journal": "BMJ case reports",
"keywords": "materno-fetal medicine; pregnancy; thyroid disease",
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"mesh_terms": "D004333:Drug Administration Routes; D005260:Female; D005315:Fetal Diseases; D006042:Goiter; D006111:Graves Disease; D006801:Humans; D007037:Hypothyroidism; D013974:Thyroxine",
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"pubdate": "2019-08-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Graves' disease complicated by fetal goitrous hypothyroidism treated with intra-amniotic administration of levothyroxine.",
"title_normalized": "graves disease complicated by fetal goitrous hypothyroidism treated with intra amniotic administration of levothyroxine"
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"abstract": "The antibody-drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial.\n\n\n\nEMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane. Enrolled patients were randomly assigned (1:1) via a hierarchical, dynamic randomisation scheme and an interactive voice response system to trastuzumab emtansine (3·6 mg/kg intravenously every 3 weeks) or control (capecitabine 1000 mg/m2 self-administered orally twice daily on days 1-14 on each 21-day cycle, plus lapatinib 1250 mg orally once daily on days 1-21). Randomisation was stratified by world region (USA vs western Europe vs or other), number of previous chemotherapy regimens for unresectable, locally advanced, or metastatic disease (0 or 1 vs >1), and disease involvement (visceral vs non-visceral). The coprimary efficacy endpoints were progression-free survival (per independent review committee assessment) and overall survival. Efficacy was analysed in the intention-to-treat population; safety was analysed in all patients who received at least one dose of study treatment, with patients analysed according to the treatment actually received. On May 30, 2012, the study protocol was amended to allow crossover from control to trastuzumab emtansine after the second interim overall survival analysis crossed the prespecified overall survival efficacy boundary. This study is registered with ClinicalTrials.gov, number NCT00829166.\n\n\n\nBetween Feb 23, 2009, and Oct 13, 2011, 991 eligible patients were enrolled and randomly assigned to either trastuzumab emtansine (n=495) or capecitabine and lapatinib (control; n=496). In this final descriptive analysis, median overall survival was longer with trastuzumab emtansine than with control (29·9 months [95% CI 26·3-34·1] vs 25·9 months [95% CI 22·7-28·3]; hazard ratio 0·75 [95% CI 0·64-0·88]). 136 (27%) of 496 patients crossed over from control to trastuzumab emtansine after the second interim overall survival analysis (median follow-up duration 24·1 months [IQR 19·5-26·1]). Of those patients originally randomly assigned to trastuzumab emtansine, 254 (51%) of 495 received capecitabine and 241 [49%] of 495 received lapatinib (separately or in combination) after study drug discontinuation. In the safety population (488 patients treated with capecitabine plus lapatinib, 490 patients treated with trastuzumab emtansine), fewer grade 3 or worse adverse events occurred with trastuzumab emtansine (233 [48%] of 490) than with capecitabine plus lapatinib control treatment (291 [60%] of 488). In the control group, the most frequently reported grade 3 or worse adverse events were diarrhoea (103 [21%] of 488 patients) followed by palmar-plantar erythrodysaesthesia syndrome (87 [18%]), and vomiting (24 [5%]). The safety profile of trastuzumab emtansine was similar to that reported previously; the most frequently reported grade 3 or worse adverse events in the trastuzumab emtansine group were thrombocytopenia (70 [14%] of 490), increased aspartate aminotransferase levels (22 [5%]), and anaemia (19 [4%]). Nine patients died from adverse events; five of these deaths were judged to be related to treatment (two in the control group [coronary artery disease and multiorgan failure] and three in the trastuzumab emtansine group [metabolic encephalopathy, neutropenic sepsis, and acute myeloid leukaemia]).\n\n\n\nThis descriptive analysis of final overall survival in the EMILIA trial shows that trastuzumab emtansine improved overall survival in patients with previously treated HER2-positive metastatic breast cancer even in the presence of crossover treatment. The safety profile was similar to that reported in previous analyses, reaffirming trastuzumab emtansine as an efficacious and tolerable treatment in this patient population.\n\n\n\nF Hoffmann-La Roche/Genentech.",
"affiliations": "Department of Medical Oncology, Institut Curie, Paris, France. Electronic address: veronique.dieras@curie.fr.;Mount Vernon Cancer Centre, Northwood, UK.;Sunnybrook Odette Cancer Centre, Toronto, ON, Canada.;Stanford Cancer Institute, Palo Alto, CA, USA.;Medical Office Hematology, Aschaffenburg, Germany.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Dana-Farber Cancer Institute, Boston, MA, USA.;Duke University Medical Center, Durham, NC, USA.;F Hoffmann-La Roche, Basel, Switzerland.;Genentech Inc, South San Francisco, CA, USA.;Genentech Inc, South San Francisco, CA, USA.;San Raffaele Hospital, Milan, Italy.",
"authors": "Diéras|Véronique|V|;Miles|David|D|;Verma|Sunil|S|;Pegram|Mark|M|;Welslau|Manfred|M|;Baselga|José|J|;Krop|Ian E|IE|;Blackwell|Kim|K|;Hoersch|Silke|S|;Xu|Jin|J|;Green|Marjorie|M|;Gianni|Luca|L|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D011799:Quinazolines; D043823:Taxoids; D000077341:Lapatinib; D008453:Maytansine; C080625:taxane; D000069287:Capecitabine; D001219:Aspartate Aminotransferases; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine",
"country": "England",
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"doi": "10.1016/S1470-2045(17)30312-1",
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"issn_linking": "1470-2045",
"issue": "18(6)",
"journal": "The Lancet. Oncology",
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"mesh_terms": "D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001219:Aspartate Aminotransferases; D001943:Breast Neoplasms; D018567:Breast Neoplasms, Male; D001952:Bridged-Ring Compounds; D000069287:Capecitabine; D003967:Diarrhea; D018572:Disease-Free Survival; D005260:Female; D060831:Hand-Foot Syndrome; D006801:Humans; D000077341:Lapatinib; D008297:Male; D008453:Maytansine; D008875:Middle Aged; D011799:Quinazolines; D018719:Receptor, ErbB-2; D066066:Response Evaluation Criteria in Solid Tumors; D019233:Retreatment; D015996:Survival Rate; D043823:Taxoids; D013921:Thrombocytopenia; D000068878:Trastuzumab; D014839:Vomiting; D055815:Young Adult",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "732-742",
"pmc": null,
"pmid": "28526536",
"pubdate": "2017-06",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "28526538;25234545;23020162;10655437;3798106;19010901;23602601;22149875;19933921;15911866;24793816;19346299;24222194;27298406;11248153;17192538;25693012",
"title": "Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial.",
"title_normalized": "trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated her2 positive advanced breast cancer emilia a descriptive analysis of final overall survival results from a randomised open label phase 3 trial"
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"abstract": "BACKGROUND\nCongestive heart failure is rarely observed in patients with acromegaly. Excessive growth hormone secretion and elevation of insulin-like growth factor 1 contribute to pathological changes in myocyte growth and structure, cardiac contractility, vascular function, and in later stage may progress to cardiac dysfunction. Early recognition of the condition is paramount, though the insidious progression of the disease commonly results in late diagnosis. Current standard regimens of pharmacological therapy, surgical treatment, radiotherapy are designed to normalize serum levels of both insulin-like growth factor 1 and growth hormone. In patients with late-stage heart failure due to acromegalic cardiomyopathy, cardiac resynchronization therapy might be a desirable treatment to help cardiac synchronization, improve symptoms, and eventually reduce hospital admissions together with mortality rates.\n\n\nMETHODS\nWe describe a case of a 49-year-old man with a history of acromegaly who presented to our hospital with a diagnosis of decompensated systolic heart failure. Serial electrocardiograms showed wide (160-200 ms) QRS duration with left bundle branch block. Echocardiography showed severe left ventricular dysfunction that simultaneously achieved a left ventricular ejection fraction of 16%. Surgical indication was rarely assessed by neurosurgeons. Given that the stereotactic radiosurgery together with pharmacotherapy produced infinitesimal effects, cardiac resynchronization therapy was performed. Owing to biventricular synchronization and holding back reverse remodeling, the patient's symptoms were successfully alleviated, and he was discharged from the hospital.\n\n\nCONCLUSIONS\nCongestive heart failure is a rare complication in acromegaly-induced cardiomyopathy (occurs in only 3% of patients). Early diagnosis and treatment with curative drugs more than cardiovascular implantable electronic devices might lead to better surgical outcomes in this group of patients.",
"affiliations": "Affiliated with Chengdu Second People's Hospital, Qinyun South Road, 10th Avenue, Chengdu, 610041, Sichuan, China.;Affiliated with Chengdu Second People's Hospital, Qinyun South Road, 10th Avenue, Chengdu, 610041, Sichuan, China. huyongmei2000@163.com.;Affiliated with Chengdu Second People's Hospital, Qinyun South Road, 10th Avenue, Chengdu, 610041, Sichuan, China.;Affiliated with Chengdu Second People's Hospital, Qinyun South Road, 10th Avenue, Chengdu, 610041, Sichuan, China.",
"authors": "Wang|Jun Yi|JY|;Hu|Yong Mei|YM|;Liu|Jian Xiong|JX|;Luo|Xiao Jia|XJ|",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s13256-019-2030-y",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 203010.1186/s13256-019-2030-yCase ReportCardiac resynchronization therapy improves heart failure in one patient with acromegaly-induced cardiomyopathy: a case report Wang Jun yi 550996916@qq.com Hu Yong mei huyongmei2000@163.com Liu Jian xiong steven.ljx@vip.163.com Luo Xiao jia xiaojialuo@hotmail.com grid.440164.3Affiliated with Chengdu Second People’s Hospital, Qinyun South Road, 10th Avenue, Chengdu, 610041 Sichuan China 25 4 2019 25 4 2019 2019 13 1064 8 2018 25 2 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nCongestive heart failure is rarely observed in patients with acromegaly. Excessive growth hormone secretion and elevation of insulin-like growth factor 1 contribute to pathological changes in myocyte growth and structure, cardiac contractility, vascular function, and in later stage may progress to cardiac dysfunction. Early recognition of the condition is paramount, though the insidious progression of the disease commonly results in late diagnosis. Current standard regimens of pharmacological therapy, surgical treatment, radiotherapy are designed to normalize serum levels of both insulin-like growth factor 1 and growth hormone. In patients with late-stage heart failure due to acromegalic cardiomyopathy, cardiac resynchronization therapy might be a desirable treatment to help cardiac synchronization, improve symptoms, and eventually reduce hospital admissions together with mortality rates.\n\nCase presentation\nWe describe a case of a 49-year-old man with a history of acromegaly who presented to our hospital with a diagnosis of decompensated systolic heart failure. Serial electrocardiograms showed wide (160–200 ms) QRS duration with left bundle branch block. Echocardiography showed severe left ventricular dysfunction that simultaneously achieved a left ventricular ejection fraction of 16%. Surgical indication was rarely assessed by neurosurgeons. Given that the stereotactic radiosurgery together with pharmacotherapy produced infinitesimal effects, cardiac resynchronization therapy was performed. Owing to biventricular synchronization and holding back reverse remodeling, the patient’s symptoms were successfully alleviated, and he was discharged from the hospital.\n\nConclusions\nCongestive heart failure is a rare complication in acromegaly-induced cardiomyopathy (occurs in only 3% of patients). Early diagnosis and treatment with curative drugs more than cardiovascular implantable electronic devices might lead to better surgical outcomes in this group of patients.\n\nKeywords\nAcromegalic cardiomyopathyHeart failureCardiac resynchronization therapyissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nAcromegaly presents with multisystem involvement, and cardiac manifestations remain an important cause of mortality [1, 2]. Chronic excess of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) leads to the development of acromegalic cardiomyopathy [3]. The clinical manifestations are biventricular hypertrophy, diastolic dysfunction, and in later stages may progress to systolic dysfunction and congestive heart failure [4]. Long-term treatments of acromegaly with pharmacological therapy, surgical treatment, and radiotherapy are extensively identified as standard regimens, among which surgical resection of the pituitary adenoma is often the first-line treatment [5]. In patients either waiting for or missing surgical indications due to severe heart failure, cardiac resynchronization therapy (CRT) might act as a desirable treatment to help synchronize cardiac contractility, improve symptoms, and reduce hospital admissions and mortality rates in patients with moderate to severe heart failure, hence ultimately creating chances for operation.\n\nWe report a case of a patient with acromegaly who was diagnosed with severe cardiac failure at the time of diagnosis and failed to recover cardiac function after pharmacotherapy and radiotherapy. Though successful resection of the pituitary adenoma was crucial, low left ventricular ejection fraction (LVEF) value in alignment with poor cardiac function could have made the surgery life-threatening. We applied mechanical therapy as CRT to this patient, which helped better control acromegalic cardiomyopathy, and this approach may create further chances for subsequent surgical resection.\n\nCase presentation\nA 49-year-old man with a history of acromegaly was admitted to our hospital with the concern of recurrent shortness of breath and dyspnea on exertion during the previous 2 years, and he had experienced an episode of presyncope 2 weeks prior without any further evaluation. He was a chef in a local restaurant for almost 30 years. He had no family history of any diseases and no past history of hypertension, diabetes mellitus, sleep apnea, or sudden cardiac death. He did not smoke or consume alcohol. The patient provided a history of stereotactic radiosurgeries twice in a decade or so and adherence to treatment with a somatostatin analog (octreotide given 40 mg once per month through intramuscular injection) at the time of diagnosis 20 years before. The patient was overweight and moderately nourished. He was 1.85 m (73 inches) tall, weighed 134 kg, and had a body mass index of 39 kg/m2. His blood pressure was 110/60 mmHg, and his heart rate was 92 beats/min with sinus rhythm. He had distinct skeletal features that included prominent superciliary arches and nose bridge, enlargement of the tongue and lip, and large hands and feet. Cardiac auscultation revealed irregular premature beats and pathological third heart sound, and a systolic murmur was discovered over the apex and aortic area. Bilateral extensive borders of cardiac dullness were noted. His physiological reflexes were present without any pathology. An electrocardiogram demonstrated sinus rhythm with wide (160 ms) QRS duration of left bundle branch block (LBBB) (Fig. 1). The patient’s condition was classified as New York Heart Association (NYHA) stage III–IV.Fig. 1 Electrocardiogram on admission demonstrating sinus rhythm with wide (160 ms) QRS duration of left bundle branch block\n\n\n\nOn admission, magnetic resonance imaging showed pituitary macroadenoma. Given the symptoms described, we arranged blood testing of myocardial injury markers showing an elevated brain natriuretic peptide level of 740 pg/ml indicating cardiac failure (Table 1). Hormone laboratory tests performed subsequently demonstrated excessive secretion of GH and IGF-1, twofold greater than the reference normal upper limit, which was consistent with pituitary macroadenoma (Table 2). Other routine analyses of liver and renal function were roughly normal.Table 1 Myocardial injury markers on admission\n\nMeasured value\tReference range\t\nCK-MB mass < 1.0 ng/ml\t0–4.3 ng/ml\t\nMyoglobin 50.8 ng/ml\t0–107 ng/ml\t\nTroponin I 0.07 ng/ml\t0–0.40 ng/ml\t\nBNP 740 pg/ml\t0–100 pg/ml\t\nD-dimer 723 ng/ml\t0–600 ng/ml\t\nBNP Brain natriuretic peptide, CK-MB Creatine kinase MB\n\nTable 2 Initial hormone laboratory tests\n\n\tMeasured value\tReference range\t\nGH\t32.5 ng/ml\t0–2.10 ng/ml\t\nIGF-1\t627.0 ng/ml\t117.0–329.2 ng/ml\t\nTSH\t0.852 mIU/L\t0.35–4.94 mIU/L\t\nfT4\t14.80 pmol/L\t9.00–19.00 pmol/L\t\nPRL\t8.60 ng/ml\t3.6–16.3 ng/ml\t\nAbbreviations: fT4 Free thyroxine, GH Growth hormone, IGF-1 Insulin-like growth factor 1, PRL Prolactin, TSH Thyroid-stimulating hormone\n\n\n\nA Holter monitor was ordered for underlying arrhythmias to explain the patient’s dyspnea, chest discomfort, and presyncope. It demonstrated sinus rhythm with an average heart rate of 68 beats/min, frequent ventricular premature beats, and nonsustained ventricular tachycardia (up to 2200 ms) (Fig. 2).Fig. 2 Dynamic electrocardiogram showing frequent ventricular premature beats and nonsustained ventricular tachycardia\n\n\n\nA chest x-ray showed a cardiothoracic ratio (CTR) of 78%. Echocardiography showed diffuse impairment of left ventricular (LV) systolic motion, reaching an LVEF of 16%. We noted hypertrophy of the ventricular septum at 18 mm, ventricular dilation, with LV diameter of 72 mm. The right ventricle and atrium and the left atrium were also dilated with moderate mitral regurgitation and mild tricuspid regurgitation. There was no associated systolic anterior motion (SAM) of the mitral valve. Dyssynchrony of the biventricular systolic motion was apparent.\n\nGiven an exertional component to the symptoms together with echo presentations in order to better exclude ischemic cardiomyopathy, coronary angiography was performed, which showed normal coronary arteries without stenosis, and left ventriculography applied simultaneously revealed an EF of 20% with diffuse LV hypokinesis.\n\nGiven the patient’s previous medical history of acromegaly, the absence of obstructive coronary artery imaging findings or segmental dyskinesia, family history of hypertrophic cardiomyopathy (HCM), symmetric hypertrophy, as well as absence of SAM of the mitral valve, acromegaly-induced cardiomyopathy was confirmed, which was absolutely opposed to coronary heart disease (CHD) and HCM.\n\nThese results indicated that it was probably not a case of hereditary cardiomyopathy; therefore, we diagnosed the patient as having secondary dilated cardiomyopathy due to acromegaly, even taking it a step further progressing to congestive heart failure secondary to acromegaly-induced dilated cardiomyopathy.\n\nChronic excess of GH and IGF-I secretion affects cardiac morphology and performance [5], so etiological treatment for acromegaly-induced cardiomyopathy is crucial to suppressing GH secretion or blocking GH action for the sake of reversing acromegaly-induced cardiomyopathy. The mainstay of treatment acknowledged globally is surgical resection of the pituitary adenoma [6], which was unfortunately considered high-risk given our patient’s cardiac condition (NYHA stage III–IV). Although stereotactic radiosurgery combined with somatostatin analogs and GH antagonists administrated previously were effective in suppressing hormones, they could not help his cardiac function. Therefore, we carefully administered diuretics, vasodilators, angiotensin-converting enzyme inhibitor (ACEI), β-blockers, and spironolactone for management of heart failure following the current guidelines [7]; in the meantime, octreotide (200 μg/day) was administered for the control of GH excess. After good compliance of pharmacotherapy and a regular medical examination regimen for nearly half a year, the serum GH and IGF-1 concentrations decreased from 32.50 ng/ml to 1.98 ng/ml and 627.00 ng/ml to 229.10 ng/ml, respectively, but the patient was hospitalized again because of uncontrollable cardiac failure. Accompanied by the normalization of GH and IGF-1 levels, the patient’s cardiac function did not seem to take a favorable turn upon readmission. Though echocardiography showed a recovered EF value from 16% to 28%, a significant ventricular mechanical dyssynchrony was detected as formerly. Electrophysiological study was performed using a nonaggressive stimulation protocol, which revealed a nonsustained ventricular monomorphic tachycardia [8]. In the presence of overt ventricular dyssynchrony, complete LBBB, LVEF< 35%, inducible ventricular tachycardia, and symptomatic heart failure despite guideline-directed medical therapy, surgical indication was rarely assessed by neurosurgeons, and stereotactic radiosurgery together with pharmacotherapy produced infinitesimal effects. Therefore, we boldly recommended cardiac resynchronization therapy with defibrillator (CRT-D) implantation based on device implantation official guidelines [7, 9]. The patient underwent CRT insertion finally and was discharged to home 5 days later, pharmacotherapy continued as usual (Fig. 3).Fig. 3 Cardiac resynchronization therapy electrode position in LAO 45 degrees, RAO 30 degrees, AP view. LAO Left anterior oblique, RAO Right anterior oblique, AP Anteroposterior position\n\n\n\nTelephone follow-up was arranged, and the patient claimed symptom improvement following the device insertion 1 month later and was basically back to normal life. We required that he return for follow-up at 1 month, 3 months, and 6 months after the interventional therapy. The patient has been followed in our outpatient clinic for nearly half a year now. During his last visit, echocardiography identified improved LVEF of 54%, and a chest x-ray showed reduced CTR of 60%. The patient was in NYHA functional class II (Fig. 4).Fig. 4 Chest x-rays at 1 month (left) and 6 months (right) after cardiac resynchronization therapy implantation, during follow-up visits\n\n\n\nDiscussion and conclusions\nWe present a case of a patient with acromegaly who had clinical signs and symptoms of refractory decompensated heart failure, diagnosed as congestive heart failure (CHF) and attributed to acromegaly-induced dilated cardiomyopathy. He eventually had a dramatic response to medical device therapy. This case reinforces the importance of careful examination, accurate diagnosis, detailed evaluation, and searching for better alternative treatments when standard therapy initially fails.\n\nAcromegaly is a rare endocrine disorder with an incidence of 3 per 1 million per year [1]. Acromegaly is characterized by chronic GH and IGF-1 hypersecretion that leads to an increased mortality rate, with cardiovascular complications accounting for the highest number of patient deaths [2, 4, 6]. GH exerts its effects by stimulating the production of IGF-I either directly or indirectly, which mediates GH action on peripheral tissues. The GH/IGF-1 axis acts through increasing biological protein synthesis, cardiomyocyte size, and muscle-specific gene expression. Specifically, IGF-1 promotes cardiac hypertrophy and increases muscle-specific gene transcription (namely, troponin I, myosin light chain 2, and α-actin) [10, 11]. Chronic excess of these hormones leads to the development of acromegalic cardiomyopathy, which in early stages manifests biventricular hypertrophy, diastolic dysfunction, and later may progress to systolic dysfunction and eventually congestive heart failure [3]. Heart failure from acromegalic cardiomyopathy is one of the most common causes of death in acromegaly and is now receiving increasing attention. The GH/IGF-1 axis regulates cardiac growth, stimulates myocardial contractility, and influences the vascular system. Epidemiological evidence suggests that serum IGF-1 levels in the low-normal range are associated with increased risk of acute myocardial infarction, ischemic heart disease, coronary and carotid artery atherosclerosis, and stroke [12–14]. Among histological abnormalities induced by the hormones, the most relevant is a proliferation of myocardial fibrous tissue leading to progressive interstitial remodeling and deterioration of diastolic and systolic cardiac performance [15]. In acromegaly, chronic GH/IGF-I excess causes a concentric cardiac hypertrophy associated with diastolic dysfunction. In later stages, impaired systolic function ending in heart failure may occur. Abnormalities of cardiac rhythm (such as premature beats, paroxysmal atrial fibrillation, paroxysmal supraventricular tachycardia, sick sinus syndrome, ventricular tachycardia, and bundle branch blocks) and of cardiac valves (the most frequent being mitral and aortic abnormalities associated with LV hypertrophy) can also occur [15–17]. The yearly incidence of acromegaly is estimated to be between 3 and 4 cases per 1 million people per year. The average age at diagnosis is 40 to 45 years [18, 19], and our 49-year-old patient was nearly in that age range.\n\nCurrent treatments aim to normalize GH and IGF-1 secretion levels in patients with acromegaly for the sake of reversing some of the morphological changes in the early stage, regression of cardiac hypertrophy and improvement of cardiac dysfunction [4, 18–20]. Different strategies for management can be divided into two components, namely to control GH and IGF-1 hypersecretion and cardiac heart failure. The normalization of GH and IGF-1 levels, whether by surgical or pharmacological therapy, is essential to reversing or arresting cardiovascular complications [5]. An earlier case report described a 43-year-old man with severe congestive heart failure produced by acromegalic cardiomyopathy who recovered significantly through octreotide followed by transsphenoidal surgery [21]. Some reports suggest that the beneficial effects obtained from hormone suppression therapy appear more significant in younger patients with short disease duration than in older patients [22]. Other reports describe how the classic treatments of acromegaly, including surgical resection of the pituitary adenoma, somatostatin analogs and GH antagonists, and stereotactic radiosurgery or fractionated radiation, might improve cardiac function in the short term but probably have very little effect on long-term prognosis [23, 24]. Successful later case reports support the idea of the use of traditional heart failure therapy, which consists of ACEIs, angiotensin receptor blockers, β-blockers, aldosterone antagonists, and diuretics, to further improve cardiovascular function because GH/IGF-1 control alone is insufficient [25, 26]. Heart transplant is an option for end-stage heart failure [24, 27]. Considering our patient’s minimal response to these acknowledged treatments mentioned above, we carefully selected CRT in this patient, and his cardiac function recovered considerably with our elaborate care. At his follow-up visits, the patient has been in good condition, with various gradually improved cardiac function indexes.\n\nCRT is an effective and well-established therapy for patients with heart failure, LV systolic dysfunction (LVEF ≤35%), and electrical dyssynchrony, demonstrated by a surface QRS duration of ≥ 130 ms [7]. It appears that CRT offers a more favorable response with regard to reverse LV remodeling in cases of nonischemic cardiomyopathy [28, 29]. The use of mechanical therapies including CRT/CRT-D implantation have not been adequately studied in acromegalic heart failure, and the long-term prognosis of CHF in patients with acromegaly remains poor. This group of patients might benefit from device therapies that restore ventricular systolic synchrony and ameliorate ventricular reverse remodeling.\n\nAbbreviations\nACEIAngiotensin-converting enzyme inhibitor\n\nBNPBrain natriuretic peptide\n\nCHFCongestive heart failure\n\nCRTCardiac resynchronization therapy\n\nCRT-DCardiac resynchronization therapy with defibrillator\n\nCTRCardiothoracic ratio\n\nGHGrowth hormone\n\nHCMHypertrophic cardiomyopathy\n\nIGF-1Insulin-like growth factor 1\n\nLBBBLeft bundle branch block\n\nLVLeft ventricular\n\nLVEFLeft ventricular ejection fraction\n\nMRMitral regurgitation\n\nNYHANew York Heart Association\n\nSAMSystolic anterior motion\n\nAcknowledgements\nSpecial thanks to the department of endocrinology, which assisted in the treatment of this patient.\n\nFunding\nNo funding was received for this study.\n\nAvailability of data and materials\nThe authors agree to make the raw data and materials described in our manuscript freely available.\n\nAuthors’ contributions\nJW was the major contributor in writing the manuscript. JW, YH, JL, and XL followed the patient clinically. YH and JL supervised the whole work. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Holdaway IM Rajasoorya C Epidemiology of acromegaly Pituitary 1999 2 29 41 10.1023/A:1009965803750 11081170 \n2. Vitale G Pivonello R Galderisi M Cardiovascular complications in acromegaly: methods of assessment Pituitary 2001 4 251 257 10.1023/A:1020750514954 12501975 \n3. Saccà L Napoli R Cittadini A Growth hormone, acromegaly, and heart failure: an intricate triangulation Clin Endocrinol 2003 59 6 660 671 10.1046/j.1365-2265.2003.01780.x \n4. Matta MP Caron P Acromegalic cardiomyopathy: a review of the literature Pituitary. 2003 6 4) 203 207 10.1023/B:PITU.0000023427.31609.a2 15237931 \n5. Mosca S Paolillo S Colao A Bossone E Cittadini A Iudice FL Parente A Conte S Rengo G Leosco D Trimarco B Filardi PP Cardiovascular involvement in patients affected by acromegaly: an appraisal Int J Cardiol 2013 167 1712 1718 10.1016/j.ijcard.2012.11.109 23219077 \n6. Vitale G Pivonello R Lombardi G Colao A Cardiac abnormalities in acromegaly: pathophysiology and implications for management Treat Endocrinol 2004 3 309 318 10.2165/00024677-200403050-00004 15330678 \n7. Ponikowski P Voors AA Anker SD 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European society of cardiology (ESC). Developed with the special contribution of the Heart failure association (HFA) of the ESC Eur Heart J 2016 37 2129 2200 10.1093/eurheartj/ehw128 27206819 \n8. Nazari N Keykhavani A Sayah S Hekmat M Golabchi A Rad MA Alizadeh A Heidarali M Role of electrophysiological study in patients with syncope and bundle branch block J Res Med Sci 2014 19 10 961 964 25538780 \n9. Brignole M Auricchio A Baron-Esquivias G 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European society of cardiology (ESC). Developed in collaboration with the European heart rhythm association (EHRA) Eur Heart J 2013 34 2281 2329 10.1093/eurheartj/eht150 23801822 \n10. Butt RP Laurent GJ Bishop JE Collagen deposition and replication by cardiac fibroblasts is enhanced in response to diverse classes of growth factors Eur J Cell Biol 1995 68 330 335 8603686 \n11. Brüel A Oxlund H Biosynthetic growth hormone increase the collagen deposition rate in rat aorta and heart Eur J Endocrinol 1995 132 195 199 10.1530/eje.0.1320195 7858738 \n12. Juul A Scheike T Davidsen M Gyllenborg J Jorgensen T Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study Circulation 2002 106 939 944 10.1161/01.CIR.0000027563.44593.CC 12186797 \n13. Johnsen SP Hundborg HH Sørensen HT Orskov H Tjønneland A Overvad K Jørgensen JO Insulin-like growth factor (IGF) I, -II, and IGF binding protein-3 and risk of ischemic stroke J Clin Endocrinol Metab 2005 90 5937 5941 10.1210/jc.2004-2088 16131586 \n14. Vasan RS Sullivan LM D’Agostino RB Roubenoff R Harris T Sawyer DB Levy D Wilson PW Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study Ann Intern Med 2004 139 642 648 10.7326/0003-4819-139-8-200310210-00007 \n15. Kahaly G Olshausen KV Mohr-Kahaly S Erbel R Boor S Beyer J Meyer J Arrhythmia profile in acromegaly Eur Heart J 1992 13 51 56 10.1093/oxfordjournals.eurheartj.a060047 1577031 \n16. Colao A Spinelli L Marzullo P Pivonello R Petretta M Di Somma C Vitale G Bonaduce D Lombardi G High prevalence of cardiac valve disease in acromegaly: an observational analytical prospective case-control study J Clin Endocrinol Metab 2003 88 3196 3201 10.1210/jc.2002-021099 12843165 \n17. Pereira AM van Thiel SW Lindner JR Roelfsema F van der Wall EE Morreau H Smit JW Romijn JA Bax JJ Increased prevalence of regurgitant valvular heart disease in acromegaly J Clin Endocrinol Metab 2004 89 71 75 10.1210/jc.2003-030849 14715829 \n18. Sharma AN Tan M Amsterdam EA Singh GD Acromegalic cardiomyopathy: epidemiology, diagnosis, and management Clin Cardiol 2018 41 3 419 425 10.1002/clc.22867 29574794 \n19. Melmed S Medical progress: acromegaly N Engl J Med 2006 355 2558 2573 10.1056/NEJMra062453 17167139 \n20. Dal J Feldt-Rasmussen U Andersen M Acromegaly incidence, prevalence, complications and long-term prognosis: a nationwide cohort study Eur J Endocrinol 2016 175 181 190 10.1530/EJE-16-0117 27280374 \n21. Shimakura A Miyakoshi H Ohkuwa H Kitabayashi M Komai T Hisada A Aoki K Sakagami S Kobayashi K Takata S Improvement of cardiac function after treatment with octreotide followed by trans-sphenoidal surgery in an acromegalic patient who presented with congestive heart failure Jpn Heart J 2002 43 1 69 77 10.1536/jhj.43.69 12041892 \n22. Colao A Vitale G Pivonello R Ciccarelli A Di Somma C Lombardi G The heart: an end-organ of GH action Eur J Endocrinol 2004 151 Suppl 1 S93 101 10.1530/eje.0.151s093 15339252 \n23. Bihan H Espinosa C Valdes-Socin H Long-term outcome of patients with acromegaly and congestive heart failure J Clin Endocrinol Metab 2004 89 5308 5313 10.1210/jc.2004-0821 15531475 \n24. MacCarthy P Kearney M Nolan J Prognosis in heart failure with preserved left ventricular systolic function: prospective cohort study BMJ 2003 327 78 79 10.1136/bmj.327.7406.78 12855525 \n25. Thomas J Dattani A Zemrak F Renin-angiotensin system blockade improves cardiac indices in acromegaly patients Exp Clin Endocrinol Diabetes 2017 125 365 367 10.1055/s-0042-123710 28166592 \n26. Schwarz ER Jammula P Gupta R A case and review of acromegaly-induced cardiomyopathy and the relationship between growth hormone and heart failure: cause or cure or neither or both? J Cardiovasc Pharmacol Ther 2006 11 232 244 10.1177/1074248406296676 17220469 \n27. Albat B Leclercq F Serre I Fille A Baldet P Grolleau-Raoux R Thevenet A Heart transplantation for terminal congestive heart failure in an acromegalic patient Eur Heart J 1993 14 11 1572 1575 10.1093/eurheartj/14.11.1572 8299642 \n28. Barra S Looi KL Gajendragadkar PR Applicability of a risk score for prediction of the long-term benefit of the implantable cardioverter defibrillator in patients receiving cardiac resynchronization therapy Europace. 2016 18 1187 1193 10.1093/europace/euv352 26566940 \n29. Ogano M Iwasaki YK Tanabe J Takagi H Umemoto T Hayashi M Miyauchi Y Shimizu W Cardiac resynchronization therapy restored ventricular septal myocardial perfusion and enhanced ventricular remodeling in patients with nonischemic cardiomyopathy presenting with left bundle branch block Heart Rhythm 2014 11 5 836 841 10.1016/j.hrthm.2014.02.014 24561161\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "13(1)",
"journal": "Journal of medical case reports",
"keywords": "Acromegalic cardiomyopathy; Cardiac resynchronization therapy; Heart failure",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000172:Acromegaly; D058406:Cardiac Resynchronization Therapy; D009202:Cardiomyopathies; D004452:Echocardiography; D006333:Heart Failure; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "106",
"pmc": null,
"pmid": "31018862",
"pubdate": "2019-04-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11081170;12041892;12186797;12501975;12843165;12855525;14568852;14715829;14974906;15237931;15330678;15339252;15531475;1577031;16131586;17167139;17220469;23219077;23801822;24561161;25538780;26566940;27206819;27280374;28166592;29574794;7858738;8299642;8603686",
"title": "Cardiac resynchronization therapy improves heart failure in one patient with acromegaly-induced cardiomyopathy: a case report.",
"title_normalized": "cardiac resynchronization therapy improves heart failure in one patient with acromegaly induced cardiomyopathy a case report"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-245795",
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"activesubstancename": "OCTREOTIDE"
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"abstract": "Eltrombopag, an oral thrombopoietin-receptor agonist, stimulates hematopoiesis in patients with acquired aplastic anemia (AA) and has higher exposure in patients of East Asian origin. We evaluated the pharmacokinetics, efficacy, and safety of eltrombopag in Japanese patients with AA refractory or intolerant to immunosuppressive therapy (IST). Twenty-one patients (15 with non-severe AA, six with severe AA) with platelet counts < 30,000/µL received eltrombopag in a dose-escalation fashion (25, 50, 75, or 100 mg once daily) depending on individual platelet responses; the responders continued eltrombopag treatment beyond 6 months. The primary endpoint was hematologic response at 6 months, defined as improvements in blood counts or transfusion requirements. Ten (48%) patients achieved hematologic responses in at least one lineage at 6 months. Six patients achieved tri- and/or bi-lineage responses with continuation of eltrombopag treatment, with two patients no longer requiring eltrombopag treatment. The most common adverse events were nasopharyngitis and abnormal hepatic function, with the majority being grade 1 or 2. Cytogenetic abnormalities were observed in three patients; however, no progression to myelodysplastic syndrome/other malignancy was observed. Eltrombopag can safely restore multi-lineage hematopoiesis in Japanese patients with AA refractory or intolerant to IST.Clinical Trial registration NCT02148133.",
"affiliations": "Division of Transfusion Medicine, Kanazawa University Hospital, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan. h-yama@staff.kanazawa-u.ac.jp.;Hematology Ohta Clinic, Osaka, Japan.;National Hospital Organization Nagoya Medical Center, Nagoya, Aichi, Japan.;Japanese Red Cross Osaka Hospital, Osaka, Japan.;University of Tsukuba, Tsukuba, Ibaraki, Japan.;Itami City Hospital, Itami, Hyogo, Japan.;Osaka University Hospital, Osaka, Japan.;NTT Medical Center Tokyo, Tokyo, Japan.;Okayama City Hospital, Okayama, Japan.;Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Aichi, Japan.;Miyagi Cancer Center, Natori, Miyagi, Japan.;Novartis Pharma K.K, Tokyo, Japan.;Novartis Pharma K.K, Tokyo, Japan.;Novartis Pharma K.K, Tokyo, Japan.;International Medical Center, Saitama Medical University, Saitama, Japan.;Kanazawa University Institute of Medical Pharmaceutical and Health Sciences, Kanazawa, Ishikawa, Japan.",
"authors": "Yamazaki|Hirohito|H|http://orcid.org/0000-0003-3018-2098;Ohta|Kensuke|K|;Iida|Hiroatsu|H|;Imada|Kazunori|K|;Obara|Naoshi|N|;Tokumine|Yukihiro|Y|;Tomiyama|Yoshiaki|Y|;Usuki|Kensuke|K|;Imajo|Kenji|K|;Miyamura|Koichi|K|;Sasaki|Osamu|O|;Fanghong|Zhang|Z|;Hattori|Toshihiro|T|;Tajima|Takeshi|T|;Matsuda|Akira|A|;Nakao|Shinji|S|",
"chemical_list": "D001565:Benzoates; D006834:Hydrazines; D007166:Immunosuppressive Agents; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C520809:eltrombopag",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-019-02683-1",
"fulltext": null,
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"issn_linking": "0925-5710",
"issue": "110(2)",
"journal": "International journal of hematology",
"keywords": "Aplastic anemia; Eltrombopag; Inter-ethnic difference; Japanese patients",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic; D001565:Benzoates; D001803:Blood Transfusion; D019070:Cell Lineage; D056486:Chemical and Drug Induced Liver Injury; D003131:Combined Modality Therapy; D004351:Drug Resistance; D057915:Drug Substitution; D005260:Female; D006410:Hematopoiesis; D006801:Humans; D006834:Hydrazines; D007166:Immunosuppressive Agents; D007564:Japan; D008297:Male; D008875:Middle Aged; D010612:Pharyngitis; D010976:Platelet Count; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "187-196",
"pmc": null,
"pmid": "31183813",
"pubdate": "2019-08",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": "17229630;17463169;19343478;20202683;20663993;20688957;22138514;22683680;22762314;22797698;23690288;24052548;24345753;25578417;26686043;26968551;27695288;28096088;28162984;30305280",
"title": "Hematologic recovery induced by eltrombopag in Japanese patients with aplastic anemia refractory or intolerant to immunosuppressive therapy.",
"title_normalized": "hematologic recovery induced by eltrombopag in japanese patients with aplastic anemia refractory or intolerant to immunosuppressive therapy"
} | [
{
"companynumb": "NVSJ2019JP004240",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
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{
"abstract": "Metformin (MET), the most commonly used insulin sensitizer, is the reference off-label drug for the treatment of polycystic ovary syndrome (PCOS), worldwide. However, its use may be limited mainly by gastrointestinal adverse effects. Myo-inositol (MI), a well-recognized food supplement, also represents an evidence-based treatment for PCOS women, popular in many countries. Our aim is to provide a systematic review of the literature and a meta-analysis which compares these two treatments, for their short-term efficacy and safety in PCOS patients. Systematic review and meta-analysis of randomized clinical trials (RCTs). RCTs were identified from 1994 through 2017 using MEDLINE, Cochrane Library, PubMed, and ResearchGate. Included studies were limited to those one directly comparing MET to MI on several hormones changes. Standardized mean difference (SMD) or risk ratios (RRs) with 95% CIs were calculated. Changes in fasting insulin was the main outcome of measure. Six trials with a total of 355 patients were included. At the end of treatment, no difference between MET and MI was found on fasting insulin (SMD=0.08 µU/ml, 95% CI: -0.31-0.46, p=.697), HOMA index (SMD =0.17, 95% CI: -0.53-0.88, p=.635), testosterone (SMD= -0.01, 95% CI: -0.24-0.21, p=.922), SHBG levels (SMD= -0.50 nmol/l, 95% CI: -1.39-0.38, p=.263) and body mass index (BMI) (SMD= -0.22, 95% CI: -0.60-0.16, p=.265). There was strong evidence of an increased risk of adverse events among women receiving MET compared to those receiving MI (RR =5.17, 95% CI: 2.91-9.17, p<.001). No differences were found in the effect of MET and MI on short-term hormone changes. The better tolerability of MI makes it more acceptable for the recovery of androgenic and metabolic profile in PCOS women.",
"affiliations": "a Department of Medical and Surgical Sciences for Mother, Child and Adult , Azienda Ospedaliero Universitaria Policlinico, University of Modena and Reggio Emilia , Modena , Italy.;b Department of Medical Affairs , Lo.Li. Pharma , Rome , Italy.;a Department of Medical and Surgical Sciences for Mother, Child and Adult , Azienda Ospedaliero Universitaria Policlinico, University of Modena and Reggio Emilia , Modena , Italy.;c Department of Developmental and Social Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome , Rome , Italy.",
"authors": "Facchinetti|Fabio|F|;Orrù|Beatrice|B|;Grandi|Giovanni|G|;Unfer|Vittorio|V|",
"chemical_list": "D007004:Hypoglycemic Agents; D007294:Inositol; D008687:Metformin",
"country": "England",
"delete": false,
"doi": "10.1080/09513590.2018.1540578",
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"issn_linking": "0951-3590",
"issue": "35(3)",
"journal": "Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology",
"keywords": "BMI; HOMA index; PCOS; SHBG; androstenedione; fasting insulin; metformin; myo-inositol; side effects; testosterone",
"medline_ta": "Gynecol Endocrinol",
"mesh_terms": "D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D007294:Inositol; D008687:Metformin; D056687:Off-Label Use; D011085:Polycystic Ovary Syndrome; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome",
"nlm_unique_id": "8807913",
"other_id": null,
"pages": "198-206",
"pmc": null,
"pmid": "30614282",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis",
"references": null,
"title": "Short-term effects of metformin and myo-inositol in women with polycystic ovarian syndrome (PCOS): a meta-analysis of randomized clinical trials.",
"title_normalized": "short term effects of metformin and myo inositol in women with polycystic ovarian syndrome pcos a meta analysis of randomized clinical trials"
} | [
{
"companynumb": "IN-ALKEM LABORATORIES LIMITED-IN-ALKEM-2019-01216",
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"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "Propofol is a potent intravenous anesthetic agent that rapidly induces sedation and unconsciousness. The potential for propofol dependency, recreational use, and abuse has only recently been recognized, and several cases of accidental overdose and suicide have emerged. In addition, the first documented case of murder using propofol was reported a few months ago, and a high profile case of suspected homicide with propofol is currently under investigation. A number of analytical methods have been employed to detect and quantify propofol concentrations in biological specimens. The reported propofol-related deaths and postmortem blood and tissue levels are reviewed. Importantly, limitations of propofol detection are discussed, and future considerations are presented. Because propofol has the potential for diversion with lethal consequences, the forensic scientist must have a basic understanding of its clinical indications and uses, pharmacologic properties, and detection methods. In addition, medical institutions should develop systems to prevent and detect diversion of this potential drug of abuse.",
"affiliations": "Children's National Medical Center, The George Washington University School of Medicine and Health Sciences, Washington, DC 20010. rlevy@cnmc.org",
"authors": "Levy|Richard J|RJ|",
"chemical_list": "D006993:Hypnotics and Sedatives; D015742:Propofol",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1556-4029.2010.01583.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "56 Suppl 1()",
"journal": "Journal of forensic sciences",
"keywords": null,
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000059:Accidents; D000138:Acidosis; D058186:Acute Kidney Injury; D016470:Bacteremia; D001919:Bradycardia; D062787:Drug Overdose; D050171:Dyslipidemias; D053593:Forensic Toxicology; D006282:Health Personnel; D006323:Heart Arrest; D006333:Heart Failure; D006708:Homicide; D006801:Humans; D015228:Hypertriglyceridemia; D006993:Hypnotics and Sedatives; D007022:Hypotension; D015394:Molecular Structure; D010195:Pancreatitis; D015742:Propofol; D012206:Rhabdomyolysis; D018805:Sepsis; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders; D013405:Suicide; D013577:Syndrome",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "S142-7",
"pmc": null,
"pmid": "20950316",
"pubdate": "2011-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D016454:Review",
"references": "18498766;16765143;11924712;11679029;17868199;11900605;9357897;17898389;19299783;11255925;8694357;8368554;16910299;1416179;10617313;17329386;7791816;1393073;19412155;12723460;1506835;15579060;11355404;9489054;15380727;17898362;17485254;16431058;7927085;18664783;10825340;7581912;10892581;15237574;8738032;16781104;16831883;19336539;3275816",
"title": "Clinical effects and lethal and forensic aspects of propofol.",
"title_normalized": "clinical effects and lethal and forensic aspects of propofol"
} | [
{
"companynumb": "SG-PFIZER INC-2013134735",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "POTASSIUM CHLORIDE"
},
"drugadditional": null... |
{
"abstract": "Pediatric patients with end-stage respiratory failure and pulmonary hypertension traditionally have poor outcomes when bridged with extracorporeal membrane oxygenation to lung or heart-lung transplantation. Therefore, several institutions have attempted paracorporeal lung assist devices as a bridge. However, given the small number of patients, little is known about approaches to anesthetic induction in these hemodynamically unstable patients either before placement of a device or anesthetic induction once a device is in situ. In this case report, we describe our anesthetic experience managing a 13-year-old boy for both paracorporeal lung assist device placement and subsequent heart-lung transplantation.",
"affiliations": "From the Departments of *Anesthesia, Perioperative and Pain Medicine, †Pediatrics, and ‡Surgery, Stanford University School of Medicine, Stanford, California.",
"authors": "Char|Danton S|DS|;Yarlagadda|Vamsi|V|;Maeda|Katsuhide|K|;Williams|Glyn|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000300",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-7237",
"issue": "6(10)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": "D000293:Adolescent; D000771:Anesthesia, Intravenous; D015199:Extracorporeal Membrane Oxygenation; D016041:Heart-Lung Transplantation; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D012131:Respiratory Insufficiency",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "308-10",
"pmc": null,
"pmid": "27002753",
"pubdate": "2016-05-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anesthesia for Placement of a Paracorporeal Lung Assist Device and Subsequent Heart-Lung Transplantation in a Child with Suprasystemic Pulmonary Hypertension and End-Stage Respiratory Failure.",
"title_normalized": "anesthesia for placement of a paracorporeal lung assist device and subsequent heart lung transplantation in a child with suprasystemic pulmonary hypertension and end stage respiratory failure"
} | [
{
"companynumb": "US-ACTELION-A-CH2016-137250",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BOSENTAN"
},
"drugadditional": null,
... |
{
"abstract": "With skin lesions that have failed previous treatments, consideration for an atypical mycobacteria, specifically Mycobacterium marinum, infection should be suspected. Importance of the history cannot be stressed as this is a clue that the patient may have been inoculated and infected in the field environment. A marine with chronic right knee plaque for 3 yr that first appeared after a field exercise at The Basic School but worsened despite treatment with clindamycin, TMP-SMX, and incision and drainage in 2012. Examination revealed a 4 × 4 cm pink, pearly, scaly plaque with scabbing. Deroofing caused puncta to bleed and suppurate. Empiric therapy with doxycycline topical fluocinonide were initiated. Histopathological findings showed dermal fibrosis, granulomatous inflammation, and overlying epidermal inflammation and hyperplasia. Sections also revealed scattered admixed non-necrotizing granulomata. Initial stains, tissue and wound cultures were negative. Acid-fast bacilli broth and smear culture with growth after 4 wk, growing M. marinum. Doxycycline was continued for 2 more months. Mycobacterium marinum is a nontuberculous mycobacterium responsible for skin infections. Sources of infections usually are non-chlorinated water. Infections are rare, an estimated annual incidence of 0.27 cases per 100,000 patients, within the USA and do not cause significant morbidity in immunocompetent patients. Initial M. marinum infections can be mistaken as methicillin resistant Staph aureus infections in the active duty population. If the infection recurs or does not resolve with methicillin resistant Staph aureus-targeted antibiotics, consider cultures specific to acid-fast bacilli and keep in the differential until long term culture results are obtained.",
"affiliations": "Marine Medium Tiltrotor Squadron 364 Flight Surgeon, Marine Air Group 39, 3D Marine Air Wing, VMM-364, Camp Pendleton, CA.;Department of Dermatology, Naval Hospital Camp Pendleton, 200 Mercy Ct, Camp Pendleton, CA.",
"authors": "Prak|Amarateedha H|AH|;Dela Rosa|Kristina M|KM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002981:Clindamycin; D004318:Doxycycline",
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"title": "Marine Develops Chronic Right Knee Granuloma After Initial Injury at The Basic School.",
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"abstract": "Corynebacteria are a bacteria usually associated as a contaminant due to their presence in normal human skin and mucosal membranes. However, they are increasingly becoming recognized as an opportunistic pathogen. Corynebacteria can be pathogens in immunocompromised patients or those with malignancies or prosthetic devices. We present a rare case of bacteremia due to multidrug resistant Corynebacterium striatum in a 52-year-old male with cirrhosis. The patient had lower extremity cellulitis which likely served as a port of entry.",
"affiliations": "Department of Medicine, Maimonides Medical Center, Brooklyn, NY, USA.;Department of Medicine, Maimonides Medical Center, Brooklyn, NY, USA.;Department of Medicine, Maimonides Medical Center, Brooklyn, NY, USA.;Infectious Disease, Department of Medicine, Maimonides Medical Center, Brooklyn, NY, USA.",
"authors": "Elkayam|Natalie|N|;Urazov|Anna|A|;Tuneev|Karen|K|;Chapnick|Edward|E|",
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"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(19)30051-410.1016/j.idcr.2019.e00575e00575ArticleCorynebacterium striatum bacteremia associated with cellulitis in a patient with cirrhosis Elkayam Natalie nelkayam@maimonidesmed.orga⁎Urazov Anna aTuneev Karen aChapnick Edward ba Department of Medicine, Maimonides Medical Center, Brooklyn, NY, USAb Infectious Disease, Department of Medicine, Maimonides Medical Center, Brooklyn, NY, USA⁎ Corresponding author. nelkayam@maimonidesmed.org13 6 2019 2019 13 6 2019 17 e0057514 3 2019 12 6 2019 12 6 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Corynebacteria are a bacteria usually associated as a contaminant due to their presence in normal human skin and mucosal membranes. However, they are increasingly becoming recognized as an opportunistic pathogen. Corynebacteria can be pathogens in immunocompromised patients or those with malignancies or prosthetic devices. We present a rare case of bacteremia due to multidrug resistant Corynebacterium striatum in a 52-year-old male with cirrhosis. The patient had lower extremity cellulitis which likely served as a port of entry.\n==== Body\nIntroduction\nCorynebacterium is a gram positive, aerobic rod. It is a bacterium which is usually thought to be a contaminant when cultured from blood because it is a normal inhabitant of skin and mucous membranes [1]. There have been numerous reports of Corynebacterium emerging as an opportunistic pathogen in patients who are immunocompromised, have a malignancy or are critically ill [1]. There are few case reports of nosocomial infections of Corynebacterium striatum associated with wound infections [2], as well as its recent emergence as a multidrug resistant nosocomial pathogen [3]. It was only until recently that Corynebacterium striatum was recognized as a pathogen and not merely a contaminant in both immunocompromised or immunocompetent hosts. We present a case of an immunocompetent patient with a bloodstream infection with Corynebacterium striatum associated with cellulitis.\n\nCase report\nA 52-year-old man presented to the Emergency Department due to altered mental status and lethargy. The patient had a past medical history of prior intravenous (IV) heroin abuse and was enrolled in a methadone program, chronic hepatitis C with concomitant liver cirrhosis and pancytopenia (Model for End-Stage Liver Disease score 18), hypothyroidism, peripheral vascular disease with chronic venous stasis in the lower extremities and essential hypertension. On presentation, his temperature was 103.3 °F, pulse rate 106 beats/minute and respiratory rate 22 breaths/minute. The patient was lethargic and minimally responsive to verbal stimuli, and responsive to painful stimuli. There was a holosystolic murmur at the cardiac apex not previously described. There was bilateral lower extremity chronic venous stasis with superimposed erythema bilaterally which was warm to touch. On the right anterior shin, there were two ecchymotic cutaneous wounds with serous exudates. On the left anterior shin, there were 3 ulcers of red granulating tissue without exudate.\n\nLaboratory evaluation showed a hemoglobin of 9.2 g/dL, a platelet count of 26,000/μL with a leukocyte count of 5,700/μL. Liver function tests were within normal limits. The ammonia level was 105 μmol/L and lactic acid was 2.7 mmol/L. Urine toxicology was positive for methadone, and the blood alcohol level was negative. The chest radiograph was unremarkable for any acute pathology. Computed tomography (CT) scan of the brain was unremarkable. CT of the abdomen and pelvis without IV contrast was consistent with hepatic cirrhosis and portal hypertension.\n\nThe patient was admitted for sepsis secondary to lower extremity cellulitis and for suspected hepatic encephalopathy. He was treated with ceftriaxone 1 g once as well as lactulose 20 g every 6 h and rifaximin 550 mg every 12 h in the emergency room. After admission, vancomycin 1500 mg every 8 h and clindamycin IV 600 mg every 8 h were given. On hospital day two, a single set of admission blood cultures grew gram positive rods at 10 h in two bottles. Due to concern for bacteremia with listeriosis, the patient’s antimicrobial coverage was changed to vancomycin 1500 mg every 8 h along with ampicillin 2000 mg every 4 h and clindamycin was discontinued. The organism was identified as Corynebacterium striatum. Repeat blood cultures yielded the same pathogen at 28 h in yet another two bottles. Blood cultures were sent to a laboratory for speciation and susceptibility testing for the blood culture isolate. The patient’s ammonia levels normalized, however, the patient continued to appear lethargic. A transthoracic echocardiogram and eventually a transesophageal echocardiogram were unremarkable for any valvular vegetations. Blood cultures were sent to a laboratory for speciation and susceptibility testing for the blood culture isolate however this data was not available during the patient’s hospital stay. Treatment was switched to daptomycin 500 mg daily on the fifth day of his admission as he was not clinically improving. Within two days of this change, the patient’s clinical status improved significantly with return to his baseline mental status. The patient completed a total of 18 days of antimicrobial therapy.\n\nDiscussion\nCorynebacterium striatum is a nondiphtherial Corynebacterium, which is gram positive, catalase positive, nonspore- forming, nonmotile, and rod-shaped [4]. It is generally considered to be a skin and mucosal colonizer. In rare cases, this microorganism has been found to be a pathogen. Case reports have shown Corynebacterium striatum to be associated with increased pathogenicity [4].\n\nOur patient presented with C. striatum bacteremia. The persistent bacteremia suggested that the organism is a pathogen in this case. The role of this bacterium in clinical disease is now more clearly established. Corynebacterium striatum is recognized as a true pathogen when isolated in several samples from sterile body sites or from indwelling medical devices [4,5]. It has been associated with bacteremia, endocarditis with valvular damage, meningitis, urinary tract infections, respiratory tract infections and skin wounds [6,7].\n\nWhile data has shown that there are high rates of resistance to many antimicrobial agents, vancomycin, linezolid, and daptomycin have been found to be effective in treating C. striatum [3]. There have been high rates of resistance found to penicillin, clindamycin, cefotaxime, erythromycin, and ciprofloxacin [3]. Since our patient failed to improve on vancomycin and susceptibility testing was unavailable, the antimicrobial therapy was changed to daptomycin. The patient was successfully treated with daptomycin, with subsequent blood cultures being negative. The cause of the patient’s altered mental status on presentation appeared to be multifactorial. The patient did not improve significantly with lactulose and rifaximin with normalization of serum ammonia. Clinical improvement occurred only with the initiation of appropriate antimicrobial therapy.\n\nPathogenicity of Corynebacterium has been significantly associated with immune compromise or indwelling catheters [8]. We wished to discuss the association of this organism in a patient with Cirrhosis. The role cirrhosis in bacteremia with a multi- drug resistant organism has been studied and reported. Cirrhotic patients have a 10-fold increase in susceptibility to blood stream infections as compared to the general population as well as a significantly higher rate of mortality [9]. Furthermore, bacteremia caused by a multi drug resistant organism accounts for nearly one-third of blood stream infections (BSI) in cirrhotic patients [9]. Risk factors for BSI were further stratified based on the stages of liver disease. Patients with cirrhosis have a greater risk of developing Gram-positive BSI as compared to patients with chronic hepatitis [10]. Our case shows the importance of understanding Corynebacterium as an emergent pathogenic microbe, risk factors for infection should be considered and appropriate treatment initiated promptly. It is important to understand when an isolate represents an infection, a colonization or a contamination. This can only be done with clinical assessment. Clinicians should also consider the possibility of multidrug resistant strains of Corynebacterium.\n\nAuthor statement\nN.E., A.U. and K.T. all wrote the presented article. E.C. reviewed and edited the article and supervised the findings of this work. All authors discussed the results and contributed to the final manuscript. All authors provided critical feedback and helped shape the analysis and manuscript\n==== Refs\nReferences\n1 Chen F. Hsueh P. Teng S. Ou Y. Lee W. Corynebacterium striatum bacteremia associated with central venous catheter infection J Microbiol Immunol Infect 45 3 2012 255 258 22154992 \n2 Biswal I. Mohapatra S. Deb M. Dazwar R. Gaind R. Corynebacterium striatum: An emerging nosocomial pathogen in a case of laryngeal carcinoma Indian J Med Microbiol 32 2014 323 324 25008830 \n3 Alibi S. Ferjani A. Boukadida J. Cano M. Fernandez-Martinez M. Martinez-Martinez L. Occurrence of Corynebacterium striatum as an emerging antibiotic-resistant nosocomial pathogen in a Tunisian hospital Sci Rep 7 1 2017 9704 28848236 \n4 McMullen A. Anderson N. Wallace M. Shupe A. Burnham C. When good bugs go bad: Eepidemiology and antimicrobial resistance profiles of Corynebacterium striatum, an emerging multidrug-resistant, opportunistic pathogen Antimicrob Agents Chemother 61 11 2017 \n5 Boltin D. Katzir M. Bugoslacsky V. Yalashvili I. Brosh-Nissimov T. Fried M. Elkayam O. Corynebacterium striatum-A classic pathogen eluding diagnosis Eur J Intern Med 20 2009 49 52 \n6 Martínez-Martínez L. Suárez A.I. Rodríguez-Baño J. Bernard K. Muniáin M.A. Clinical significance of Corynebacterium striatum isolated from human samples Clin Microbiol Infect 3 1997 634 639 11864205 \n7 Ishiwada N. Watanabe M. Murata S. Takeuchi N. Taniguchi T. Igari H. Clinical and bacteriological analyses of bacteremia due to Corynebacterium striatum J Infect Chemother 22 2016 790 793 27654073 \n8 Van der Auwera P. Ex vivo study of serum bactericidal titers and killing rates of daptomycin (LY146032) combined or not combined with amikacin compared with those of vancomycin Antimicrob Agents Chemother 33 1989 1783 1790 2556079 \n9 Bartoletti M. Giannella M. Lewis R. Caraceni P. Tedeschi S. Paul M. A prospective multicentre study of the epidemiology and outcomes of bloodstream infection in cirrhotic patients, European Society of Clinical Microbiology and Infectious Diseases Soc Clin Microbiol Infect Dis 24 546 2018 e.1–546 e.2 \n10 Brandolini M. Corbella M. De Silvestri A. Tinelli C. Albonico G. Albertini R. Epidemiological characteristics of bloodstream infections in patients with different degrees of liver disease Infection 43 2015 561 25976737\n\n",
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"title": "Corynebacterium striatum bacteremia associated with cellulitis in a patient with cirrhosis.",
"title_normalized": "corynebacterium striatum bacteremia associated with cellulitis in a patient with cirrhosis"
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"abstract": "Acute generalized exanthematous pustulosis (AGEP) is a dramatic generalized pustular rash of severe onset, which is considered a serious cutaneous adverse reaction to drugs. However, even though the clinical features are impressive and are often accompanied by systemic inflammation, it can be controlled quickly and safely by topical steroids subsequent to interruption of the offending drug. Here, we describe the management of a case and the evolution of the pustular rash. An elderly woman consulted with a generalized crop of 2-3 mm, nonfollicular pustules on erythematous background. In the 4 preceding weeks, she had been using amoxicillin/clavulanic acid for a bacterial implant infection and rivaroxaban. The clinical EuroSCAR criteria including the histology confirmed AGEP. Her medication was stopped and topical clobetasol propionate was used. Within 24 h, the development of new pustules ceased and the patient was discharged after 7 days of hospitalization with only a faint, diffuse erythema and focal desquamation remaining. This and many other cases in the literature suggest that topical steroids should be considered as a first-line treatment option, especially as systemic steroids themselves can sometimes induce generalized pustulosis.",
"affiliations": "Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.;Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.;Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.;Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.;Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.;Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.",
"authors": "Kley|Christiane|C|;Murer|Carla|C|;Maul|Julia-Tatjana|JT|;Meier|Barbara|B|;Anzengruber|Florian|F|;Navarini|Alexander A|AA|",
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"fulltext": "\n==== Front\nCase Rep DermatolCase Rep DermatolCDECase Reports in Dermatology1662-6567S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000471842cde-0009-0135Single CaseRapid Involution of Pustules during Topical Steroid Treatment of Acute Generalized Exanthematous Pustulosis Kley Christiane Murer Carla Maul Julia-Tatjana Meier Barbara Anzengruber Florian Navarini Alexander A. *Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland*Prof. Dr. Dr. Alexander A. Navarini, Department of Dermatology, University Hospital of Zurich, CH–8091 Zurich (Switzerland), E-Mail alexander.navarini@usz.chJan-Apr 2017 27 4 2017 27 4 2017 9 1 135 139 24 10 2016 21 3 2017 Copyright © 2017 by S. Karger AG, Basel2017This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Acute generalized exanthematous pustulosis (AGEP) is a dramatic generalized pustular rash of severe onset, which is considered a serious cutaneous adverse reaction to drugs. However, even though the clinical features are impressive and are often accompanied by systemic inflammation, it can be controlled quickly and safely by topical steroids subsequent to interruption of the offending drug. Here, we describe the management of a case and the evolution of the pustular rash. An elderly woman consulted with a generalized crop of 2–3 mm, nonfollicular pustules on erythematous background. In the 4 preceding weeks, she had been using amoxicillin/clavulanic acid for a bacterial implant infection and rivaroxaban. The clinical EuroSCAR criteria including the histology confirmed AGEP. Her medication was stopped and topical clobetasol propionate was used. Within 24 h, the development of new pustules ceased and the patient was discharged after 7 days of hospitalization with only a faint, diffuse erythema and focal desquamation remaining. This and many other cases in the literature suggest that topical steroids should be considered as a first-line treatment option, especially as systemic steroids themselves can sometimes induce generalized pustulosis.\n\nKeywords\nAcute generalized exanthematous pustulosisTopical steroidsCutaneous adverse reactionPustular rashPustulesEuroSCAR criteriaCorticosteroids\n==== Body\nIntroduction\nA 64-year-old Swiss pensioner presented to our hospital with a pustular rash and signs of systemic inflammation. The C-reactive protein was 62 mg/L and the differential blood count revealed leukocytosis (15.39 G/L) and neutrophilia (10.39 G/L). Five days before, she had first noticed abrupt onset of sheets composed of small pustules on her stomach, subsequently spreading to affect the neck and the palms. The day before admission, lakes of pustules and papules formed on the whole body surface except the face and scalp. The trunk was covered with coarse scales on dark red erythema. Nikolski signs I and II were negative. There was no sign of mucous skin involvement. Furthermore, the patient suffered from severe pruritus in the affected areas. In the 4 weeks preceding the admission, she had been treated with amoxicillin/clavulanic acid for a knee prosthesis infection caused by beta-hemolytic streptococci (groups B and G), as well as with the anticoagulant rivaroxaban. A biopsy confirmed neutrophil infiltrates in the upper layers of the epidermis, as well as perivascular and interstitial neutrophil- and eosinophil-rich infiltrates mixed with lymphocytes and plasma cells [1, 2]. Microbiology swabs revealed neither bacteria nor fungi.\n\nAccording to the EuroSCAR criteria [3, 4] (Table 1), the diagnosis of an acute generalized exanthematous pustulosis (AGEP) was made. Thus, the suspected offending drugs amoxicillin/clavulanic acid and rivaroxaban were replaced with clindamycin and fractionated heparin. Topical clobetasol propionate 0.05% ointment was generously applied to all affected areas once daily and cold cream with 5% polidocanol, a local anesthetic, was given for the pruritus. Development of new pustules ceased within 24 h (Fig. 1) and pustules shed within 72 h. The patient was discharged in good general condition after 7 days of hospitalization with only a faint, diffuse erythema with focal desquamation remaining (Fig. 1). Patch testing for the potential offending drugs was scheduled several months later.\n\nDiscussion\nIn over 90% of cases, AGEP is caused by medications. The patient has received both amoxicillin/clavulanic acid and rivaroxaban during the last 4 weeks before development of the disease. Amoxicillin has been reported to cause AGEP in multiple cases. It is also atypical that the drugs had started to be administered 4 weeks before the onset of disease. The increased C-reactive protein is an indicator of inflammation. It is widely accepted that in a minority of cases also infections can cause AGEP. Our patient was suffering from an infected knee prosthesis, which was the target of the antibiotic treatment. Strikingly, AGEP rarely manifests several weeks after the culprit drugs have been initially administered. Furthermore, rivaroxaban has not been reported to induce an AGEP. Unfortunately, the patient did not return to our clinic for further diagnostic procedures.\n\nCurrently, there is no specific treatment against AGEP. The foremost intervention leading to clearing of AGEP-related pustules is the interruption of the offending drug. During the pustular phase, a local antiseptic treatment and moist dressings are useful, as well as topical corticosteroids. The latter are also effective against severe pruritus [5, 6]. Application of steroids more than once per day does not increase efficacy, but the onset of the therapeutic effect may be faster [7]. In patients with systemic inflammation such as our case, systemic steroids themselves can induce pustulosis [8], which may be considered a reason to avoid them if possible. All reports on AGEP favor the application of parental steroids. It remains uncertain, if a systemic application is necessary. Our patient recovered in a very short time by stopping the medication intake and by the use of highly potent topical corticosteroids once daily.\n\nStatement of Ethics\nThe patient has given informed consent.\n\nDisclosure Statement\nF.A. is funded by the HSM2 (Hochspezialisierte Medizin) and the KTI grant. He has received payments from Abbott®, Celgene®, and is on the advisory board of LEO® Pharma. A.A.N. is funded by the Promedica and Bruno-Bloch Foundation. Funding for the study was provided by the Department of Dermatology. There are no conflicts of interest regarding the publication of this case report.\n\nChristiane Kley and Carla Murer shared first authorship.\n\nFig. 1 Flank of the patient at admission (a) and after 24 h (b), 48 h (c), 72 h (d), 4 days (e), and 5 days (f).\n\nTable 1 EuroSCAR criteria: diagnostic score for validation of AGEP\n\nPustules\t\t\nTypical\t+2\t\nCompatible with the disease\t+1\t\nInsufficient\t0\t\n\t\nErythema\t\t\nTypical\t+2\t\nCompatible with the disease\t+1\t\nInsufficient\t0\t\n\t\t\nDistribution\t\nTypical\t0+2\t\nCompatible with the disease\t0+1\t\nInsufficient\t0\t\n\t\nPostpustular desquamation\t\t\nYes\t0+1\t\nNo\t0\t\n\t\nCourse\t\t\nMucous membrane involvement\t\t\n Yes\t−2\t\n No\t0\t\nAcute onset\t\t\n Yes\t0\t\n No\t0–2\t\nResolution\t\t\n Yes\t0\t\n No\t−4\t\nFever >38°C\t\t\n Yes\t0+1\t\n No\t0\t\nPolymorphonuclear cells ≥7/µL\t\t\n Yes\t0+1\t\n No\t0\t\nHistology\t\t\n Other disease\t−10\t\n Not representative\t0\t\n Exocytosis of polymorphonuclear cells\t+1\t\n Subcorneal and/or intraepidermal nonspongi-form pustules or\t\t\n NOS pustules with papillary edema or subcorneal and/or intraepidermal spongiform pustules or NOS pustules without papillary edema\t+2\t\n Spongiform subcorneal and/or intraepidermal pustules with papillary edema\t+3\t\n<0: excluded; 1–4: possible; 5–7: probable; 8–12: definite. NOS, not otherwise specified.\n==== Refs\nReferences\n1 Buettiker U Keller M Pichler WJ Braathen LR Yawalkar N Oral prednisolone induced acute generalized exanthematous pustulosis due to corticosteroids of group A confirmed by epicutaneous testing and lymphocyte transformation tests Dermatology 2006 213 40 43 16778426 \n2 Halevy S Kardaun SH Davidovici B Wechsler J The spectrum of histopathological features in acute generalized exanthematous pustulosis: a study of 102 cases Br J Dermatol 2010 163 1245 1252 20698849 \n3 Sidoroff A Dunant A Viboud C Halevy S Bavinck JN Naldi L Mockenhaupt M Fagot JP Roujeau JC Risk factors for acute generalized exanthematous pustulosis (AGEP) – results of a multinational case-control study (EuroSCAR) Br J Dermatol 2007 157 989 996 17854366 \n4 Sidoroff A Halevy S Bavinck JN Vaillant L Roujeau JC Acute generalized exanthematous pustulosis (AGEP) – a clinical reaction pattern J Cutan Pathol 2001 28 113 119 11168761 \n5 Lee HY Chou D Pang SM Thirumoorthy T Acute generalized exanthematous pustulosis: analysis of cases managed in a tertiary hospital in Singapore Int J Dermatol 2010 49 507 512 20534083 \n6 Ingen-Housz-Oro S Hotz C Valeyrie-Allanore L Sbidian E Hemery F Chosidow O Wolkenstein P Acute generalized exanthematous pustulosis: a retrospective audit of practice between 1994 and 2011 at a single centre Br J Dermatol 2015 172 1455 1457 25399843 \n7 Fredriksson T Lassus A Bleeker J Treatment of psoriasis and atopic dermatitis with halcinonide cream applied once and three times daily Br J Dermatol 1980 102 575 577 6992844 \n8 Ishii S Hasegawa T Hirasawa Y Tsunemi Y Kawashima M Ikeda S Acute generalized exanthematous pustulosis induced by oral prednisolone J Dermatol 2014 41 1135 1136 25327275\n\n",
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"keywords": "Acute generalized exanthematous pustulosis; Corticosteroids; Cutaneous adverse reaction; EuroSCAR criteria; Pustular rash; Pustules; Topical steroids",
"medline_ta": "Case Rep Dermatol",
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"title": "Rapid Involution of Pustules during Topical Steroid Treatment of Acute Generalized Exanthematous Pustulosis.",
"title_normalized": "rapid involution of pustules during topical steroid treatment of acute generalized exanthematous pustulosis"
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"abstract": "Doxorubicin is one of the most active drugs available for the treatment of sarcoma. Pegylated-liposomal doxorubicin (PLD) is a formulation of doxorubicin in which the doxorubicin is encapsulated in liposomes coated with methoxypoly (ethylene glycol); this formulation results in decreased uptake by the reticuloendothelial system, higher concentrations of drug in tumor, and less toxicity, including reduced cardiotoxicity, nausea, alopecia, and myelosuppression. No premedication is necessary. While PLD has a better toxicity profile than free doxorubicin, there is no consensus on the relative efficacy of PLD and free doxorubicin in sarcoma.\nIn this report, we describe a patient with high-grade metastatic soft tissue sarcoma with rapid recurrence after adjuvant treatment with free doxorubicin, cisplatin, ifosfamide, and dacarbazine. Second-line treatment with PLD resulted in long-term disease remission during a 20-year follow-up period. Mucositis and hand-foot syndrome were controlled by adjustment of dose and treatment interval.\nThis case illustrates the curative potential of PLD after failure of free doxorubicin and the absence of long term cardiotoxicity with PLD. As with all drugs, individual adjustment of dose and treatment interval is important.",
"affiliations": "1Department of Medicine, University of Minnesota Medical School, Office Mayo Mail Code 480, 420 Delaware St. SE, Minneapolis, MN 55455 USA.;2Masonic Cancer Center, Minneapolis, MN USA.;1Department of Medicine, University of Minnesota Medical School, Office Mayo Mail Code 480, 420 Delaware St. SE, Minneapolis, MN 55455 USA.",
"authors": "Savani|Malvi|M|;Murugan|Paari|P|;Skubitz|Keith M|KM|0000-0002-0690-9595",
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"fulltext": "\n==== Front\nClin Sarcoma ResClin Sarcoma ResClinical Sarcoma Research2045-3329BioMed Central London 11110.1186/s13569-018-0111-0Case ReportLong-term cure of soft tissue sarcoma with pegylated-liposomal doxorubicin after doxorubicin and ifosfamide failure Savani Malvi mbsavani@umn.edu 1Murugan Paari pmurugan@umn.edu 23http://orcid.org/0000-0002-0690-9595Skubitz Keith M. (612) 624-5944skubi001@umn.edu 121 0000000419368657grid.17635.36Department of Medicine, University of Minnesota Medical School, Office Mayo Mail Code 480, 420 Delaware St. SE, Minneapolis, MN 55455 USA 2 0000000419368657grid.17635.36Masonic Cancer Center, Minneapolis, MN USA 3 0000000419368657grid.17635.36Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN USA 15 1 2019 15 1 2019 2019 9 124 9 2018 4 12 2018 © The Author(s) 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nDoxorubicin is one of the most active drugs available for the treatment of sarcoma. Pegylated-liposomal doxorubicin (PLD) is a formulation of doxorubicin in which the doxorubicin is encapsulated in liposomes coated with methoxypoly (ethylene glycol); this formulation results in decreased uptake by the reticuloendothelial system, higher concentrations of drug in tumor, and less toxicity, including reduced cardiotoxicity, nausea, alopecia, and myelosuppression. No premedication is necessary. While PLD has a better toxicity profile than free doxorubicin, there is no consensus on the relative efficacy of PLD and free doxorubicin in sarcoma.\n\nCase presentation\nIn this report, we describe a patient with high-grade metastatic soft tissue sarcoma with rapid recurrence after adjuvant treatment with free doxorubicin, cisplatin, ifosfamide, and dacarbazine. Second-line treatment with PLD resulted in long-term disease remission during a 20-year follow-up period. Mucositis and hand-foot syndrome were controlled by adjustment of dose and treatment interval.\n\nConclusions\nThis case illustrates the curative potential of PLD after failure of free doxorubicin and the absence of long term cardiotoxicity with PLD. As with all drugs, individual adjustment of dose and treatment interval is important.\n\nKeywords\nPegylated-liposomal doxorubicinDoxorubicinSarcomaissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nThe median survival of patients with metastatic soft tissue sarcomas (STS) is only 12–15 months [1]. Doxorubicin is one of the most active drugs available for treatment of STS [2–6], although cardiotoxicity can be dose-limiting. Pegylated-liposomal doxorubicin (PLD) is a formulation of doxorubicin in which the doxorubicin is encapsulated in liposomes coated with methoxypoly (ethylene glycol). Unlike doxorubicin, PLD’s uptake by the reticuloendothelial system is decreased, resulting in different pharmacologic properties, including a longer half-life in blood and different toxicities [7–10]. PLD is associated with less cardiotoxicity, nausea, alopecia, and myelosuppression than free doxorubicin; this reduced toxicity obviates the need for premedication [6, 9–14]. PLD’s main toxicities are hand-foot syndrome, low risk of infusion reaction, and some fatigue [6, 9–11, 13, 14]. It has been hypothesized that the symptoms of the infusion reaction, which are associated with transient neutropenia, reflect neutrophil sludging in the microvasculature as observed with hemodialysis neutropenia [15]. We do not routinely pre-medicate patients receiving PLD. In addition, PLD has been shown to localize to implanted tumors in animals [16] and deliver more doxorubicin to the tumor than free doxorubicin in Kaposi sarcoma, prostate cancer, and breast cancer [9, 17, 18]. While PLD has a better toxicity profile than free doxorubicin, there is no consensus on the relative efficacy of PLD and free doxorubicin in STS because of the small number of trials directly comparing these two agents.\n\nIn this report, we describe a patient with high-grade metastatic STS with rapid recurrence after adjuvant treatment with free doxorubicin, cisplatin, ifosfamide, and dacarbazine. The patient’s treatment was changed to PLD, and no recurrence was observed during a follow-up period of more than 20 years. This case illustrates the curative potential of PLD after treatment failure with free doxorubicin and the absence of long-term cardiotoxicity with PLD.\n\nCase presentation\nA 37-year-old white man with a past medical history of mitral valve prolapse and gastritis presented with abdominal pain. A computed tomography (CT) scan revealed an 18 cm × 17 cm × 11 cm colonic flexure mass. The patient underwent a resection of the intraabdominal mass with partial small bowel resection, resection of distal transverse and descending colon with enteroenterostomy, as well as colocolostomy, appendectomy and gastrostomy (Fig. 1). Pathology was thought to be consistent with leiomyosarcoma, grade 3/3.Fig. 1 Timeline of treatment\n\n\n\n\nThe gastric wall tumor showed a high-grade spindle cell neoplasm with focal epithelioid features (Fig. 2B). Numerous atypical mitotic figures were noted. The background showed moderate amounts of chronic inflammatory infiltrate. The tumor was originally thought to represent a gastrointestinal leiomyosarcoma. Subsequent studies performed 20 years later (Fig. 2) included immunohistochemical stains showing patchy reactivity for vimentin, cytokeratin AE1/AE3 and cytokeratin 7, while other markers tested, including gastrointestinal stromal tumor and smooth muscle markers were negative. Notably, calretinin was also negative. This histology and immunoprofile were thought to represent an undifferentiated pleomorphic sarcoma (UPS).Fig. 2 A, C, and E (bladder wall tumor): A highly cellular epithelioid (top right) and spindle cell (bottom left) malignancy involving the outer wall of the urinary bladder (A) (H&E ×100). The cells demonstrate round to oval nuclei with variably prominent nucleoli, moderate eosinophilic cytoplasm and indistinct borders (C) (H&E ×400). Immunohistochemistry shows diffuse reactivity for cytokeratin AE1/AE3 and calretinin (inset) (E) (IHC ×100). B, D, and F (remote abdominal tumor): A moderately cellular malignancy with intermixed spindled and epithelioid cells involving the outer gastric wall (B) (H&E ×200). The cells demonstrate irregular nuclei with prominent multiple eosinophilic nucleoli, abundant eosinophilic cytoplasm and indistinct borders (D) (H&E ×400). Immunohistochemistry shows reactivity for cytokeratin AE1/AE3 and negative calretinin (inset) (F) (IHC ×100)\n\n\n\n\nTwo months after resection of the intra-abdominal mass, the tumor recurred (Fig. 1). He underwent resection of multiple masses in the falciform ligament, left pelvic side wall, small bowel, mesentery, and retroperitoneum. Multiple lymph nodes were also resected. Pathological examination was again thought to be consistent with leiomyosarcoma.\n\nAfter recovery from surgery the patient received three courses of adjuvant chemotherapy with cisplatin, ifosfamide, dacarbazine, and doxorubicin. This involved 50 mg/m2 of cisplatin on day 1; doxorubicin 65 mg/m2 on day 1; dacarbazine 300 mg/m2 on days 1, 2 and 3; and ifosfamide 2.5 grams/m2 a day by continuous infusion for 3 days. This treatment was well tolerated, aside from neutropenic fevers requiring hospitalization.\n\nThree months later, however, a CT scan revealed a 4-cm metastatic lesion in the left lobe of the liver. The patient underwent a partial left hepatectomy and cholecystectomy.\n\nThree months later, a CT revealed multiple 2–3 cm lesions along the margin of the previous partial left hepatectomy. At the time, the patient noted night sweats and low-grade fevers of 99–100 °F, but good appetite and no significant weight loss. The tumor doubled in size during the next 5 weeks and imaging revealed multiple lesions throughout the remaining left lobe. He subsequently underwent a complete left hepatectomy and excision of perigastric lymph nodes. Pathological examination was thought to confirm metastatic grade 3 leiomyosarcoma of the liver. No extrahepatic involvement or lesions in the right lobe were noted by intraoperative ultrasound.\n\nFive weeks later, the patient noted right upper abdominal fullness and pain, left shoulder pain, and presented to our clinic. Pathology review of the earlier resections at our institution and at another large sarcoma center in the US agreed with the diagnosis of leiomyosarcoma. A CT scan showed multiple metastases in the right lobe of the liver and splenic metastases. Immediately before starting PLD, CT imaging revealed multiple metastases in the remaining left lobe of the liver, the largest being 4 × 4 cm, and one spleen nodule. The left ventricular ejection fraction (EF) was 58% by multi-gated acquisition (MUGA). The patient began treatment with PLD at 55 mg/m2 monthly. After 2 cycles of PLD a CT scan showed regression of tumor nodules. Because of mucositis and hand-foot syndrome the dose was reduced 10% for cycles 2–4 and 50% for cycle 5; thereafter, the dose was increased to 30.8 mg/m2 monthly starting with cycle 6 and the treatment interval lengthened to every 6 weeks starting with cycle 7. The left ventricular EF was 61% by MUGA before cycle 12. After 14 cycles the EF was 62% by MUGA and a CT scan showed a persistent lesion in the spleen. At this point, after 14 cycles of PLD, CT imaging revealed no visible disease in the liver and the spleen nodule that was unchanged in size but had a lower density. Thus, while a complete response by RECIST criteria was evident in the liver, the stable size of the spleen nodule indicated a partial response to PLD by RECIST. A splenectomy was performed revealing some viable tumor cells in a necrotic nodule. The patient received 3 more cycles of PLD for a total PLD dose of 595 mg/m2 and a total dose of free doxorubicin of 196 mg/m2. CT imaging revealed no tumor and MUGA showed an EF of 70%. The patient was followed with interval imaging with no recurrence.\n\nTwenty-two years later, the patient experienced several months of scrotal pain radiating to his urethra and localized to his right testicle. An ultrasound showed a 2.8 cm × 1.6 cm × 0.8 cm mass on the outer surface of the bladder. Fine needle aspiration of the mass showed poorly differentiated carcinoma that was CK7+/CD20+ and histologically compatible with urothelial origin. A PET-CT revealed an intense hypermetabolic pelvic mass contiguous with the right side of the bladder. An exploratory laparotomy, intraabdominal mass resection, and partial cystectomy were performed.\n\nPathologic examination of the bladder wall tumor showed a 5.5 cm high-grade malignancy with epithelioid and sarcomatoid features (Fig. 2A). Margins were negative on the perivesical soft tissue mass, and 16 of 16 lymph nodes were negative for malignancy. Mitotic activity was high, and the background showed moderate chronic inflammation. It appeared predominantly located in the outer half of the bladder wall, involving the muscularis propria and perivesical fat. No mucosal involvement or in situ urothelial carcinoma was identified. The tumor was diffusely and strongly positive for calretinin, vimentin and cytokeratin. It was negative for all other markers tested, including gastrointestinal stromal tumor and smooth muscle markers. Given the presence in the bladder and co-expression of keratin and vimentin, it was possible that this represented a urothelial or a urachal remnant-based carcinoma with sarcomatoid differentiation. However, the location of the tumor (posterior dome, per imaging), lack of associated mucosal lesion, positive calretinin stain, and lack of reactivity for urothelial markers such as GATA3, p63, and CK5/6 were unusual for the above diagnosis. The diffuse calretinin reactivity, in conjunction with co-expression of keratin and vimentin, raised the possibility of mesothelial differentiation/origin. While the morphology was not incompatible with a poorly differentiated biphasic mesothelioma, the overall clinical presentation, lack of serosal continuity and non-reactivity for ancillary mesothelial markers (WT1, D2-40 and CK 5/6) precluded a definitive diagnosis of the same.\n\nThe morphology and immunohistochemical staining patterns of the remote gastric lesion were compared to that of the bladder neoplasm. Both were poorly differentiated neoplasms, but the high magnification cytology and calretinin reactivity were dissimilar; there was no clear evidence that the tumor on the bladder wall represented a recurrence of the remote malignancy. His hospital course was complicated by Citrobacter urinary tract infections and intraabdominal abscesses requiring three intraabdominal drains and intravenous antibiotics. EF by ultrasound was normal at 55–60%. He subsequently underwent neoadjuvant gemcitabine and cisplatin followed by total cystectomy; the cystectomy specimen showed no evidence of residual tumor. He continues to do well 4 months after surgery, with no evidence of tumor recurrence.\n\nDiscussion and conclusions\nDoxorubicin remains one of the most active agents with therapeutic activity against advanced STS [2–6]. Numerous phase II and III trials have been conducted showing superior response rates using a combination of doxorubicin and other agents in the treatment of metastatic STS, though demonstration of a clear survival benefit has been elusive. A phase III trial conducted by Judson et al. found no statistically significant improvement in overall survival with the addition of ifosfamide to doxorubicin for palliative treatment of advanced STS [19]. However, this study did show a higher response rate (26% vs 14%) and longer median progression-free survival (7.4 months vs 4.6 months) in the combination cohort, raising the argument in favor of adding ifosfamide to doxorubicin [2, 19]. Our case failed adjuvant treatment with a combination of doxorubicin, cisplatin, ifosfamide, and dacarbazine, but was cured by subsequent treatment with PLD and resection of one remaining nodule. One could question exactly what it means to be “doxorubicin resistant/refractory.” Technically, we did not demonstrate tumor growth while the patient was receiving doxorubicin. However, the patient was treated with 3 cycles of a doxorubicin containing regimen starting at a time when there was no tumor detectable by CT imaging. Three months after stopping the doxorubicin containing regimen, CT imaging revealed a sizable tumor burden. One must conclude that either the tumor was not inhibited by the doxorubicin containing regimen or that it kept residual tumor cells dormant until it was stopped and then those tumor cells grew very rapidly, or alternatively, some tumor cells were killed by the doxorubicin containing regimen, but the remaining cells grew very rapidly over 3 months. In any of these cases, it seems very unlikely that it would have been possible to cure the patient with further doxorubicin if 3 cycles starting with no residual tumor detectable did not, especially given the size of the tumor burden and the issue of dose related cardiotoxicity.\n\nPLD is a unique formulation of doxorubicin in that the agent is contained in liposomes coated with hydrophilic methoxypoly (ethylene glycol), that diminishes uptake of the agent by the reticuloendothelial system and consequently increases the half-life of the drug in blood to approximately 50–60 h [7, 9, 20]. PLD localizes to tumors due to increased vascular permeability, resulting in greater drug concentration in tumor in comparison to free doxorubicin [9, 16–18]. A number of trials have demonstrated activity of PLD in a variety of tumors, including sarcomas (Table 1) [6, 10, 13, 14, 21, 22]. A phase II trial by the EORTC Soft Tissue and Bone Sarcoma Group compared the results of 50 patients treated with PLD at 50 mg/m2 every 4 weeks and 44 patients treated with doxorubicin at 75 mg/m2 every 3 weeks for advanced STS; they found that PLD had equivalent activity as doxorubicin with an improved toxicity profile, including lower incidence of myelosuppression and alopecia. However, a higher incidence of palmar-plantar erythrodysesthesia was noted in the cohort receiving PLD [6]. This study had a high proportion of gastrointestinal stromal tumors. They also concluded that further studies of PLD in combination with other drugs should be considered.Table 1 Summary of clinical trial results of PLD in sarcoma\n\nStudy\tDisease\tDosing regimen\tOrganizer/sponsor\t# of patients\tResponses and toxicities\tReferences\t\nPhase 2\tSTS (many patients had poor prognostic features, including low-grade tumors\tPLD 50 mg/m2 every 4 weeks\t\t13\tNone\nTreatment responses possibly affected by poor prognostic features\tGarcia et al. [13]\t\nPhase 2\tAdvanced and/or metastatic STS\nPatients were previously treated with an anthracycline-based chemotherapy\tPLD 30–50 mg/m2 every 3 weeks\t\t25\t3 PRs, 4 minor responses, and 17 patients with SD\tToma et al. [22]\t\nPhase 2 randomized\tAdvanced STS, with a high proportion of gastrointestinal stromal tumors\tPLD 50 mg/m2 every 4 weeks\nDoxorubicin 75 mg/m2 every 3 weeks\tEORTC Soft Tissue and Bone Sarcoma Group\t94 (50 PLD, 44 doxorubicin)\tPLD had equivalent activity as doxorubicin with an improved toxicity profile, including lower incidence of myelosuppression and alopecia. However, a higher incidence of palmar-plantar erythrodysesthesia was noted in the cohort receiving PLD\tJudson et al. [6]\t\nPhase 2\tPreviously treated sarcomas or sarcomas considered unresponsive to chemotherapy\tPLD 55 mg/m2 with subsequent dose adjustment\t\t47\t3 CR or PR and 15 clinical benefit\nTreatment was generally well tolerated, and mucositis and hand-foot syndrome were the dose-limiting toxicities\tSkubitz [10]\t\nPhase 2\tAdvanced leiomyosarcoma of the uterus\tPLD 50 mg/m2 every 4 weeks\t\t31\tCR in 1, PR in 4, and SE in 10 patients\tSutton et al. [21]\t\nRetrospective analysis\tMetastatic STS\tInitial PLD 40–60 mg/m2 every 4 weeks\t\t11\tPR in 6 with extended time to progression, SD in 2, and PD in 3\n(One patient was progression free for 60 months after receiving seven cycles of PLD)\tGrenader et al. [14]\t\n\n\n\nIn addition to its activity in STS, PLD has an improved toxicity profile as compared with free doxorubicin. An important limiting toxicity of doxorubicin is cardiotoxicity. In contrast, PLD has much less cardiotoxicity [10, 12, 20, 23–25]. A recent retrospective study [12] showed no definitive doxorubicin-induced clinical heart failure (HF) in 56 patients receiving a cumulative dose of free doxorubicin and PLD comparable or higher than the dose our case received (PLD: 595 mg/m2 and free doxorubicin: 196 mg/m2). In this retrospective study, 56 patients received a cumulative dose of free doxorubicin and PLD of > 450 mg/m2, 49 patients received > 500 mg/m2, 14 > 1000 mg/m2 and 5 > 1400 mg/m2. While modest changes in EF were noted over time in the absence of clinical signs or symptoms of HF, EF was not considered a useful predictor of doxorubicin-induced cardiotoxicity, at least in the case of PLD [12]. Our case’s EF remained within or above the normal range before, during, and after PLD treatment for the 20-year follow-up period. While dexrazoxane is occasionally employed during initiation of bolus doxorubicin to reduce long-term cardiotoxicity, this is not required with administration of PLD, eliminating any concern that dexrazoxane might decrease anti-tumor activity.\n\nPLD is a different formulation of doxorubicin with different pharmacologic properties and different toxicities than bolus free doxorubicin. In addition to reduced cardiotoxicity, PLD has markedly reduced nausea, alopecia, and myelosuppression, and no anti-emetics or other pre-medications or growth factors are usually needed. A small number of patients experience an infusion reaction in the first few minutes of the first treatment, that manifests as shortness of breath or low back pain. It has been suggested that the symptoms of the infusion reaction, which are associated with transient neutropenia, reflect neutrophil sludging in the microvasculature as observed with hemodialysis neutropenia [15]. Pre-medications have not been shown to prevent this reaction, which usually only occurs with the first treatment. The main toxicities of PLD are mucositis, hand-foot syndrome, and mild fatigue. Notably, not all liposomal formulations are the same; non-pegylated liposomal anthracyclines have different pharmacologic properties and lack some of the favorable properties of PLD.\n\nWhile some early studies used doses of PLD as high as 55 mg/m2, this dose is usually too high for a monthly treatment schedule; a more typical monthly starting dose is 45 mg/m2. When dose-limiting toxicities are seen, the next dose should be delayed until there is no pain from mucositis or hand-foot syndrome. Cardiotoxicity is rare, and there is no study demonstrating that monitoring the EF as a predictor of cardiotoxicity is useful [10, 12, 24, 25]. In conclusion, PLD has a more favorable toxicity profile, including reduced incidences of cardiotoxicity, nausea, myelosuppression, and alopecia. As a result no pre-medications or growth factor is required [6–15, 20, 24, 25]. Furthermore, PLD results in higher concentrations of drug in tumor than free doxorubicin [9, 16–18]. Our case highlights that PLD can cure a patient with a doxorubicin-resistant tumor, demonstrating that in some cases PLD is more efficacious than free doxorubicin with a more favorable toxicity profile. As with all drugs, individual adjustment of dose and treatment interval is important.\n\nAbbreviations\nPLDpegylated-liposomal doxorubicin\n\nSTSsoft-tissue sarcoma\n\nEFejection fraction\n\nHFheart failure\n\nAuthors’ contributions\nConception and design: KS; Manuscript writing: MS, PM, and KS; Final approval: MS, PM, and KS; Pathological explorations: PM; Patient’s management: KS. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe thank Michael Franklin for editorial assistance, and support from the Kevin Franklin family and the James Dinnerstein family.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images.\n\nEthics approval and consent to participate\nNot applicable.\n\nFunding\nNot applicable.\n\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. 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Gottlieb JA Baker LH Quagliana JM Luce JK Whitecar JP Jr Sinkovics JG Rivkin SE Brownlee R Frei E 3rd Chemotherapy of sarcomas with a combination of adriamycin and dimethyl triazeno imidazole carboxamide Cancer 1972 30 6 1632 1638 10.1002/1097-0142(197212)30:6<1632::AID-CNCR2820300632>3.0.CO;2-S 4663966 \n6. Judson I Radford JA Harris M Blay JY van Hoesel Q le Cesne A van Oosterom AT Clemons MJ Kamby C Hermans C Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group Eur J Cancer 2001 37 7 870 877 10.1016/S0959-8049(01)00050-8 11313175 \n7. Gabizon A Catane R Uziely B Kaufman B Safra T Cohen R Martin F Huang A Barenholz Y Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes Cancer Res 1994 54 4 987 992 8313389 \n8. Gabizon AA Barenholz Y Bialer M Prolongation of the circulation time of doxorubicin encapsulated in liposomes containing a polyethylene glycol-derivatized phospholipid: pharmacokinetic studies in rodents and dogs Pharm Res 1993 10 5 703 708 10.1023/A:1018907715905 8321835 \n9. Northfelt DW Martin FJ Working P Volberding PA Russell J Newman M Amantea MA Kaplan LD Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi’s sarcoma J Clin Pharmacol 1996 36 1 55 63 10.1002/j.1552-4604.1996.tb04152.x 8932544 \n10. Skubitz KM Phase II trial of pegylated-liposomal doxorubicin (Doxil) in sarcoma Cancer Invest 2003 21 2 167 176 10.1081/CNV-120016412 12743981 \n11. Northfelt DW Dezube BJ Thommes JA Levine R Von Roenn JH Dosik GM Rios A Krown SE DuMond C Mamelok RD Efficacy of pegylated-liposomal doxorubicin in the treatment of AIDS-related Kaposi’s sarcoma after failure of standard chemotherapy J Clin Oncol 1997 15 2 653 659 10.1200/JCO.1997.15.2.653 9053490 \n12. Skubitz KM Blaes AH Konety SH Francis GS Cardiac safety profile of patients receiving high cumulative doses of pegylated-liposomal doxorubicin: use of left ventricular ejection fraction is of unproven value Cancer Chemother Pharmacol 2017 80 4 787 798 10.1007/s00280-017-3420-8 28856562 \n13. Garcia AA Kempf RA Rogers M Muggia FM A phase II study of Doxil (liposomal doxorubicin): lack of activity in poor prognosis soft tissue sarcomas Ann Oncol 1998 9 10 1131 1133 10.1023/A:1008439013169 9834828 \n14. 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Sutton G Blessing J Hanjani P Kramer P Gynecologic Oncology G Phase II evaluation of liposomal doxorubicin (Doxil) in recurrent or advanced leiomyosarcoma of the uterus: a Gynecologic Oncology Group study Gynecol Oncol 2005 96 3 749 752 10.1016/j.ygyno.2004.11.036 15721421 \n22. Toma S Tucci A Villani G Carteni G Spadini N Palumbo R Liposomal doxorubicin (Caelyx) in advanced pretreated soft tissue sarcomas: a phase II study of the Italian Sarcoma Group (ISG) Anticancer Res 2000 20 1B 485 491 10769710 \n23. Ewer MS Martin FJ Henderson C Shapiro CL Benjamin RS Gabizon AA Cardiac safety of liposomal anthracyclines Semin Oncol 2004 31 6 Suppl 13 161 181 10.1053/j.seminoncol.2004.08.006 15717742 \n24. Gill SE Savage K Wysham WZ Blackhurst DW Winter WE Puls LE Continuing routine cardiac surveillance in long-term use of pegylated liposomal doxorubicin: is it necessary? Gynecol Oncol 2013 129 3 544 547 10.1016/j.ygyno.2013.03.012 23523653 \n25. Kushnir CL Angarita AM Havrilesky LJ Thompson S Spahlinger D Sinno AK Tanner EJ Secord AA Roche KL Stone RL Selective cardiac surveillance in patients with gynecologic cancer undergoing treatment with pegylated liposomal doxorubicin (PLD) Gynecol Oncol. 2015 3 503 507 10.1016/j.ygyno.2015.02.020\n\n",
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"journal": "Clinical sarcoma research",
"keywords": "Doxorubicin; Pegylated-liposomal doxorubicin; Sarcoma",
"medline_ta": "Clin Sarcoma Res",
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"pmid": "30651969",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
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"title": "Long-term cure of soft tissue sarcoma with pegylated-liposomal doxorubicin after doxorubicin and ifosfamide failure.",
"title_normalized": "long term cure of soft tissue sarcoma with pegylated liposomal doxorubicin after doxorubicin and ifosfamide failure"
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"abstract": "3,4-methylenedioxypyrovalerone (MDPV) is a synthetic cathinone belonging to the class of α-pyrrolidinophenones that become increasingly popular as a designer psychostimulant. Here, we report a comprehensive collection of MDPV exposure with quantitative serum level confirmation in Germany. During the years 2014-2016, we could proof consumption of MDPV in 23 cases where urine and blood samples were submitted to our laboratory by the police of Lower Saxony. Most of the samples underwent systematic toxicological analysis by gas chromatography-mass spectrometry (GC-MS), where MDPV could be detected in urine and/or serum samples. The determined concentrations of MDPV in serum showed a high variability, ranging from traces (<10ng/mL) up to 576ng/mL with a mean concentration of 118ng/mL and median of 47ng/mL. The majority of MDPV users were men (87%) and the age ranged from 23 to 49 years (mean 35.9, median 37 years). For most of the analytically confirmed MDPV cases we could prove co-consumption of other psychotropic drugs with frequent occurrence of opiates and cannabinoids in 22% of the cases, followed by benzodiazepines and cocaine in 17%. Analysis of urine samples by GC-MS disclosed the presence of MDPV and its metabolites 2'-oxo-MDPV, demethylenyl-MDPV, demethylenyl-methyl-MDPV, demethylenyl-oxo-MDPV, demethylenyl-methyl-oxo-MDPV and demethylenyl-methyl-N,N-bisdealkyl-MDPV. The metabolite pattern substantiates previous suggestions for principle metabolic pathways of MDPV in humans.",
"affiliations": "Forensic Toxicological Laboratory, University Medical Center Göttingen, Georg-August-University, 37075 Göttingen, Germany. Electronic address: mgrapp@med.uni-goettingen.de.;Forensic Toxicological Laboratory, University Medical Center Göttingen, Georg-August-University, 37075 Göttingen, Germany.;GIZ-Nord Poisons Center, University Medical Center Göttingen, Georg-August-University, 37075 Göttingen, Germany.",
"authors": "Grapp|Marcel|M|;Kaufmann|Christoph|C|;Ebbecke|Martin|M|",
"chemical_list": "D052117:Benzodioxoles; D015198:Designer Drugs; D011619:Psychotropic Drugs; D011759:Pyrrolidines; C554666:3,4-methylenedioxypyrovalerone",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2017.01.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "273()",
"journal": "Forensic science international",
"keywords": "3,4-methylenedioxypyrovalerone; MDPV; New psychoactive substances; Pyrrolidinophenone; Synthetic cathinones; Systematic toxicological analysis",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D052117:Benzodioxoles; D015198:Designer Drugs; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D011619:Psychotropic Drugs; D011759:Pyrrolidines; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders; D055815:Young Adult",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "1-9",
"pmc": null,
"pmid": "28187296",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Toxicological investigation of forensic cases related to the designer drug 3,4-methylenedioxypyrovalerone (MDPV): Detection, quantification and studies on human metabolism by GC-MS.",
"title_normalized": "toxicological investigation of forensic cases related to the designer drug 3 4 methylenedioxypyrovalerone mdpv detection quantification and studies on human metabolism by gc ms"
} | [
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"companynumb": "DE-MYLANLABS-2019M1002507",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
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{
"abstract": "Relapse after allogeneic hematopoietic stem cell transplantation (AHSCT) in myelofibrosis (MF) patients remains as a significant issue despite advances in transplantation procedures and significant prolongation in survival. Second AHSCT is a potential treatment option but associated with high treatment-related mortality and novel less toxic conditioning regimens are needed. In 33 MF patients with relapse after AHSCT and failure to donor lymphocyte infusion (DLI) we investigated treosulfan (36-42 g/m2) in combination with fludarabine and anti-thymocyte globulin (ATG) as conditioning regimen for a second AHSCT with matched related (n = 2), unrelated (n = 23), or mismatched unrelated (n = 8) donors. All patients achieved leukocyte engraftment after a median of 11 days, and 56 ± 13% experienced acute GVHD grade II-IV at day 100. The therapy-related mortality at day 100 and at 3 years was 16% and 31%, respectively. The cumulative incidence of relapse at 5 years was 16%, resulting in a 5-year disease-free and overall survival of 45% and 47%, respectively. Treosulfan-based conditioning for second allograft in relapsed MF patients resulted in about 50% of the patients in long-term freedom from disease.",
"affiliations": "Hematology Department, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.;Hematology Department, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.;Hematology Department, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.;Hematology Department, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.;Hematology Department, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.;Hematology Department, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.;Hematology Department, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.;Hematology Department, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.",
"authors": "Atagunduz|Isik Kaygusuz|IK|;Klyuchnikov|Evgeny|E|;Wolschke|Christine|C|;Janson|Dietlinde|D|;Heidenreich|Silke|S|;Christopeit|Maximilian|M|;Ayuk|Francis|F|;Kröger|Nicolaus|N|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/cancers12113098",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694 MDPI \n\n33114179\n10.3390/cancers12113098\ncancers-12-03098\nArticle\nTreosulfan-Based Conditioning Regimen for Second Allograft in Patients with Myelofibrosis\nAtagunduz Isik Kaygusuz 12 Klyuchnikov Evgeny 1 Wolschke Christine 1 Janson Dietlinde 1 Heidenreich Silke 1 Christopeit Maximilian 1 Ayuk Francis 1 Kröger Nicolaus 1* 1 Hematology Department, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; isik.kaygusuz@marmara.edu.tr (I.K.A.); eklyuchnikov@uke.de (E.K.); wolschke@uke.de (C.W.); d.janson@uke.de (D.J.); s.heidenreich@uke.de (S.H.); m.christopeit@uke.de (M.C.); ayuketang@uke.de (F.A.)\n2 Hematology Department, Marmara University Pendik Training and Research Hospital, 34899 Istanbul, Turkey\n* Correspondence: nkroeger@uke.de; Tel.: +49-40-7410-54851\n23 10 2020 \n11 2020 \n12 11 309831 8 2020 21 10 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Simple Summary\nCurrently, the only curative therapy in myelofibrosis is allogeneic hematopoietic stem cell transplantation. Donor lymphocyte infusion and second stem cell transplantation are the two main treatment options for myelofibrosis patients who relapse after the first transplantation. The optimal conditioning regimen for the second transplantation in myelofibrosis patients is not well defined. Our study aimed to address this question and showed that treosulfan-based conditioning for second allograft in relapsed myelofibrosis patients resulted in longtime freedom from disease in about 50% of the patients. This data supports the second allogeneic hematopoietic stem cell transplantation with a less toxic treosulfan-based conditioning regimen that is effective in relapsed, donor lymphocyte infusion resistant myelofibrosis patients with long term low transplant-related mortality and relapse rates.\n\nAbstract\nRelapse after allogeneic hematopoietic stem cell transplantation (AHSCT) in myelofibrosis (MF) patients remains as a significant issue despite advances in transplantation procedures and significant prolongation in survival. Second AHSCT is a potential treatment option but associated with high treatment-related mortality and novel less toxic conditioning regimens are needed. In 33 MF patients with relapse after AHSCT and failure to donor lymphocyte infusion (DLI) we investigated treosulfan (36–42 g/m2) in combination with fludarabine and anti-thymocyte globulin (ATG) as conditioning regimen for a second AHSCT with matched related (n = 2), unrelated (n = 23), or mismatched unrelated (n = 8) donors. All patients achieved leukocyte engraftment after a median of 11 days, and 56 ± 13% experienced acute GVHD grade II–IV at day 100. The therapy-related mortality at day 100 and at 3 years was 16% and 31%, respectively. The cumulative incidence of relapse at 5 years was 16%, resulting in a 5-year disease-free and overall survival of 45% and 47%, respectively. Treosulfan-based conditioning for second allograft in relapsed MF patients resulted in about 50% of the patients in long-term freedom from disease.\n\ntreosulfanmyelofibrosissecond allogeneic transplantstem cell transplantation\n==== Body\n1. Introduction\nMyelofibrosis (MF) is a clonal hematopoietic stem cell disorder characterized by clonal ineffective hematopoiesis, a reactive reticulin deposition and fibrosis in bone marrow, circulating CD34+ progenitor cells, extramedullary hematopoiesis, and leukemic progression [1]. Allogeneic hematopoietic stem cell transplantation (AHSCT) is the only potentially curative treatment option for patients with MF with a cure rate of 30–65% [2,3,4].\n\nProspective and retrospective studies reported an overall survival (OS) rate of 30–60% at 3–5 years for AHSCT with myeloablative conditioning (MAC) regimen in patients with MF and a non-relapse mortality (NRM) rate ranging from 30% to 48% at 1 year, 24% to 43% at 3–5 years [2,3,4,5]. Over the past decades, the use of reduced-intensity conditioning (RIC) has lowered the rate of NRM in comparison with MAC [6,7,8].\n\nRelapse is one of the major causes of treatment failure after AHSCT in MF patients. Clinical relapses can be treated preferentially by donor lymphocyte infusion (DLI) and/or with a second AHSCT [5,9] in the presence of limited information on the efficacy and safety of the second AHSCT driven from case reports and studies with small patient numbers [9,10,11]. The preferred conditioning regimens for myelofibrosis are either busulfan or melphalan based [4,7,8]. The optimal conditioning regimen for the second AHSCT in MF patients that should provide a lower treatment-related mortality with high anti-malignancy efficacy is not well defined. Due to intense previous treatment regimens and infection-related complications, the treatment related mortality (TRM) and relapse rates may be expected to be high in these high-risk patients.\n\nTreosulfan is a water-soluble, bifunctional, alkylating drug that shows strong myelotoxic, immunosuppressive properties, and is effective against a variety of human tumor cell lines including hematologic malignancies such as leukemia, lymphoma, and myeloma [12]. Preclinical studies showed that treosulfan has a myeloablative effect on committed and noncommitted stem cells and possesses potent immunosuppressive characteristics as the prodrug of a alkylating cytotoxic agent [13]. Treosulfan and fludarabine combination has been proven to be effective in AML and MDS patients and provided full donor chimerism with less toxicity and therefore it is accepted as a myeloablative preconditioning regimen with reduced toxicity [14]. The only retrospective study on MF patients reported that a treosulfan and fludarabine based conditioning for the first AHSCT has a potent myeloablative and antidisease activity [15].\n\nOur study aims to analyze the safety and efficacy of a treosulfan-based conditioning regimen for the second AHSCT in patients with MF.\n\n2. Materials and Methods\n2.1. Patient Selection\nIn this cross-sectional study, we retrospectively evaluated the safety and efficacy of treosulfan-based conditioning regimen for second AHSCT in patients with MF. We identified 33 patients with MF who received second AHSCT between November 2005 and May 2020 at the University Medical Center Hamburg-Eppendorf, Germany.\n\n2.2. Patient Characteristics\nA total of 33 patients were studied with a median follow-up of 28.36 months (range: 0.3–146.36). Median age at transplantation of the whole study population was 59 years (range: 37–76). Twelve patients (36%) had primary MF (PMF), eight (24%) had post essential thrombocythemia (ET) myelofibrosis, seven (21%) had post polycythemia vera (PV) myelofibrosis, and six patients had acute myeloid leukemia (transformed from primary MF in four patients and post PV-MF in two patients). All patients had received busulfan (10 mg/kg orally or 8 mg/kg IV), fludarabine (150 mg/m2), and anti-thymocyte globulin (ATG) as a conditioning regimen in the first AHSCT. Median time from the first transplant to relapse was 5.5 months (range: 0.4–11.8). Median time from the first transplant to the second AHSCT was 15.5 months (range: 4.1–116.9). Median time from relapse to the second AHSCT was 6.25 months (range: 1.0–52.1). Four patients did not receive any therapy before the second AHSCT. Twelve patients received only DLI (1–5 doses), one patient DLI and hydroxyurea, five patients DLI (1–5 doses) and ruxolitinib, one patient two doses of DLI and stem cell boost, six patients only ruxolitinib, one patient one dose of DLI and azacytidine and two patients one dose of DLI and chemotherapy combination. All but leukemia patients were transplanted in an active disease status. Four of the six patients with leukemia transformation from MF were transplanted with progressive disease, one with complete remission, and one in aplasia.\n\nAfter excluding patients with leukemia at the time of transplantation, Dynamic International Prognostic Scoring System (DIPSS) score at transplantation was available in 22 out of 27 patients. DIPSS score was low to intermediate-1 in six patients (18.2%), and intermediate-2 to high in 16 patients (48.5%). Four patients had been splenectomized and 18 patients had splenomegaly at the time of second transplantation with a spleen size ranging between 14.5 and 29.5 cm. Spleen size was normal in seven patients, larger than 20 cm in nine patients, and the data was missing in four patients. Patients did not receive radiotherapy or undergo any specific intervention for splenomegaly before transplantation. Cytogenetic analysis was available in 11 cases and showed normal karyotype (n = 6), complex karyotype (n = 1), and other abnormalities (n = 4).\n\nAll patients received peripheral blood stem cells as stem cell source from an either fully human leukocyte antigen (HLA)-matched related donor (MRD, n = 2), matched unrelated donors (MUD, n = 23), or mismatched unrelated donors (MMUD, n = 8). Mismatched donors had at least one allele or antigen mismatch: A locus, n = 3, B locus, n = 1, C locus, n = 1, DRB1 locus, n = 2, locus B plus C, n = 1. The median number of transplanted CD34+ cells/kg BW was 8.0 × 106 (range: 2.56–15.7). Twenty-four patients had a positive cytomegalovirus (CMV) status before transplantation, and nine patients had a negative CMV serostatus at the time of transplantation. Patient characteristics are shown in Table 1.\n\n2.3. Donor Characteristics\nThe median age was 40 years (range: 20–66) of donors (M/F = 26/7). Six male patients received a graft from a female donor. Four patients were transplanted from the same donor of the first transplant and the remaining 29 had an alternative new donor.\n\n2.4. Therapy Plan\nConditioning regimen consisted of treosulfan (36–42 g/m2, given in daily single doses on day-7 to -5 in a dose of 12–14 g/m2: 36 g/m2: n = 32 and 42 g/m2: n = 1), fludarabine (150 mg/m2 intravenously (i.v.) given divided from day-7 to -3), anti-thymocyte globulin (ATG; rabbit, Fresenius, Bad Homburg, Germany, n = 6), given at a dose of 30–60 mg/kg or thymoglobulin (Genzyme GmbH, Neu-Isenburg, Germany, n = 26) given at a dose of 4–8 mg/kg, followed by AHSCT on day 0. Patients with leukemic transformation received fludarabine, amsacrine, cytosine arabinoside (FLAMSA) (n = 4), gemtuzumab, mitoxantrone and cytosine arabinoside (n = 1), or thiotepa (n = 1) with treosulfan.\n\n2.5. Supportive Care\nThe graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine A (CSA) and mycophenolate mofetil (MMF) in 26 patients, CSA and methotrexate in four patients, and tacrolimus and MMF in three patients. Standard criteria were used for grading of acute and chronic GvHD [16,17]. Immunosuppressive drugs doses, growth factor, antibacterial, antiviral, antifungal prophylaxis, and infection treatments were performed in accordance with the center’s follow-up protocols [18].\n\n2.6. Statistical Analysis\nStatistical analysis of demographic variables was expressed descriptively. Data distribution was assessed using the Kruskal–Wallis test. We used Student’s t-test to compare continuous data with the normal distribution. The survival data were estimated using the Kaplan Meier method and log-rank test, respectively. Overall survival (OS) was calculated from the date of AHSCT until death or last observation alive. Disease-free survival (DFS) was defined as the time from AHSCT to death or relapse whichever came first. Estimation of relapse incidence and treatment-related mortality incidence was carried out using the proper estimation of the cumulative incidence curve.\n\n3. Results\n3.1. Engraftment\nThe median time until leukocyte (>0.5 × 109/L) and platelet (>20 × 109/L) engraftment was 11 days (range: 9–78) and 14 days (range: 9–119), respectively (Table 2). One patient died before engraftment at day nine of AHSCT. Except this patient, all patients achieved leukocyte engraftment and 27 out of 32 patients achieved thrombocyte engraftment.\n\nAll patients but one had complete data for engraftment. Only one patient died before the engraftment. Primary graft failure was observed only in one of 32 patients. This patient died 16 months after AHSCT due to aspergillus pneumonia and acute respiratory distress syndrome (ARDS). None of the patients developed secondary graft failure. Chimerism analysis was available in 28 out of 33 patients. All of 28 patients reached full donor chimerism at a median of 99 days (range: 19–1632). Twenty of 26 patients achieved full donor chimerism at the 30th day of AHSCT and 18 out of these 20 patients maintained their full donor chimerism status. Twenty-one of 28 patients who achieved full donor chimerism at any time point after AHSCT maintained their full donor chimerism status.\n\n3.2. Graft-versus-Host Disease\nAt day 100, the cumulative incidence of acute GvHD in any grade, grade II–IV acute GvHD and grade III–IV acute GvHD was 73 ± 10%, 56 ± 13% and 33 ± 13%, respectively. One year cumulative incidence of moderate to severe chronic GvHD was 28 ± 12%. Median time to acute and chronic GvHD in all grades were 18.5 days (range: 9–137) and 197 days (range: 33–1412), respectively.\n\n3.3. Response\nMaximum response was evaluated in only 27 patients due to missing data. Overall response rate (ORR) was 85%. Nineteen patients (70%) achieved molecular complete response, two patients achieved complete histo-hematological response, two had partial responses, and the remaining patients had stable disease. The median time to maximum response was 90 days (range: 17–882).\n\n3.4. Toxicity and TRM\nMucositis (n = 20), liver (n = 8), kidney (n = 4), gastrointestinal system (n = 1) toxicities developed during follow up. Twenty-seven out of 33 patients experienced an infection in the first 30 days of AHSCT. CMV reactivation developed in a total of 15 patients. In 10 of these patients, reactivation developed within the first month of AHSCT. Organ involvement (CMV—pneumonia) was observed in two of 15 patients who developed CMV reactivation. Ebstein–Barr virus (EBV) reactivation was observed in nine patients. In five of these patients EBV reactivation developed within the first month after AHSCT. Organ involvement was seen in two patients. EBV-encephalitis was detected in one patient and gastrointestinal system (GIS) involvement in one patient. The list of documented infections is given in Table 3.\n\nFour patients experienced moderate liver veno-occlusive disease (VOD) within the first 30 days after transplant. All patients received defibrotide plus supportive therapy and VOD resolved in all.\n\nAt the time of analysis and in a median follow-up of 28.36 months (range: 0.3–146.36), 16 out of 33 patients (49%) were alive; of those, 13 (81%) were in remission.\n\nCause of death was not recorded for two patients, four patients died of relapse related complications and 11 of transplant related causes (GVHD:5, infection:5, GVHD and infection:1 patient). The following complications resulted in death in patients with infections: CVM pneumonia, ileitis, and intestinal perforation in one, neutropenic fever and Grade 4 GVHD-related liver failure in one, septic shock in two, mucor pneumonia in one, and aspergillus pneumonia and ARDS in one patient.\n\nThe cumulative incidence of TRM at day 100 was 16% (95% CI: 5.5–30.3). The 3-year TRM was 31% (95% CI: 16–47.7) and the 5-year TRM was 34% (95% CI: 18.4–50.9) (Figure 1).\n\n3.5. Outcome/Overall and Disease-Free Survival\nAfter a median follow-up of 21.4 months (range: 3.4–116.6), nine out of 32 patients relapsed. The 3 or 5-years cumulative incidences of relapse were both 16% (95% CI: 5.5–30.4) (Figure 2).\n\nThe 3-year and 5-year estimated disease-free survival rates and overall survival rates were 49% (95% CI: 27.7–75.2)–45% (95% CI: 23.9–72.9), and 59% (95% CI: 39.1–82.02)–47% (95% CI: 27.7–75.2), respectively (Figure 3).\n\nAfter excluding patients with leukemia at the time of transplantation, the 3 and 5-year OS rates for the remaining 27 patients were 62% (95% CI: 40–85) and 47% (95% CI: 25.6–78), respectively. The 3- and 5-year DFS were 49% (95% CI: 25.6–78), and 44% (95% CI: 20–75.3), respectively.\n\nThree out of six patients diagnosed with leukemic transformation prior to transplantation died within the first 100 days after transplant due to transplant-related causes. One patient died of grade 4 acute GVHD (grade 4 acute liver GVHD-induced liver failure) and septic shock, one patient of grade 4 acute GVHD, and one patient of septic shock.\n\n4. Discussion\nMyelofibrosis is a clonal hematopoietic stem cell disorder. An optimal conditioning regimen for the second AHSCT in MF patients should provide low treatment-related mortality with high anti-malignancy efficacy.\n\nThe current study shows that treosulfan in combination with fludarabine as dose-reduced conditioning for patients with MF before the second AHSCT is a feasible and effective conditioning regimen.\n\nIn the current literature, knowledge on the second transplant in relapsing MF patients is sparse, and the efficacy or safety of an optimal conditioning regimen for the second transplant in these patients is not well defined. RIC regimens, fludarabine/busulfan (FB) or fludarabine/melphalan (FM) are widely used for conditioning prior to the first transplantation in MF [4,6,19,20]. The only retrospective study on MF patients reported that a treosulfan and fludarabine based conditioning for the first AHSCT has a potent myeloablative and antidisease activity [15]. There is an unmet need for novel conditioning regimens that will reduce AHSCT-related toxicity while retaining maximal antimalignancy effect [13].\n\nTo the best of our knowledge, this is the first study evaluating safety and efficacy in MF patients after the second AHSCT.\n\nIn a recent and large retrospective study of EBMT in AML, a treosulfan based conditioning regimen was similar to busulfan, at a myeloablative or a reduced dose, in achieving 2 years OS in AML patients with a possibly better safety profile in older patients, with lower rates of graft-versus-host disease and possibly better outcomes in patients with active leukemia [21]. A further prospective, phase III study of treosulfan reported that treosulfan is non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for AHSCT for older or comorbid patients with acute myeloid leukemia or myelodysplastic syndrome [14]. The improved outcomes in patients treated with the treosulfan–fludarabine regimen as a potential standard preparative regimen in this population suggest that the same regimen may be considered as effective and less toxic conditioning for MF.\n\nTreatment of MF after the first relapse is a challenging medical condition and an optimal conditioning regimen for a more resistant MF with lower treatment-related mortality and high antimalignancy efficacy, such as treosulfan based conditioning regimens, may, therefore, be promising in these high-risk MF patients.\n\nIn the only study evaluating the effectiveness of treosulfan based conditioning regimen in the first transplant of MF, Claudiani et al. reported the outcome of 14 patients. In this group of patients with a median age of 57, full myeloablation was achieved in all patients, and full donor chimerism was achieved in 12 out of 13 patients that could be evaluated in the first month and continued in 10 out of 13 patients until a median of 39 months. Non-hematological toxicity was modest, and no patients developed VOD. After a median follow-up of 39 months (range: 2–107), the 3-year probability of OS is 54 ± 14% and the 3-year probability of DFS is 46 ± 14%. The cumulative incidence of NRM at 2 years was 39 ± 15%. Causes of NRM were infection (n = 2), GVHD (n = 2), and hemorrhage (n = 1). In particular, all four patients receiving a MUD SCT died because of NRM [15].\n\nIn our previous study evaluating the outcome and treatment strategies of 27 MF patients who relapsed after RIC-based transplantation, 13 of 17 patients who were treated with a second transplant with a treosulfan/fludarabine conditioning regimen and 1-year cumulative incidence of non-relapse mortality was 6%, and the cumulative incidence of relapse was 24%. These encouraging results are the first observations supporting a treosulfan based conditioning regimen in the second AHSCT in MF [9].\n\nThe importance of our present study lies in that it is the first study addressing the long-term follow-up and survival rates of a treosulfan based conditioning regimen in MF patients with relapse after the first transplant. In our study, full donor chimerism was achieved in all patients, and TRM (16% on the 100th day, 31% on the 3rd year), and relapse rates (16% on the 3rd and 5th years) were low with promising survival rates (3 yearly DFS 49%, OS 59%) better than in the previously published data [15].\n\nOur aforementioned low TRM and relapse rates for the second AHSCT with a treosulfan based conditioning regimen are comparable with, if not better than, the TRM and relapse rates of MF patients who underwent Bu/Flu based RIC in the first AHSCT. This previous, prospective multicenter study reported the cumulative incidence of NRM at 1 year as 16%, the relapse rate at 3 years as 22% [4]. A similar, large retrospective registry analysis of the Center for International Blood and Marrow Transplant Research (CIBMTR), that included MF patients that received AHSCT with RIC regimen, the probabilities of OS at 5 years were 47% and the cumulative incidence of NRM and relapse/progression at 5 years were 24% and 48%, respectively [22].\n\nGraft failure is one of the major complications in patients with MF undergoing AHSCT, especially after RIC regimen, with an incidence ranging from 2% to 24% [4,23]. We observed only one primary graft failure in our study. On the 30th day, full chimerism was achieved in 20 out of 26 patients, and after a median of 99 days follow-up, complete chimerism was achieved in the all 26 remaining patients.\n\nSecond AHSCT in MF is not studied in detail in the literature and only case reports and studies with small patient numbers are available [9,10,11]. We previously reported acceptable toxicity and outcomes in a cohort of relapsed patients who underwent a second AHSCT with the majority receiving fludarabine, treosulfan, and ATG-based conditioning. In this study, 13 patients with DLI failure and four patients not suitable for DLI treatment achieved 60% CR and 80% ORR with second AHSCT. Thirteen of 17 patients received treosulfan (36 g/m2) and fludarabine (150 mg/m2) as a conditioning regimen. One-year cumulative incidence of non-relapse mortality for recipients of a second allograft was 6% (95% CI: 0–18%) and the cumulative incidence of relapse was 24%, the 1-year OS and PFS for 17 patients who underwent the second AHSCT was 82% (95% CI: 58–100%) and 70% (95% CI: 35–100%), respectively [9]. These aforementioned results are in line with our current long-term follow-up data.\n\nIn conclusion, our data support a second AHSCT in relapsed, DLI resistant MF patients with a treosulfan based, effective and less toxic conditioning regimen that has long-term low transplant-related mortality and relapse rates.\n\n5. Conclusions\nTreosulfan-based conditioning for second allograft in relapsed myelofibrosis patients resulted in about 50% of the patients in long-term freedom from disease.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor Contributions\nI.K.A. and N.K. designed the study, collected and analyzed data, and wrote the manuscript. E.K., C.W., D.J., S.H., M.C., and F.A. collected data. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Cumulative incidence of treatment related mortality.\n\nFigure 2 Cumulative incidence of relapse.\n\nFigure 3 Disease free survival and overall survival.\n\ncancers-12-03098-t001_Table 1Table 1 Patient characteristics.\n\nNumber of Patients\tn = 33\t\nMedian patient age at AHSCT (years)\t59 years (range: 37–76)\t\nMedian donor age at AHSCT (years)\t40 years (range: 20–66)\t\nRecipient gender\t\n\t\nMale/Female\tn = 19/14\t\nDonor gender\t\n\t\nMale/Female\tn = 26/7\t\nMale patient/female donor\tn = 6\t\nDiagnosis at transplantation\t\n\t\nPrimary myelofibrosis\tn = 12 (36 %)\t\nPost-PV myelofibrosis\tn = 7 (21%)\t\nPost-ET myelofibrosis\tn = 8 (24%)\t\nAcute Myeloid Leukemia\tn = 6 (18%)\t\nDIPSS at transplantation\t\n\t\nLow-Int-1\tn = 6 (18.2 %)\t\nInt-2-High\tn = 16 (48.5%)\t\nCytogenetic analysis\t\n\t\nNormal karyotype\tn = 6\t\nComplex karyotype\tn = 1\t\nOther abnormalities\tn = 4 \t\nStem cell source\t\n\t\nPeripheral blood stem cells\tn = 33\t\nBone marrow \tn = 0\t\nDonor Type\t\n\t\nUnrelated donor\tn = 31\t\nRelated donor \tn = 2 \t\nDonor Status\t\n\t\nSame donor\tn = 4\t\nAlternative donor\tn = 29\t\nHLA-Status\t\n\t\nMatched\tn = 25\t\nMismatched\tn = 8\t\nCMV Status of recipient/donor\t\n\t\n+/+\tn = 23\t\n-/-\tn = 5\t\n+/-\tn = 4\t\n-/+\tn = 1\t\nMedian number of transplanted CD34+ cells/kg BW \t8.0 × 106 (range: 2.56–15.7)\t\nConditioning regimen\t\n\t\nTreosulfan/Fludarabine\tn = 26\t\nFLAMSA/Treosulfan\tn = 4\t\nTreo/AraC/Mitox/Gemtu\tn = 1\t\nTreosulfan/Fludarabine/Thiotepa\tn = 1\t\nTreosulfan/Thiotepa\tn = 1\t\nGVHD prophylaxis\t\n\t\nCSA + MMF\tn = 26\t\nCSA + Methotrexate\tn = 4\t\nTacrolimus and MMF\tn = 3\t\nAbbreviations: AHSCT: allogeneic hematopoietic stem cell transplantation, DIPSS: Dynamic International Prognostic Scoring System, CSA: cyclosporine-A, MMF: mycofenolate mofetil, AraC: Cytosine arabinoside, Mitox: Mitoxantron, Gemtu: Gemtuzumab, GVHD: graft-versus-host disease. Data were presented as median (range).\n\ncancers-12-03098-t002_Table 2Table 2 Results.\n\nMedian time until leukocyte engraftment (days).\t11 days (range, 9–78)\t\nMedian time until thrombocyte engraftment (days)\t14 days (range, 9–119)\t\nResponse Rates (n = 27)\t\n\t\nORR\n mCR\n hCR\n PR\tn = 23 (85%)\n\nn = 19 (70%)\n\nn = 2 (7%)\n\nn = 2 (7%)\t\nCumulative incidence of acute GvHD at day 100 (n = 33)\t\n\t\nAll Grades\n Grade II-IV\n Grade III-IV\t73 ± 10 %\n 56 ± 13 %\n 33 ± 13 % \t\nCumulative incidence of chronic GvHD at 1 year (n = 33)\t\n\t\nModerate or severe \t28 ± 12 %\t\n3-year cumulative incidence of relapse\t16% (CI: 5.5–30.4)\t\nDay 100 treatment related mortality\t16% (CI: 5.5–30.3)\t\n3-year treatment related mortality\t31% (CI: 16–47.7)\t\n3-year disease-free survival\t49% (CI: 27.7–75.2)\t\n5- year disease-free survival \t45% (CI: 23.9–72.9)\t\n3-year overall survival\t59% (CI: 39.1–82)\t\n5- year overall survival\t47% (CI: 27.7–75.2)\t\nAbbreviations: ORR; overall response rate, mCR; molecular complete response, hCR; histo-hematological response; PR; partial response; GVHD; graft-versus-host disease.\n\ncancers-12-03098-t003_Table 3Table 3 The list of infections in the follow-up of AHSCT.\n\nInfections\tNumber of Patients\t\nPneumonia\n Bacterial pneumonia\n Viral pneumonia\n Fungal pneumonia (Aspergillus/Mucor)\n CMV-pneumonia\n H1N1-pneumonia\tn = 13\n\nn = 3\n\nn = 2\n\nn = 5 (4/1)\n\nn = 2\n\nn = 1\t\nCatheter related infection\tn = 5\t\nBlood culture positive septicemia\tn = 9\t\nSepsis\n Catheter related sepsis\n Bacterial Sepsis\tn = 7\n\nn = 2\n\nn = 5\t\nBK/JCV Cystitis\tn = 5\t\nHSV-viremia\tn = 1\t\nHHV-6 infection\tn = 1\t\nNeutropenic Colitis \tn = 1\n==== Refs\nReferences\n1. Barbui T. Barosi G. Birgegard G. Cervantes F. Finazzi G. Griesshammer M. Harrison C. Hasselbalch H.C. Hehlmann R. Hoffman R. Philadelphia-Negative Classical Myeloproliferative Neoplasms: Critical Concepts and Management Recommendations From European LeukemiaNet J. Clin. Oncol. 2011 29 761 770 10.1200/JCO.2010.31.8436 21205761 \n2. Robin M. De Wreede L.C. Wolschke C. Schetelig J. Eikema D.-J. Van Lint M.T. Knelange N.S. Beelen D. Brecht A. Niederwieser D. Long-term outcome after allogeneic hematopoietic cell transplantation for myelofibrosis Haematologica 2019 104 1782 1788 10.3324/haematol.2018.205211 30733269 \n3. Deeg H.J. Bredeson C. Farnia S. Ballen K. Gupta V. Mesa R.A. Popat U. Hari P. Saber W. Seftel M. Hematopoietic Cell Transplantation as Curative Therapy for Patients with Myelofibrosis: Long-Term Success in all Age Groups Biol. Blood Marrow Transplant. 2015 21 1883 1887 10.1016/j.bbmt.2015.09.005 26371371 \n4. Kroeger N. Holler E. Kobbe G. Bornhäuser M. Schwerdtfeger R. Baurmann H. Nagler A. Bethge W. Stelljes M. Uharek L. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: A prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation Blood 2009 114 5264 5270 10.1182/blood-2009-07-234880 19812383 \n5. Kröger N. Alchalby H. Klyuchnikov E. Badbaran A. Hildebrandt Y. Ayuk F. Bacher U. Bock O. Kvasnicka M. Fehse B. JAK2-V617F–triggered preemptive and salvage adoptive immunotherapy with donor-lymphocyte infusion in patients with myelofibrosis after allogeneic stem cell transplantation Blood 2009 113 1866 1868 10.1182/blood-2008-11-190975 19228938 \n6. Rondelli D. Barosi G. Bacigalupo A. Prchal J.T. Popat U. Alessandrino E.P. Spivak J.L. Smith B.D. Klingemann H.G. Fruchtman S. Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia Blood 2005 105 4115 4119 10.1182/blood-2004-11-4299 15671439 \n7. Robin M. Porcher R. Wolschke C. De Fontbrune F.S. Alchalby H. Christopeit M. Cassinat B. Zabelina T. De Latour R.P. Ayuk F. Outcome after Transplantation According to Reduced-Intensity Conditioning Regimen in Patients Undergoing Transplantation for Myelofibrosis Biol. Blood Marrow Transplant. 2016 22 1206 1211 10.1016/j.bbmt.2016.02.019 26970380 \n8. Jain T. Kunze K.L. Temkit M. Partain D.K. Patnaik M.M. Slack J.L. Khera N. Hogan W.J. Roy V. Noel P. Comparison of reduced intensity conditioning regimens used in patients undergoing hematopoietic stem cell transplantation for myelofibrosis Bone Marrow Transplant. 2018 54 204 211 10.1038/s41409-018-0226-1 29795431 \n9. Klyuchnikov E. Holler E. Bornhäuser M. Kobbe G. Nagler A. Shimoni A. Könecke C. Wolschke C. Bacher U. Zander A.R. Donor lymphocyte infusions and second transplantation as salvage treatment for relapsed myelofibrosis after reduced-intensity allografting Br. J. Haematol. 2012 159 172 181 10.1111/bjh.12013 22909192 \n10. McLornan D.P. Szydlo R. Robin M. Van Biezen A. Koster L. Blok H.J.P. Van Lint M.T. Finke J. Vitek A. Carlson K. Outcome of patients with Myelofibrosis relapsing after allogeneic stem cell transplant: A retrospective study by the Chronic Malignancies Working Party of EBMT Br. J. Haematol. 2018 182 418 422 10.1111/bjh.15407 29808926 \n11. Tanvetyanon T. Stiff P. Second allogeneic transplantation using a reduced-intensity preparative regimen for relapsed myelofibrosis Am. J. Hematol. 2004 77 204 205 10.1002/ajh.20156 15389913 \n12. Shimoni A. Hardan I. Shem-Tov N. Rand A. Yerushalmi R. Nagler A. Fludarabine and treosulfan: A novel modified myeloablative regimen for allogeneic hematopoietic stem-cell transplantation with effective antileukemia activity in patients with acute myeloid leukemia and myelodysplastic syndromes Leuk. Lymphoma 2007 48 2352 2359 10.1080/10428190701671051 18067010 \n13. Danylesko I. Shimoni A. Nagler A. Treosulfan-based conditioning before hematopoietic SCT: More than a BU look-alike Bone Marrow Transplant. 2011 47 5 14 10.1038/bmt.2011.88 21478921 \n14. Beelen D.W. Trenschel R. Stelljes M. Groth C. Masszi T. Reményi P. Wagner-Drouet E.-M. Hauptrock B. Dreger P. Luft T. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): A randomised, non-inferiority, phase 3 trial Lancet Haematol. 2019 7 e28 e39 10.1016/S2352-3026(19)30157-7 31606445 \n15. Claudiani S. Marktel S. Piemontese S. Assanelli A. Lupo-Stanghellini M.T. Carrabba M. Guggiari E. Giglio F. De Freitas T. Marcatti M. Treosulfan based reduced toxicity conditioning followed by allogeneic stem cell transplantation in patients with myelofibrosis Hematol. Oncol. 2014 34 154 160 10.1002/hon.2183 25469485 \n16. Przepiorka D. Weisdorf D. Martin P. Klingemann H.G. Beatty P. Hows J. Thomas E.D. 1994 Consensus Conference on Acute GVHD Grading Bone Marrow Transplant. 1995 15 825 828 7581076 \n17. Jagasia M.H. Greinix H.T. Arora M. Williams K.M. Wolff D. Cowen E.W. Palmer J. Weisdorf D. Treister N.S. Cheng G.-S. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report Biol. Blood Marrow Transplant. 2015 21 389 401.e1 10.1016/j.bbmt.2014.12.001 25529383 \n18. Kröger N. Shimoni A. Zabelina T. Schieder H. Panse J. Ayuk F. Wolschke C. Renges H. Dahlke J. Atanackovic D. Reduced-toxicity conditioning with treosulfan, fludarabine and ATG as preparative regimen for allogeneic stem cell transplantation (alloSCT) in elderly patients with secondary acute myeloid leukemia (sAML) or myelodysplastic syndrome (MDS) Bone Marrow Transplant. 2006 37 339 344 10.1038/sj.bmt.1705259 16415898 \n19. Patriarca F. Bacigalupo A. Sperotto A. Isola M. Soldano F. Bruno B. Van Lint M.T. Iori A.P. Santarone S. Porretto F. Allogeneic hematopoietic stem cell transplantation in myelofibrosis: The 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) Haematologica 2008 93 1514 1522 10.3324/haematol.12828 18728030 \n20. Gupta V. Kröger N. Aschan J. Xu W. Leber B. Dalley C. Sabloff M. Lipton J.H. Messner H. Brüne M. A retrospective comparison of conventional intensity conditioning and reduced-intensity conditioning for allogeneic hematopoietic cell transplantation in myelofibrosis Bone Marrow Transplant. 2009 44 317 320 10.1038/bmt.2009.10 19234505 \n21. Shimoni A. Labopin M. Savani B. Hamladji R.-M. Beelen D. Mufti G. Socié G. Delage J. Blaise D. Chevallier P. Intravenous Busulfan Compared with Treosulfan-Based Conditioning for Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia: A Study on Behalf of the Acute Leukemia Working Party of European Society for Blood and Marrow Transplantation Biol. Blood Marrow Transplant. 2018 24 751 757 10.1016/j.bbmt.2017.12.776 29247780 \n22. Gupta V. Malone A.K. Hari P.N. Ahn K.W. Hu Z.-H. Gale R.P. Ballen K.K. Hamadani M. Olavarria E. Gerds A.T. Reduced-Intensity Hematopoietic Cell Transplantation for Patients with Primary Myelofibrosis: A Cohort Analysis from the Center for International Blood and Marrow Transplant Research Biol. Blood Marrow Transplant. 2014 20 89 97 10.1016/j.bbmt.2013.10.018 24161923 \n23. Alchalby H. Yunus D.-R. Zabelina T. Ayuk F. Kröger N. Incidence and risk factors of poor graft function after allogeneic stem cell transplantation for myelofibrosis Bone Marrow Transplant. 2016 51 1223 1227 10.1038/bmt.2016.98 27088376\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2072-6694",
"issue": "12(11)",
"journal": "Cancers",
"keywords": "myelofibrosis; second allogeneic transplant; stem cell transplantation; treosulfan",
"medline_ta": "Cancers (Basel)",
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"nlm_unique_id": "101526829",
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"pubdate": "2020-10-23",
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"title": "Treosulfan-Based Conditioning Regimen for Second Allograft in Patients with Myelofibrosis.",
"title_normalized": "treosulfan based conditioning regimen for second allograft in patients with myelofibrosis"
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"abstract": "Herpes simplex virus 2 (HSV-2) is a very rare cause of central nervous system (CNS) infections. We report a case of a young woman with a left middle cerebral artery (MCA) ischemic stroke. The patient had history of HIV-1 infection, with periods of therapeutic non-compliance. Initial computed tomography (CT) imaging studies showed stenosis of the M1 segment of the left MCA, and magnetic resonance imaging (MRI) confirmed infarction of the MCA territory. Serial transcranial Doppler ultrasound revealed progressive occlusion of the MCA and stenosis of the left anterior cerebral artery. Systemic investigation for other causes of stroke was normal. Lumbar puncture revealed a mildly inflammatory cerebrospinal fluid, and HSV-2 DNA was identified by PCR, with a positive viral load in favor of active replication. No other viral or microbiological infections were identified. MRI angiography confirmed a vasculitic process involving the left carotid artery, and a HSV-2 vasculitis diagnosis was assumed. The patient started acyclovir with improvement of clinical features and imaging abnormalities. In the HIV-infected patient, stroke is a multifactorial common cause of morbidity. The physician should take into account a broad differential diagnosis including rare causes and atypical presentations of common etiologies, including HSV-1 and HSV-2 CNS infection.",
"affiliations": "Neurology, Department of Neurosciences and Mental Health, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal. mlealrato@gmail.com.;Neurology, Department of Neurosciences and Mental Health, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.;Serviço de Doenças Infecciosas, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.;Serviço de Doenças Infecciosas, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.;Neurology, Department of Neurosciences and Mental Health, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.;Neurology, Department of Neurosciences and Mental Health, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.",
"authors": "Leal Rato|Miguel|M|0000-0003-2233-0468;Nunes Vicente|Beatriz|B|;da Cunha|Maria Ribeiro|MR|;Marques|Tiago|T|;Aguiar de Sousa|Diana|D|;Canhão|Patrícia|P|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "United States",
"delete": false,
"doi": "10.1007/s13365-020-00894-5",
"fulltext": null,
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"issn_linking": "1355-0284",
"issue": "26(5)",
"journal": "Journal of neurovirology",
"keywords": "HIV; HSV; Stroke; Stroke in young adults; Vasculitis",
"medline_ta": "J Neurovirol",
"mesh_terms": "D000212:Acyclovir; D023241:Antiretroviral Therapy, Highly Active; D000998:Antiviral Agents; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes; D005260:Female; D015658:HIV Infections; D006561:Herpes Simplex; D018258:Herpesvirus 2, Human; D006801:Humans; D016867:Immunocompromised Host; D020244:Infarction, Middle Cerebral Artery; D000083242:Ischemic Stroke; D018810:Magnetic Resonance Angiography; D010349:Patient Compliance; D014657:Vasculitis; D019562:Viral Load; D055815:Young Adult",
"nlm_unique_id": "9508123",
"other_id": null,
"pages": "805-807",
"pmc": null,
"pmid": "32839946",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Herpes simplex virus 2 vasculitis as cause of ischemic stroke in a young immunocompromised patient.",
"title_normalized": "herpes simplex virus 2 vasculitis as cause of ischemic stroke in a young immunocompromised patient"
} | [
{
"companynumb": "PT-VIIV HEALTHCARE LIMITED-PT2020GSK209315",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ABACAVIR SULFATE"
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{
"abstract": "Renal injury almost always accompanies the multisystem organ failure that precedes cardiac transplantation and renal function is further compromised by the nephrotoxicity of calcineurin inhibitors posttransplant. Renal dysfunction in turn causes significant morbidity and mortality. The development of belatacept was motivated by need for an alternative to calcineurin-based immunosuppression, particularly in renal transplantation where the nephrotoxicity of calcineurin inhibitors reduce graft longevity and adverse cardiovascular effects of calcineurin inhibitors increase overall mortality. In 2011, the FDA approved belatacept for use in renal transplantation. Seven-year data from the multicenter randomized phase III BENEFIT trial, which compared belatacept with cyclosporine in renal transplant recipients, show belatacept therapy offers both improved renal function and 43% risk reduction for the combined endpoint of graft loss and death. At present, belatacept use is predominantly confined to renal transplant recipients; however, reports of belatacept use in other transplant settings are emerging. Here, we describe successful long-term use of belatacept in a kidney-after-heart transplant recipient and review use of belatacept in cardiothoracic and other nonrenal transplant settings.",
"affiliations": "Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH.;Department of Surgery, Emory Transplant Center, Atlanta, GA.;Department of Surgery, Emory Transplant Center, Atlanta, GA.;Department of Surgery, Emory Transplant Center, Atlanta, GA.;Department of Surgery, Emory Transplant Center, Atlanta, GA.",
"authors": "Schenk|Austin D|AD|;Anderson|Douglas J|DJ|;Cole|Robert T|RT|;Badell|Idelberto R|IR|;Larsen|Christopher P|CP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/TXD.0000000000000967",
"fulltext": "\n==== Front\nTransplant DirectTransplant DirectTXDTransplantation Direct2373-8731Wolters Kluwer Health 0000410.1097/TXD.0000000000000967Heart TransplantationDe Novo Belatacept in a Kidney-After-Heart Transplant Recipient Schenk Austin D. MD, PhD1Anderson Douglas J. MD2Cole Robert T. MD2Badell Idelberto R. MD2Larsen Christopher P. MD, DPhil21 Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH.2 Department of Surgery, Emory Transplant Center, Atlanta, GA.Correspondence: Austin D. Schenk MD, PhD, Department of Surgery, Division of Transplantation, The Ohio State University Wexner Medical Center, 395 W 12th Ave, Suite 168, Columbus, OH 43210. (austin.schenk@osumc.edu).1 2020 24 12 2019 6 1 e51520 8 2019 4 11 2019 08 11 2019 Copyright © 2019 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.2019This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Renal injury almost always accompanies the multisystem organ failure that precedes cardiac transplantation and renal function is further compromised by the nephrotoxicity of calcineurin inhibitors posttransplant. Renal dysfunction in turn causes significant morbidity and mortality. The development of belatacept was motivated by need for an alternative to calcineurin-based immunosuppression, particularly in renal transplantation where the nephrotoxicity of calcineurin inhibitors reduce graft longevity and adverse cardiovascular effects of calcineurin inhibitors increase overall mortality. In 2011, the FDA approved belatacept for use in renal transplantation. Seven-year data from the multicenter randomized phase III BENEFIT trial, which compared belatacept with cyclosporine in renal transplant recipients, show belatacept therapy offers both improved renal function and 43% risk reduction for the combined endpoint of graft loss and death. At present, belatacept use is predominantly confined to renal transplant recipients; however, reports of belatacept use in other transplant settings are emerging. Here, we describe successful long-term use of belatacept in a kidney-after-heart transplant recipient and review use of belatacept in cardiothoracic and other nonrenal transplant settings.\n\nOPEN-ACCESSTRUE\n==== Body\nSolid organ transplantation saw enormous gains in short-term graft survival with the advent of calcineurin inhibitors (CNIs) in the 1980s. Paradoxically, CNI-related morbidity, including significant nephrotoxicity, now stands as a leading barrier to long-term graft survival. CNIs are universally used for immunosuppression in cardiac transplantation, and renal injury is common through the induction of chronic allograft nephropathy and interstitial fibrosis and tubular atrophy. Indeed over 10% of heart transplant recipients have a GFR <30 mL/min by 5 years posttransplant, and the risk of ESRD is estimated at 1%–1.5% per year of follow-up.1 CNIs also potentiate diabetes, hypertension, and hyperlipidemia leading to more rampant cardiovascular disease and increased overall mortality in transplant recipients when compared with the general population.2 Despite these known adverse effects, CNIs remain a mainstay of contemporary immunosuppression because few proven alternatives exist.\n\nBelatacept was FDA approved in 2011 for use in renal transplantation as a nonnephrotoxic CNI-alternative for maintenance immunosuppression. Belatacept is a fusion protein composed of the Fc fragment of human IgG1 linked to the extracellular domain of cytotoxic T-lymphocyte-associated antigen 4 that selectively inhibits T-cell activation through co-stimulation blockade. Despite higher rates of early acute rejection, 7-year outcomes demonstrated improved renal function and 43% reduction in the risk of patient death and graft loss in comparison to the CNI cyclosporine.3 CNI-avoidance with belatacept has the additional benefits of equivalent safety and improved cardiovascular and metabolic risk profiles along with lower rates of de novo donor-specific antibody formation in renal transplant recipients.4,5 This favorable toxicity profile and improved long-term outcomes in renal transplantation render belatacept as an attractive alternative immunosuppressant for CNI-avoidance in cardiac transplantation.\n\nTo date, belatacept has been predominantly administered in kidney transplant recipients and scant data describe use in heart transplant recipients. Enderby et al6 reported on use of belatacept in a noncompliant 26-year-old female heart transplant recipient with postpartum cardiomyopathy who experienced 6 episodes of grade 3R rejection associated with de novo DSA within the first 20 months posttransplant. After the initiation of belatacept to mitigate her noncompliance, 2 allograft biopsies during an 8-month period showed no histologic evidence of cellular or humoral rejection. However, the long-term impact of belatacept utilization in this heart transplant recipient could not be ascertained due to her premature death from an unexplained cardiac arrest 2 years and 3 months posttransplant. Recently, Kumar et al7 reported on a 61-year-old female simultaneous heart-liver transplant recipient who required kidney transplant 3 years after SHLT that was converted to belatacept for oliguric DGF, resulting in good function of all 3 allografts 1 year post kidney transplant. Here, we provide the first report of de novo belatacept-based immunosuppression in a kidney-after-heart transplant recipient with excellent long-term renal function.\n\nPRESENTATION OF CASE\nThe patient is a 27-year-old Asian-born female who developed congestive heart failure of unclear etiology at the age of 14. She was born at 38 weeks without perinatal complications, moved to the United States at the age of 6, and had no significant past medical history. Thirty-one days after presentation, she received a 6-antigen disparate heart transplant. Her early posttransplant course was complicated by tamponade, need for mediastinal reexploration, cardiac arrest, transient need for ECMO, and delayed sternal closure. Despite these initial setbacks, she was discharged to home 26 days after heart transplant and continues to have normal cardiac function 11 years later. Pathology from the native explant was suggestive of a “burned out” hypertrophic cardiomyopathy. Daclizumab and methylprednisolone were used for induction therapy. Initial maintenance immunosuppression was with cyclosporine, mycophenolate mofetil, and a steroid taper. After 60 days, cyclosporine was discontinued and tacrolimus therapy was started with an initial trough goal of 8–12 mg/dL.\n\nBefore transplantation, the patient had normal renal function with a serum creatinine of 0.9 mg/dL (Figure 1). She experienced perioperative acute kidney injury at the time of heart transplantation with a maximum serum Cr of 2.0 mg/dL but recovered fully and was discharged with a Cr of 0.9. After discontinuing cyclosporine, tacrolimus trough goals were slowly reduced during posttransplant years 1–5. Renal function remained normal until an acute kidney injury associated with a UTI 2 years posttransplant at which time the serum creatinine reached a maximum value of 3.2 mg/dL. Thereafter, there was residual chronic renal insufficiency, proteinuria, and the serum Cr never fell below 1.3 mg/dL. A native renal biopsy showed glomerular and vascular changes suggestive of acute and chronic thrombotic microangiopathy as well as acute and chronic tubulointerstitial nephritis associated with diffuse mild to moderate interstitial fibrosis and 30% tubular atrophy. At 5 years posttransplant, mild distal pruning of the coronary arteries was observed on a left heart catheterization. This prompted discontinuation of mycophenelate and an attempt to begin sirolimus and wean tacrolimus. Renal function abruptly declined and the treating clinicians feared sirolimus was potentiating the nephrotoxic effects of tacrolimus. Although the original regimen of tacrolimus, mycophenolate, and steroid was restarted renal function never recovered.\n\nFIGURE 1. Serum tacrolimus level, serum creatinine, and cardiac ejection fraction as a function of time following heart and kidney transplantation.\n\nDialysis was initiated 6 years and 2 months post heart transplant and 1 day after her first hemodialysis treatment the patient received a haploidentical living related renal transplant from her father. There were no A, B, or DR alleles shared between the heart and kidney donors. Induction immunosuppression consisted of methylprednisolone and basiliximab. Belatacept, tacrolimus, mycophenolate, and prednisone were initiated for maintenance therapy according to institutional protocol.8 A brief period of delayed graft function was managed with 2 posttransplant hemodialysis sessions. An echocardiogram on POD#5 showed a mildly reduced ejection fraction of 35%–40% and a renal allograft protocol biopsy showed mild acute tubular necrosis. By POD#12 the ejection fraction had recovered to 45%–50% and on POD#13 the patient was discharged to home, off dialysis, on mycophenolate, prednisone, tacrolimus, and once monthly belatacept. The initial tacrolimus trough goal was 4–6 mg/dL.\n\nAfter kidney transplantation, the patient has maintained excellent renal function without any episodes of rejection. The most recent serum Cr 5 years post renal transplant was 0.9 mg/dL. Tacrolimus was slowly weaned and then discontinued in the first 2 years following renal transplant. The current maintenance regimen consists of 5 mg prednisone daily, 750 mg mycophenolic acid twice daily, and 5 mg/kg belatacept monthly. Three protocol myocardial biopsies after kidney transplant have twice shown ISHLT grade 0 pathology and once shown grade 1A pathology. Allomap analyses were also followed in liu of additional cardiac biopsies and scores have yet to exceed 29. The ejection fraction was 50% on the most recent ECHO now >11 years after heart transplant. Aside from chronic sinusitis, the patient has had few complications. With respect to protective immunity the patient has never developed CMV viremia and had a single low-positive EBV titer that spontaneously resolved. At her most recent office visit, a low-positive BK titer was noted. Importantly, she has not developed any detectable donor-specific anti-HLA antibodies.\n\nDISCUSSION\nThe 5-year risk of stage IV or V chronic kidney disease in nonrenal organ transplant recipients is estimated between 7% and 21% with an associated 4-fold increased risk of death.1 It is estimated that 4.6%–8%,9 7.7%,10 and 22%11 of heart, lung, and liver transplant recipients progress to require renal replacement therapy. The need to transplant for CNI-induced renal failure adds to an already overwhelming shortage of donor organs. The renal-sparing properties of belatacept are appealing for heart transplant recipients that suffer from CNI-associated nephrotoxicity, hypertension, hyperlipidemia, and new onset diabetes mellitus after transplant. Additionally, given belatacept’s IV formulation and infusion requirement, transplant centers have the opportunity to better track compliance. Importantly, posttransplant de novo donor-specific antibodies are an increasingly recognized source of graft dysfunction and death following heart transplantation, suggesting the need to reassess immunosuppressant strategies in this population.12 Costimulation blockade remains the most promising agent in this regard, as the risk of de novo donor-specific antibodies is considerably lower with belatacept compared with a CNI-based regimen in the renal transplant population.3 It remains to be determined if this holds true in a nonrenal transplant population.\n\nFew reports exist documenting the use of belatacept following nonrenal solid organ transplants. At the University of Maryland 8 lung transplant recipients were transitioned to belatacept because of acute or chronic renal insufficiency (median GFR 24).13 GFR stabilized in 2 patients and increased in 5 while 1 patient died from multisystem organ failure after only 1 dose of belatacept. During 6 months of follow-up, there was a single instance of mild acute cellular rejection. Hui et al14 describe 24 months of successful use of belatacept in a lung transplant recipient taken off of CNIs because of thrombotic microangiopathy, and Haidar et al15 issue a cautionary note describing fatal invasive tracheobronchiolar aspergillosis in a lung transplant recipient treated with belatacept after developing HUS/TTP on tacrolimus and posterior reversible encephalopathy on cyclosporine.\n\nOne hundred fifty-three liver transplant recipients were treated with belatacept in a phase II randomized trial designed to evaluate the safety and efficacy of belatacept relative to tacrolimus.16 Belatacept use was associated with higher rates of graft loss and death leading to termination of the study after 1 year; however, some speculate that liver disease itself creates a high degree of endogenous immunosuppression that cannot safely be combined with potent costimulatory blockade.17 In a much smaller series, LaMattina et al18 describe safe 1- to 3-month use of belatacept “bridge” therapy in hepatitis C positive liver transplant recipients with perioperative renal dysfunction. Isolated reports of belatacept use in islet19 and pancreas20 transplantation also exist.\n\nBelatacept use in renal transplant recipients has been associated with higher rates of early acute rejection, yet long-term outcomes and renal function remain superior to CNI-based regimens.3 Identifying strategies to overcome this observed belatacept-resistant rejection is an active area of investigation. We have adopted transient CNI therapy as one method to prevent higher rates of acute rejection with belatacept and facilitate improved long-term renal allograft function.8 This alternative belatacept-based strategy reduces rates of early acute rejection to levels equivalent with standard-of-care therapy while still allowing for long-term CNI-free maintenance immunosuppression. While this strategy proved effective in the case reported here, much remains to be determined regarding the use of costimulation blockade in heart transplantation. Clinicians unfamiliar with belatacept should remember that use is constrained to transplant recipients with known EBV-positive serostatus as there is an increased risk of posttransplant lymphoproliferative disease in recipients with negative or unknown EBV serostatus. In addition, clinicians should be aware that progressive multifocal leukoencephalopathy, polyoma-virus associated nephropathy, and other serious infections, though rare, have been associated with belatacept use.\n\nIn summary, there is indisputable need for nonnephrotoxic immunosuppression in all organ transplant recipients. Safety and efficacy of belatacept are proven in renal transplant recipients and selective use in nonrenal transplant recipients has been reported. Here, we describe successful long-term use of de novo belatacept in a young kidney-after-heart transplant recipient who developed CNI-induced renal failure. Clinicians should take a cautious and thoughtful approach when extrapolating results of the BENEFIT trials and considering belatacept use in nonrenal transplant recipients; however, belatacept will likely have utility in many extra-renal transplant settings. Larger comparative studies are needed. This case report highlights belatacept as an option for long-term maintenance immunosuppression in heart transplant recipients and should stimulate interest in clinical trials to prospectively evaluate efficacy.\n\nPublished online 24 December, 2019.\n\nA.D.S., D.J.A., R.T.C., I.R.B. performed article writing/editing. C.P.L. performed article writing/editing and patient care.\n\nC.P.L. is an investigator on BMS sponsored clinical trials. The other authors declare no conflicts of interest.\n==== Refs\nREFERENCES\n1. Ojo AO Held PJ Port FK Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003 349 931 940 12954741 \n2. Wheeler DC Steiger J Evolution and etiology of cardiovascular diseases in renal transplant recipients. Transplantation. 2000 70 11 Suppl SS41 SS45 11152230 \n3. Vincenti F Rostaing L Grinyo J Belatacept and long-term outcomes in kidney transplantation. N Engl J Med. 2016 374 333 343 26816011 \n4. Rostaing L Vincenti F Grinyó J Long-term belatacept exposure maintains efficacy and safety at 5 years: results from the long-term extension of the BENEFIT study. Am J Transplant. 2013 13 2875 2883 24047110 \n5. Vanrenterghem Y Bresnahan B Campistol J Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation. 2011 91 976 983 21372756 \n6. Enderby CY Habib P Patel PC Belatacept maintenance in a heart transplant recipient. Transplantation. 2014 98 e74 e75 25285956 \n7. Kumar D Yakubu I Cooke RH Belatacept rescue for delayed kidney allograft function in a patient with previous combined heart-liver transplant. Am J Transplant. 2018 18 2613 2614 29981184 \n8. Adams AB Goldstein J Garrett C Belatacept combined with transient calcineurin inhibitor therapy prevents rejection and promotes improved long-term renal allograft function. Am J Transplant. 2017 17 2922 2936 28544101 \n9. Wyatt CM Arons RR The burden of acute renal failure in nonrenal solid organ transplantation. Transplantation. 2004 78 1351 1355 15548974 \n10. Rocha PN Rocha AT Palmer SM Acute renal failure after lung transplantation: incidence, predictors and impact on perioperative morbidity and mortality. Am J Transplant. 2005 5 1469 1476 15888056 \n11. Paramesh AS Grosskreutz C Florman SS Thrombotic microangiopathy associated with combined sirolimus and tacrolimus immunosuppression after intestinal transplantation. Transplantation. 2004 77 129 131 14724447 \n12. Smith JD Banner NR Hamour IM De novo donor HLA-specific antibodies after heart transplantation are an independent predictor of poor patient survival. Am J Transplant. 2011 11 312 319 21219570 \n13. Timofte I Terrin M Barr E Belatacept for renal rescue in lung transplant patients. Transpl Int. 2016 29 453 463 26678245 \n14. Hui C Kern R Wojciechowski D Belatacept for maintenance immunosuppression in lung transplantation. J Investig Med High Impact Case Rep. 2014 2 2324709614546866 \n15. Haidar G Crespo M Maximous S Invasive tracheobronchial aspergillosis in a lung transplant recipient receiving belatacept as salvage maintenance immunosuppression: a case report. Transplant Proc. 2016 48 275 278 26915884 \n16. Klintmalm GB Feng S Lake JR Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II randomized study. Am J Transplant. 2014 14 1817 1827 25041339 \n17. Knechtle SJ Adams AB Belatacept: is there BENEFIT for liver transplantation too? Am J Transplant. 2014 14 1717 1718 25041120 \n18. LaMattina JC Jason MP Hanish SI Safety of belatacept bridging immunosuppression in hepatitis C-positive liver transplant recipients with renal dysfunction. Transplantation. 2014 97 133 137 24342980 \n19. Posselt AM Szot GL Frassetto LA Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on T-cell adhesion or costimulation blockade. Transplantation. 2010 90 1595 1601 20978464 \n20. Mujtaba MA Sharfuddin AA Taber T Conversion from tacrolimus to belatacept to prevent the progression of chronic kidney disease in pancreas transplantation: case report of two patients. Am J Transplant. 2014 14 2657 2661 25179306\n\n",
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"title": "De Novo Belatacept in a Kidney-After-Heart Transplant Recipient.",
"title_normalized": "de novo belatacept in a kidney after heart transplant recipient"
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"abstract": "BACKGROUND\nBased on preclinical data for the antitumour effect of zoledronate in osteosarcoma, we assessed whether zoledronate combined with chemotherapy and surgery improved event-free survival in children and adults with osteosarcoma.\n\n\nMETHODS\nIn this randomised, multicentre, open-label, phase 3 trial (OS2006), patients aged between 5 years and 50 years with newly diagnosed high-grade osteosarcoma were randomly assigned to receive standard chemotherapy with or without ten zoledronate intravenous infusions (four preoperative and six postoperative). Adults older than 25 years received 4 mg zoledronate per infusion, patients aged 18-25 years received 0·05 mg/kg for the first two infusions and 4 mg for the remaining eight infusions, and younger patients received 0·05 mg/kg per infusion. Chemotherapy comprised high-dose methotrexate based chemotherapy in patients younger than 18 years, and doxorubicin, ifosfamide, and cisplatin in adults older than 25 years; patients aged 18-25 years were treated with either regime at the discretion of the treating centre. Balanced randomisation between the two groups was done centrally with online randomisation software, based on a minimisation algorithm taking into account centre, age, combined with chemotherapy regimen, and risk group (resectable primary and no metastasis vs other). Patients and investigators were not masked to treatment assignment, but the endpoint adjudication committee members who reviewed suspected early progressions were masked to group allocation. The primary endpoint was event-free survival, estimated from the randomisation to the time of first failure (local or distant relapse, progression, death) or to the last follow-up visit for the patients in first complete remission, analysed on a modified intention-to-treat population, which excluded patients found not to have a malignant tumour after central review. Three interim analyses were planned. This trial is registered with ClinicalTrials.gov, number NCT00470223.\n\n\nRESULTS\nBetween April 23, 2007, and March 11, 2014, 318 patients, median age 15·5 years (range 5·8-50·9), were enrolled from 40 French centres; of whom 158 were assigned to the control group (chemotherapy alone) and 160 to the zoledronate group, including 55 (17%) patients with definite metastases. The trial was stopped for futility after the second interim analysis. With a median follow-up of 3·9 years (IQR 2·7-5·1), 125 events occurred (55 in the control group and 70 in the with zoledronate group). Event-free survival at 3 years for all 315 randomly assigned patients was 60·3% (95% CI 64·5-65·9); 3-year event-free survival was 63·4% (55·2-70·9) for the control group and 57·1% (48·8-65·0) for the zoledronate group. The risk of failure was not reduced and was even marginally higher in the zoledronate group than in the control group (hazard ratio [HR] 1·36 [95% CI 0·95-1·96]; p=0·094). No major increase in severe toxic effects of grade 3 or higher associated with zoledronate, barring expected hypocalcaemia (45 [29%] of 153 participants in the zoledronate group vs ten [6%] of 155 participants in the control group; p<0·0001) and hypophosphataemia (61 [40%] of 151 in the zoledronate group vs 26 [17%] of 156 in the control group; p<0·0001). No significant difference in orthopaedic complications was noted between the two groups (27 in the control group and 29 in the zoledronate group). Two treatment-related deaths were reported (one from cardiomyopathy in the control group and one from multiorgan failure in the zoledronate group before the first zoledronate infusion).\n\n\nCONCLUSIONS\nFrom the results observed in this study, we do not recommend zoledronate in osteosarcoma patients. Further biological studies are required to understand the discordance between the results of OS2006 trial and preclinical data.\n\n\nBACKGROUND\nFrench National Cancer Institute (INCa), Novartis, Chugai, Ligue Nationale contre le Cancer, Fédération Enfants et Santé, Société Française des Cancers et Leucémies de l'Enfant.",
"affiliations": "Medical Oncology Department, Institut Curie, Paris, France. Electronic address: sophie.piperno-neumann@curie.fr.;Paris-Saclay University, Paris-Sud University, CESP, INSERM, Villejuif, France; Biostatistics Unit, Gustave Roussy, Villejuif, France.;UMR 957, INSERM, Université de Nantes, France.;Pediatric Oncology Department, Institut Curie, Paris, France.;Pediatric Oncology Department, Centre Léon Bérard, Lyon, France.;Department of Radiology, CHU La Timone, Marseille, France.;Department of Radiology, Institut Curie, Paris, France.;Pediatric Oncology Department, Centre Oscar Lambret, Lille, France.;Pediatric Oncology Department, CHU La Timone, Marseille, France.;Pediatric Oncology Department, CHU Hautepierre, Strasbourg, France.;Medical Oncology Department, Institut Bergonié, Bordeaux, France.;Pediatric Oncology Department, Hôpital Mère-enfant, Nantes, France.;Medical Oncology Department, Institut de Cancérologie de l'Ouest, Saint Herblain, France.;Medical Oncology Department, Centre Oscar Lambret, Lille, France.;Pediatric Oncology Department, Hôpital Trousseau, Paris, France.;Pathology Department, CHU Toulouse, France.;Pathology Department, Institut Curie, Saint-Cloud, France.;Pediatric Orthopedic Surgery Department, Hôpital Necker Enfants Malades, Paris, France.;CHU Hôtel-Dieu, and INSERM UI957, Nantes, France.;Biostatistics Unit, Gustave Roussy, Villejuif, France.;Unicancer, Paris, France.;Medical Oncology Department Centre Léon Bérard, and Claude Bernard University, Lyon, France.;Department of Children and Adolescents Oncology, Gustave Roussy, Villejuif, France.",
"authors": "Piperno-Neumann|Sophie|S|;Le Deley|Marie-Cécile|MC|;Rédini|Françoise|F|;Pacquement|Hélène|H|;Marec-Bérard|Perrine|P|;Petit|Philippe|P|;Brisse|Hervé|H|;Lervat|Cyril|C|;Gentet|Jean-Claude|JC|;Entz-Werlé|Natacha|N|;Italiano|Antoine|A|;Corradini|Nadège|N|;Bompas|Emmanuelle|E|;Penel|Nicolas|N|;Tabone|Marie-Dominique|MD|;Gomez-Brouchet|Anne|A|;Guinebretière|Jean-Marc|JM|;Mascard|Eric|E|;Gouin|François|F|;Chevance|Aurélie|A|;Bonnet|Naïma|N|;Blay|Jean-Yves|JY|;Brugières|Laurence|L|;|||;|||;|||",
"chemical_list": "D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D004317:Doxorubicin; D002945:Cisplatin; D007069:Ifosfamide",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(16)30096-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "17(8)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin; D003131:Combined Modality Therapy; D004164:Diphosphonates; D004317:Doxorubicin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007069:Ifosfamide; D007093:Imidazoles; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012516:Osteosarcoma; D011379:Prognosis; D015996:Survival Rate; D055815:Young Adult; D000077211:Zoledronic Acid",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "1070-1080",
"pmc": null,
"pmid": "27324280",
"pubdate": "2016-08",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial.",
"title_normalized": "zoledronate in combination with chemotherapy and surgery to treat osteosarcoma os2006 a randomised multicentre open label phase 3 trial"
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"abstract": "Stiff-person syndrome (SPS) is a neurologic disorder characterized by muscle stiffness, rigidity, and muscle spasms, and it can increase a patient's risk for falls. It is recognized as a rare disease with limited clinical guidelines to manage the condition and its symptoms. Currently, there is even less clinical guidance for the management of common comorbid conditions in these patients. This patient case report aims to evaluate the efficacy of various medications for symptom management in a patient with SPS and comorbid psychiatric disorders, specifically bipolar I and panic disorder. Throughout the patient's course of treatment, various medications were trialed, including fluoxetine, hydroxyzine, valproic acid, propranolol, and clonazepam. Ultimately, fluoxetine, hydroxyzine, and propranolol were discontinued due to adverse drug reactions and incomplete symptom resolution. The patient's bipolar I disorder was adequately managed with valproic acid. Once the clonazepam was changed from as-needed to scheduled dosing, the patient's panic disorder and anxiety-triggered spasms were well controlled. The efficacy of benzodiazepines, specifically high doses of diazepam, in alleviating muscle spasms and anxiety in SPS has been demonstrated in the literature. Case reports including patients with SPS that are prescribed selective serotonin reuptake inhibitors provide controversial evidence as some studies report exacerbation of SPS symptoms with prolonged use. As this case report and literature review suggest, patients with SPS and comorbid panic disorder and anxiety-triggered spasms may benefit from the use of benzodiazepines. The use of other medication classes for the treatment of other comorbid psychiatric disorders in a patient with SPS is lacking evidence.",
"affiliations": null,
"authors": "Patel|Karishma|K|https://orcid.org/0000-0002-4660-9810;Stummer|Lauren|L|https://orcid.org/0000-0002-3703-7937;Patel|Krina|K|https://orcid.org/0000-0001-5093-7772",
"chemical_list": null,
"country": "United States",
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"doi": "10.9740/mhc.2020.05.095",
"fulltext": "\n==== Front\nMent Health Clin\nMent Health Clin\nmhcl\nMent Health Clin\nThe Mental Health Clinician\n2168-9709 College of Psychiatric & Neurologic Pharmacists \n\n10.9740/mhc.2020.05.095\nmhcl-10-03-01\nMHC-D-19-00053\nCase Reports\nStiff-person syndrome in a patient with comorbid bipolar and panic disorders: A case report and literature review\nPatel Karishma PharmD1https://orcid.org/0000-0002-4660-9810 Stummer Lauren PharmD, BCPPhttps://orcid.org/0000-0002-3703-7937 Patel Krina PharmD, BCPP3https://orcid.org/0000-0001-5093-7772 1Post-Doctoral Fellow, Genentech in Conjunction with Rutgers Institute for Pharmaceutical Industry Fellowships, Piscataway, New Jersey\n\n2 Clinical Operational Pharmacist, McLean Hospital, Belmont, Massachusetts, lstummer@partners.org3Clinical Pharmacy Specialist, University of Texas Medical Branch, Galveston, Texas\n\nDisclosures: Nothing to disclose.\n\n\n5 2020 \n7 5 2020 \n10 3 95 99\n© 2020 CPNP. The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists.2020This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Stiff-person syndrome (SPS) is a neurologic disorder characterized by muscle stiffness, rigidity, and muscle spasms, and it can increase a patient's risk for falls. It is recognized as a rare disease with limited clinical guidelines to manage the condition and its symptoms. Currently, there is even less clinical guidance for the management of common comorbid conditions in these patients. This patient case report aims to evaluate the efficacy of various medications for symptom management in a patient with SPS and comorbid psychiatric disorders, specifically bipolar I and panic disorder. Throughout the patient's course of treatment, various medications were trialed, including fluoxetine, hydroxyzine, valproic acid, propranolol, and clonazepam. Ultimately, fluoxetine, hydroxyzine, and propranolol were discontinued due to adverse drug reactions and incomplete symptom resolution. The patient's bipolar I disorder was adequately managed with valproic acid. Once the clonazepam was changed from as-needed to scheduled dosing, the patient's panic disorder and anxiety-triggered spasms were well controlled. The efficacy of benzodiazepines, specifically high doses of diazepam, in alleviating muscle spasms and anxiety in SPS has been demonstrated in the literature. Case reports including patients with SPS that are prescribed selective serotonin reuptake inhibitors provide controversial evidence as some studies report exacerbation of SPS symptoms with prolonged use. As this case report and literature review suggest, patients with SPS and comorbid panic disorder and anxiety-triggered spasms may benefit from the use of benzodiazepines. The use of other medication classes for the treatment of other comorbid psychiatric disorders in a patient with SPS is lacking evidence.\n\nstiff-person syndromestiff-man syndromeSPSbipolar disorderpanic disorderbenzodiazepinesclonazepamselective serotonin reuptake inhibitorsSSRIsfluoxetineCitationHow to cite: Patel K, Stummer L, Patel K. Stiff-person syndrome in a patient with comorbid bipolar and panic disorders: A case report and literature review. Ment Health Clin [Internet].\n==== Body\nBackground\nStiff-person syndrome (SPS), also known as stiff-man syndrome, was first reported in 1956.1 It is an uncommon neurologic disorder characterized by muscle stiffness, rigidity, and muscle spasms, and it increases the patient's risk of falls. Stiff-person syndrome occurs in women 2 to 3 times more frequently than men, and the prevalence is approximately 1 in 1 million.2,3 Most patients with SPS present with autoantibodies against glutamic acid decarboxylase. This can lead to inhibition of glutamic acid decarboxylase and gamma-amino butyric acid (GABA) synthesis. Gamma-amino butyric acid is the brain's primary inhibitory neurotransmitter, and a decrease in GABA may cause muscle hyperactivity.3\n\nIn addition to neurological abnormalities, patients with SPS are frequently diagnosed with psychiatric disorders, such as depression, anxiety, and phobias.4 In 1 study5 including 43 patients with SPS, 44% of patients reported agoraphobia and other situation-specific phobias. Currently, pharmacologic management of comorbid psychiatric disorders in patients with SPS is not well defined. The aim of this case report is to review both the treatment of SPS in a patient with comorbid psychiatric disorders and the management of psychiatric disorders in a patient with SPS. Specific psychiatric disorders that are reviewed in this case report are bipolar I and panic disorder.\n\nCase Report\nThe patient was a 58-year-old white female with past medical history significant for SPS, panic disorder with agoraphobia, bipolar I disorder, posttraumatic stress disorder, type 1 diabetes, hypothyroidism, and chronic leukemia. Within the year preceding the initial visit, she had fallen 5 times. Social history for this patient included both emotional and physical abuse. She reported smoking 1 pack of cigarettes per day starting at age 13 but quit smoking in 2011. The patient denied excessive use of caffeine or alcohol and denied any illicit substance use. The time between visits was approximately 1 month.\n\nShe presented to an outpatient behavioral health clinic for an initial appointment (Table) with the following medication regimen: valproic acid 1000 mg extended-release at bedtime for bipolar I disorder, clonazepam 0.5 mg twice daily as needed for panic disorder, insulin lispro 5 units 3 times daily before meals and insulin glargine 18 units at bedtime for type 1 diabetes, and levothyroxine 100 mcg daily for hypothyroidism (Table). The patient's primary concern for this visit was her SPS, which she believed was being exacerbated by her uncontrolled panic disorder and vice versa. During this visit, she described stiffening episodes during which she could not move her legs because they felt “too heavy” and was stuck midstride. The patient presented with tremors, stiffness, and jerking movements throughout her appointment. She used a quad cane and could walk steadily.\n\nTABLE Timeline of patient's clinical course\n\nVisit No.a\tVisit Summaries\t\n1\tIntake appointment\n\nCurrently prescribed medications: valproic acid 1000 mg HS, insulin lispro 5 units TID before meals, insulin glargine 18 units HS, levothyroxine 100 mcg daily, clonazepam 0.5 mg BID as needed\n\nNumber of PRNs used per month: 12 tablets of clonazepam 0.5 mg\n\nReported psychiatric symptoms: uncontrolled panic disorder, unspecified symptoms\n\nReported SPS symptoms: stiffening, unable to move legs, getting stuck midstride\n\nMedication adjustments made: added fluoxetine 10 mg daily and hydroxyzine 25 mg PRN\n\n\n\t\n2\tCurrently prescribed medications: valproic acid 1000 mg HS, insulin lispro 5 units TID before meals, insulin glargine 18 units HS, levothyroxine 100 mcg daily, clonazepam 0.5 mg BID as needed, fluoxetine 10 mg daily, hydroxyzine 25 mg PRN\n\nNumber of PRNs used per month: 10 tablets of clonazepam 0.5 mg, fewer than 10 capsules of hydroxyzine 25 mg\n\nReported psychiatric symptoms: improved mood and decreased anxiety\n\nReported SPS symptoms: none documented\n\nMedication adjustments made: increased fluoxetine to 20 mg daily\n\n\n\t\n3\tCurrently prescribed medications: valproic acid 1000 mg HS, insulin lispro 5 units TID before meals, insulin glargine 18 units HS, levothyroxine 100 mcg daily, clonazepam 0.5 mg BID as needed, fluoxetine 20 mg daily, hydroxyzine 25 mg PRN\n\nNumber of PRNs used per month: 10 tablets of clonazepam 0.5 mg, fewer than 10 capsules of hydroxyzine 25 mg\n\nReported psychiatric symptoms: improved sleep quality\n\nReported SPS symptoms: decreased tremulousness\n\nMedication adjustments made: fluoxetine increased to 40 mg daily\n\n\n\t\n4\tCurrently prescribed medications: valproic acid 1000 mg HS, insulin lispro 5 units TID before meals, insulin glargine 18 units HS, levothyroxine 100 mcg daily, clonazepam 0.5 mg BID as needed, fluoxetine 40 mg daily, hydroxyzine 25 mg PRN\n\nNumber of PRNs used per month: 10 tablets of clonazepam 0.5 mg, fewer than 10 capsules of hydroxyzine 25 mg\n\nReported psychiatric symptoms: decreased anxiety\n\nReported SPS symptoms: increased stiffness and tremor while eating\n\nMedication adjustments made: clonazepam 0.5 mg BID PRN changed to BID scheduled\n\n\n\t\n5\tCurrently prescribed medications: valproic acid 1000 mg HS, insulin lispro 5 units TID before meals, insulin glargine 18 units HS, levothyroxine 100 mcg daily, clonazepam 0.5 mg BID, fluoxetine 40 mg daily, hydroxyzine 25 mg PRN\n\nNumber of PRNs used per month: fewer than 10 capsules of hydroxyzine 25 mg\n\nReported psychiatric symptoms: decreased panic symptoms, patient appeared brighter and more calm\n\nReported SPS symptoms: decreased stiffness\n\nMedication adjustments made: no medication changes\n\n\n\t\n6\tCurrently prescribed medications: valproic acid 1000 mg HS, insulin lispro 5 units TID before meals, insulin glargine 18 units HS, levothyroxine 100 mcg daily, clonazepam 0.5 mg BID, fluoxetine 40 mg daily, hydroxyzine 25 mg PRN\n\nNumber of PRNs used per month: fewer than 10 capsules of hydroxyzine 25 mg\n\nReported psychiatric symptoms: patient reports, “I am doing the best on these medications and they are working for me.”\n\nReported SPS symptoms: none documented\n\nMedication adjustments made: no medication changes\n\n\t\n7\tCurrently prescribed medications: valproic acid 1000 mg HS, insulin lispro 5 units TID before meals, insulin glargine 18 units HS, levothyroxine 100 mcg daily, clonazepam 0.5 mg BID, fluoxetine 40 mg daily, hydroxyzine 25 mg PRN\n\nNumber of PRNs used per month: fewer than 10 capsules of hydroxyzine 25 mg\n\nReported psychiatric symptoms: patient reports “feeling like a zombie” and hydroxyzine making her “feel funny”\n\nReported SPS symptoms: none documented\n\nMedication adjustments made: discontinued fluoxetine 40 mg daily and hydroxyzine 25 mg as needed by patient, added propranolol 10 mg BID for tremors\n\n\n\t\n8\tCurrently prescribed medications: valproic acid 1000 mg HS, insulin lispro 5 units TID before meals, insulin glargine 18 units HS, levothyroxine 100 mcg daily, clonazepam 0.5 mg BID, propranolol 10 mg BID\n\nNumber of PRNs used per month: none\n\nReported psychiatric symptoms: less anxiety due to dietary changes\n\nReported SPS symptoms: less stiffness due to dietary changes\n\nMedications adjustments: discontinued propranolol 10 mg BID due to edema\n\n\t\nBID = twice daily; HS = bedtime; PRN = as needed; SPS = stiff-person syndrome; TID = three times daily.\n\na The time between visits was approximately 1 month.\n\nDuring the initial appointment, fluoxetine 10 mg daily and hydroxyzine 25 mg as needed were added to her medication regimen. During the second visit, she presented with less anxiety. Because the fluoxetine seemed to be improving symptoms related to mood and anxiety, it was increased to 20 mg daily. When the patient presented to the clinic on the following visit, she reported improved sleep quality and a reduction in tremors. At this time, the fluoxetine dose was increased to 40 mg daily.\n\nAfter the fluoxetine dose was increased to 40 mg daily, the patient reported an improvement in her symptoms related to anxiety, but she had been feeling more stiff and tremulous when attempting to eat. Clonazepam 0.5 mg twice daily as needed was changed to scheduled dosing for panic disorder and anxiety-triggered spasms. Prior to this change, the patient was utilizing 10 to 12 tablets of clonazepam 0.5 mg each month. At the following appointment, the patient reported that clonazepam was beneficial for morning stiffness and reducing panic symptoms that occur at the onset of stiffness. It was also reported that the patient seemed brighter and calmer with the increase in her fluoxetine dose to 40 mg daily. During the sixth visit, the patient stated, “I am doing the best on these medications, and they are working for me.” She confirmed medication compliance and denied side effects. At the seventh visit, she endorsed to noncompliance with fluoxetine due to “feeling like a zombie” and hydroxyzine due to “funny feeling.” She was taking less than 10 capsules of hydroxyzine each month prior to discontinuing both the hydroxyzine and the fluoxetine on her own. Propranolol 10 mg twice daily was added for tremors and high blood pressure; however, she self-discontinued due to edema. The patient reports reduced frequency of panic attacks and less anxiety and stiffness, which she attributes to unspecified diet changes.\n\nDiscussion\nAlthough evidence is limited, previous case reports and studies have demonstrated the safe and effective use of antidepressant and anxiolytic medications in treating patients with SPS and comorbid bipolar and panic disorders. The initial regimen included 3 different classes of medications, which were intended to alleviate symptoms related to bipolar I and panic disorder. Selective serotonin reuptake inhibitors (SSRIs) are recommended as first-line treatment for panic disorder by the American Psychiatric Association and have also demonstrated efficacy for bipolar depression.6,7 The anxiety and depression symptoms in a patient with SPS may be a result of reduced or impaired GABAergic inhibition; however, in the case of our patient, the symptoms exist comorbidly.8 Our patient also exhibited a level of agoraphobia in the presence of her motor symptoms, which may have increased her risk of falls.5 Phobias may be managed with the use of benzodiazepines and SSRIs.9 Due to the rarity of SPS with comorbid bipolar and panic disorders, few studies have been published to support the use of antidepressants, particularly SSRIs, for symptom management. The efficacy of benzodiazepines in the treatment of SPS has been demonstrated in literature with results similar to the outcome of this case.2 The National Institute of Neurological Disorders and Stroke has conducted research related to SPS and has shown that patients with SPS respond to high doses of diazepam.10 Benzodiazepines enhance the GABA-inhibitory effect at receptors, alleviating muscle spasms and anxiety; this class is considered the first therapeutic option for SPS. The National Institute of Neurological Disorders and Stroke does not include any data or information regarding the treatment of patients with SPS and comorbid psychiatric illness.\n\nInitially, fluoxetine and hydroxyzine were efficacious in the management of the patient's SPS symptoms, panic disorder, and depressive symptoms related to bipolar I disorder. The gradual titration of fluoxetine was intended to avoid an increase in anxiety symptoms, which can be caused by the activating property of serotonergic agents.11 Although the patient was prescribed fluoxetine 40 mg, she reported using clonazepam as needed more frequently due to the lack of full symptom management, which led to clonazepam 0.5 mg becoming scheduled twice daily. This could have been due to the delayed onset of action of SSRIs as these medications can take 4 to 8 weeks to reach their full potential.11 Both fluoxetine and hydroxyzine were eventually discontinued from our patient's medication regimen due to side effects, such as sedation, and lack of full symptom resolution.\n\nA previous case report, completed by Culav-Sumić et al,8 included a patient with SPS and depressive symptoms that was initially treated with paroxetine. Despite an adequate duration of treatment and dose, the patient's anxiety and depression symptoms worsened and eventually remained resistant to medication trials, including the high-dose diazepam regimen. Another study completed by Benavides et al12 compiled 4 case reports, which highlighted the exacerbation of SPS symptoms related to the starting dose of serotonin-norepinephrine reuptake inhibitors. These patients reported “worsening spasms” and “mental fogging” despite the addition of supplemental treatment with benzodiazepines and intrathecal baclofen. Currently, there are no recommendations for the use of SSRIs or serotonin-norepinephrine reuptake inhibitors in patients with SPS. Based on evidence from previous studies and our case report, use of these medication classes seems controversial, and more studies are needed to assess their use in patients with SPS.\n\nAnticipatory anxiety is common in patients with SPS, and frightening situations may precipitate stiffness and spasms leading to falls, which has been reported in this patient case.12 Early recognition of stressors is essential in developing a strategy to effectively manage and reduce the risk of falls. A prior case report13 of a 51-year-old female with progressing SPS and generalized anxiety disorder has supported the hypothesis that the use of benzodiazepines is effective by enhancing GABAergic inhibitory transmission. Although there are confounding factors, it is thought that the increased frequency of clonazepam use in this patient resulted in improvement of the patient's symptoms with less frequency of stiffness and anxiety. Clonazepam 2.5 to 6 mg is the most commonly used dose for patients with SPS symptoms overall.3\n\nThroughout the patient's treatment at the outpatient behavioral health clinic, the patient was followed by the clinical pharmacists. Because SPS is a relatively rare condition, the clinical pharmacists were essential in researching pharmacologic treatment options for patients with SPS and comorbid psychiatric illnesses. As discussed in this case report, there is not a clear guideline on how to manage both SPS and psychiatric illnesses concurrently. The clinical pharmacists were able to use their clinical judgment to help the treatment team determine what medication changes should be made.\n\nConclusion\nOur patient with SPS and comorbid bipolar and panic disorder benefited most from benzodiazepine therapy. The treatment regimen with an SSRI failed to adequately maintain the patient's symptoms and led to a need for increased frequency of benzodiazepine use. This antianxiety class of medication has shown in this patient to alleviate psychiatric symptoms associated with SPS although more studies are needed to define optimal management for a patient with SPS with comorbid bipolar and panic disorder. It is important for providers to discuss patient goals and expectations prior to, during, and at discontinuation of medication management. The role of a clinical pharmacist is essential in monitoring and managing patient history and management.\n==== Refs\nReferences\n1 Moersch FP Woltman HW Progressive fluctuating muscular rigidity and spasm (“stiff-man” syndrome); report of a case and some observations in 13 other cases Proc Staff Meet Mayo Clin 1956 31 15 421 7 PubMed PMID: 13350379 13350379 \n2 Baizabal-Carvallo JF Jankovic J Stiff-person syndrome: insights into a complex autoimmune disorder J Neurol Neurosurg Psychiatry 2015 86 8 840 8 DOI: 10.1136/jnnp-2014-309201 PubMed PMID: 25511790 25511790 \n3 Dalakas MC Stiff person syndrome: advances in pathogenesis and therapeutic interventions Curr Treat Options Neurol 2009 11 2 102 10 DOI: 10.1007/s11940-009-0013-9 PubMed PMID: 19210912 19210912 \n4 Tinsley JA Barth EM Black JL Williams DE Psychiatric consultations in stiff-man syndrome J Clin Psychiatry 1997 58 10 444 9 DOI: 10.4088/jcp.v58n1007 PubMed PMID: 9375596 9375596 \n5 Henningsen P Specific phobia is a frequent non-motor feature in stiff man syndrome J Neurol Neurosurg Psychiatry 2003 74 4 462 5 DOI: 10.1136/jnnp.74.4.462 PubMed PMID: 12640064 PubMed Central PMCID: PMC1738373 12640064 \n6 American Psychiatric Association [Internet] Treatment of patients with panic disorder [cited 2019 Aug]. Available from: http://www.psychiatryonline.com/pracGuide/pracGuideTopic_9.aspx \n7 Yatham LN Kennedy SH Parikh SV Schaffer A Beaulieu S Alda M Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013 Bipolar Disord 2013 15 1 1 44 DOI: 10.1111/bdi.12025 PubMed PMID: 23237061 23237061 \n8 Culav-Sumić J Bosnjak I Pastar Z Jukić V Anxious depression and the stiff-person plus syndrome Cogn Behav Neurol 2008 21 4 242 5 DOI: 10.1097/WNN.0b013e318185e6d2 PubMed PMID: 19057174 19057174 \n9 Choy Y Fyer AJ Lipsitz JD Treatment of specific phobia in adults Clin Psychology Rev 2007 27 3 266 86 DOI: 10.1016/j.cpr.2006.10.002 PubMed PMID: 17112646 \n10 Kennedy SH Lam RW McIntyre RS Tourjman SV Bhat V Blier P Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3 Pharmacological Treatments. Can J Psychiatry 2016 61 9 540 60 DOI: 10.1177/0706743716659417 PubMed PMID: 27486148 PubMed Central PMCID: PMC4994790 27486148 \n11 Zdziarski P A case of stiff person syndrome: immunomodulatory effect of benzodiazepines: successful rituximab and tizanidine therapy Medicine (Baltimore) 2015 94 23 e954 DOI: 10.1097/MD.0000000000000954 PubMed PMID: 26061327 26061327 \n12 Benavides DR Newsome SD Serotonin-norepinephrine reuptake inhibitors may exacerbate stiff-person syndrome Neurol Neuroimmunol Neuroinflamm 2016 3 6 e281 DOI: 10.1212/NXI.0000000000000281 PubMed PMID: 27606356 PubMed Central PMCID: PMC5004527 27606356 \n13 Cerqueira ACR de Bezerra JMF Rozenthal M Nardi AE Stiff-person syndrome and generalized anxiety disorder Arq Neuropsiquiatr 2010 68 4 659 61 DOI: 10.1590/S0004-282X2010000400036 PubMed PMID: 20730330 20730330\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2168-9709",
"issue": "10(3)",
"journal": "The mental health clinician",
"keywords": "SPS; SSRIs; benzodiazepines; bipolar disorder; clonazepam; fluoxetine; panic disorder; selective serotonin reuptake inhibitors; stiff-man syndrome; stiff-person syndrome",
"medline_ta": "Ment Health Clin",
"mesh_terms": null,
"nlm_unique_id": "101728585",
"other_id": null,
"pages": "95-99",
"pmc": null,
"pmid": "32420007",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports",
"references": "27486148;27606356;26061327;9375596;25511790;13350379;23237061;12640064;19210912;19057174;20730330;17112646",
"title": "Stiff-person syndrome in a patient with comorbid bipolar and panic disorders: A case report and literature review.",
"title_normalized": "stiff person syndrome in a patient with comorbid bipolar and panic disorders a case report and literature review"
} | [
{
"companynumb": "US-MLMSERVICE-20200528-2323107-1",
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"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
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{
"abstract": "Chronic rhinosinusitis (CRS) is a frequently observed condition in patients with immunodeficiency secondary to tumor necrosis factor alpha inhibitors (TNFαis). The histologic features of CRS caused by TNFαis have yet to be determined and may have important implications in understanding the pathophysiology of the disease process.\n\n\n\nA structured histopathology report was used to analyze sinus tissue removed during functional endoscopic sinus surgery (FESS). These structured histopathology variables were compared among patients with CRS on TNFαi (CRSαi), CRS without nasal polyps (CRSsNP) patients, and CRS with nasal polyps (CRSwNP) patients.\n\n\n\nEighteen CRSαi, 91 CRSwNP, and 113 CRSsNP patients undergoing FESS were analyzed. Compared to CRSsNP, CRSαi patients exhibited increased mucosal ulceration (16.7% vs 0.9%, p < 0.008), increased fibrosis (100% vs 34.5%, p < 0.001), and increased presence of Charcot-Leiden crystals (16.7% vs 0%, p < 0.002). Compared to CRSwNP, CRSαi patients demonstrated increased fibrosis (100% vs 54.9%, p < 0.001), decreased presence of subepithelial edema (44.4% vs 69.2% p < 0.043), decreased eosinophil aggregates (22.2% vs 47.3% p < 0.042), and fewer eosinophils per high-power field (44.4% vs 73.6%, p < 0.017).\n\n\n\nCRSαi exhibits structured histopathology more similar to CRSsNP. In the appropriate clinical context, it may be reasonable that the medical regimen for these patients be focused on a more antineutrophilic, macrolide-based approach. This study provides insight into the inflammatory environment of patients with CRSαi and may have implications for disease management.",
"affiliations": "Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA.;Department of Pathology, University of Pennsylvania, Philadelphia, PA.;Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA.;Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA.;Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA.;Department of Otorhinolaryngology-Head and Neck Surgery, Rush University Medical Center, Chicago, IL.;Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA.;Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA.;Department of Otorhinolaryngology-Head and Neck Surgery, Rush University Medical Center, Chicago, IL.;Department of Otolaryngology-Head and Neck Surgery, University of California, Irvine, Irvine, CA.;Department of Otorhinolaryngology-Head and Neck Surgery, Rush University Medical Center, Chicago, IL.;Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA.;Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA.;Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA.;Department of Pathology, University of Pennsylvania, Philadelphia, PA.;Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA.",
"authors": "Papagiannopoulos|Peter|P|;Devins|Kyle|K|;Tong|Charles Ching Lick|CCL|0000-0002-4471-5134;Yver|Christina|C|;Patel|Neil N|NN|0000-0003-1365-9130;Kuhar|Hannah N|HN|0000-0003-4276-1193;Bosso|John V|JV|;Kohanski|Michael A|MA|;Tajudeen|Bobby A|BA|;Kuan|Edward C|EC|0000-0003-3475-0718;Batra|Pete S|PS|;Cohen|Noam A|NA|;Kennedy|David W|DW|;Palmer|James N|JN|;Montone|Kathy|K|;Adappa|Nithin D|ND|",
"chemical_list": "D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha",
"country": "United States",
"delete": false,
"doi": "10.1002/alr.22462",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2042-6976",
"issue": "10(1)",
"journal": "International forum of allergy & rhinology",
"keywords": "pathology; sinusitis; therapeutics; treatment outcome; tumor necrosis factor alpha",
"medline_ta": "Int Forum Allergy Rhinol",
"mesh_terms": "D002908:Chronic Disease; D004724:Endoscopy; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D009298:Nasal Polyps; D010256:Paranasal Sinuses; D010641:Phenotype; D012220:Rhinitis; D012852:Sinusitis; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101550261",
"other_id": null,
"pages": "23-28",
"pmc": null,
"pmid": "31794110",
"pubdate": "2020-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Chronic rhinosinusitis precipitated by tumor necrosis factor alpha inhibitors is the phenotype of chronic rhinosinusitis without nasal polyps.",
"title_normalized": "chronic rhinosinusitis precipitated by tumor necrosis factor alpha inhibitors is the phenotype of chronic rhinosinusitis without nasal polyps"
} | [
{
"companynumb": "US-CELLTRION INC.-2020US019046",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Background The thiopurine S-methyltransferase (TPMT)/azathioprine (AZA) gene-drug pair is one of the most well-known pharmacogenetic markers. Despite this, few studies investigated the implementation of TPMT testing and the combined evaluation of genotype and phenotype in multidisciplinary clinical settings where patients are undergoing chronic therapy with AZA. Methods A total of 356 AZA-treated patients for chronic autoimmune diseases were enrolled. DNA was isolated from whole blood and the samples were analyzed for the c.460G>A and c.719A>G variants by the restriction fragment length polymorphism (RFLP) technique and sequenced for the c.238G>C variant. The TPMT enzyme activity was determined in erythrocytes by a high-performance liquid chromatography (HPLC) assay. Results All the patients enrolled were genotyped while the TPMT enzyme activity was assessed in 41 patients. Clinical information was available on 181 patients. We found no significant difference in the odds of having adverse drug reactions (ADRs) in wild-type patients and variant allele carriers, but the latter had an extra risk of experiencing hematologically adverse events. The enzyme activity was significantly associated to genotype. Conclusions TPMT variant allele carriers have an extra risk of experiencing hematologically adverse events compared to wild-type patients. Interestingly, only two out of 30 (6.6%) patients had discordant results between genotype, phenotype and onset of ADRs.",
"affiliations": "Department of Laboratory Medicine, Medical Genetics, ASST Niguarda Hospital, Piazza Ospedale Maggiore, 3-20162 - Milan, Italy, Tel. +39 0264442803.;Department of Laboratory Medicine, Medical Genetics, ASST Niguarda Hospital, Milan, Italy.;Department of Internal Medicine, University of Genova, Genova, Italy.;Department of Internal Medicine, University of Genova, Genova, Italy.;Department of Internal Medicine, University of Genova, Genova, Italy.;Department of Internal Medicine, University of Genova, Genova, Italy.;Department of Laboratory Medicine, Medical Genetics, ASST Niguarda Hospital, Milan, Italy.;University of Milan, Department of Oncology and Onco-Hematology, Postgraduate School of Clinical Pharmacology and Toxicology, Milan, Italy.;Department of Laboratory Medicine, ASST Niguarda Hospital, Milan, Italy.;Department of Laboratory Medicine, Medical Genetics, ASST Niguarda Hospital, Milan, Italy.;Department of Laboratory Medicine, ASST Niguarda Hospital, Milan, Italy.",
"authors": "Rucci|Francesco|F|https://orcid.org/0000-0003-0965-7191;Cigoli|Maria Sole|MS|;Marini|Valeria|V|;Fucile|Carmen|C|;Mattioli|Francesca|F|;Robbiano|Luigi|L|;Cavallari|Ugo|U|;Scaglione|Francesco|F|;Perno|Carlo F|CF|;Penco|Silvana|S|;Marocchi|Alessandro|A|",
"chemical_list": "D008780:Methyltransferases; C000628225:TPMT protein, human; D001379:Azathioprine",
"country": "Germany",
"delete": false,
"doi": "10.1515/dmpt-2018-0037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2363-8915",
"issue": "34(1)",
"journal": "Drug metabolism and personalized therapy",
"keywords": "TPMT enzyme activity; TPMT genotyping; azathioprine; personalized medicine; pharmacogenetics; thiopurine S-methyltransferase (TPMT)",
"medline_ta": "Drug Metab Pers Ther",
"mesh_terms": "D001327:Autoimmune Diseases; D001379:Azathioprine; D002851:Chromatography, High Pressure Liquid; D002908:Chronic Disease; D004912:Erythrocytes; D005260:Female; D005838:Genotype; D006801:Humans; D007558:Italy; D008297:Male; D008780:Methyltransferases; D010641:Phenotype",
"nlm_unique_id": "101653409",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30840585",
"pubdate": "2019-03-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Combined evaluation of genotype and phenotype of thiopurine S-methyltransferase (TPMT) in the clinical management of patients in chronic therapy with azathioprine.",
"title_normalized": "combined evaluation of genotype and phenotype of thiopurine s methyltransferase tpmt in the clinical management of patients in chronic therapy with azathioprine"
} | [
{
"companynumb": "IT-SHIRE-IT201917163",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3",
... |
{
"abstract": "Pyridoxine (vitamin B6) is an essential vitamin playing a crucial role in amino acid metabolism. Pyridoxine is used for isoniazid side-effects prevention, pyridoxine-dependent epilepsy treatment and cystathionine beta-synthase deficiency (homocystinuria) treatment. However, vitamin B6 hypervitaminosis is neurotoxic and may provoke a progressive sensory neuronopathy (sensory ganglionopathy), usually when daily uptake is above 50 mg. We describe the case of a 30-year-old patient with homocystinuria who was treated with pyridoxine 1250-1750 mg/day for 20 years and developed progressive sensory neuropathy with ataxia and impaired sensation in the extremities. Electrodiagnostic testing demonstrated non-length-dependent abnormalities of sensory nerve potentials, and sensory ganglionopathy was diagnosed. Pyridoxine dosage was reduced to 500 mg/day, resulting in the disappearance of sensory symptoms and ataxia, and the normalisation of sensory nerve potentials. Our case indicates that pyridoxine-induced sensory ganglionopathy may be reversible, even after prolonged ingestion of high doses of vitamin B6 for more than 20 years.",
"affiliations": "Neurologie, Hopitaux universitaires de Strasbourg, Strasbourg, France.;Medecine Interne, Hopitaux universitaires de Strasbourg, Strasbourg, France.;Medecine Interne, Hopitaux universitaires de Strasbourg, Strasbourg, France.;Neurologie, Hopitaux universitaires de Strasbourg, Strasbourg, France.",
"authors": "Echaniz-Laguna|Andoni|A|;Mourot-Cottet|Rachel|R|;Noel|Esther|E|;Chanson|Jean-Baptiste|JB|",
"chemical_list": "D014815:Vitamins; D011736:Pyridoxine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225059",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "contraindications and precautions; peripheral nerve disease; vitamins and supplements",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D001259:Ataxia; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy; D005260:Female; D006712:Homocystinuria; D006801:Humans; D011115:Polyneuropathies; D011736:Pyridoxine; D020127:Recovery of Function; D019966:Substance-Related Disorders; D016896:Treatment Outcome; D014815:Vitamins",
"nlm_unique_id": "101526291",
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"pmid": "29954767",
"pubdate": "2018-06-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15318336;28583326;25137514;6380540;10341670;25056196;6308447;8444262;18060778;28716455;29737502;27778219",
"title": "Regressive pyridoxine-induced sensory neuronopathy in a patient with homocystinuria.",
"title_normalized": "regressive pyridoxine induced sensory neuronopathy in a patient with homocystinuria"
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"abstract": "This report was written to describe a case of unilateral brimonidine-induced conjunctival lichen planus. Because the ophthalmic examination indicated chronic conjunctivitis or drug-induced pseudopemphigoid, the patient underwent thorough ophthalmic and systemic examinations, as well as conjunctival biopsy and direct immunofluorescence studies. A 71-year-old woman with unilateral left eye findings of chronic conjunctivitis was referred to our Ophthalmology Department. The patient reported that chronic conjunctivitis began shortly after she initiated use of topical brimonidine. Ophthalmic examination revealed foreshortening of the inferior fornix and symblepharon. Conjunctival biopsy revealed submucous lymphocytes and shaggy distribution of fibrinogen on direct immunofluorescence; this was suggestive of ocular lichen planus. No other systemic lesions were found that were consistent with the presentation of lichen planus. A good response was observed to topical cyclosporine treatment. To our knowledge, this may be the first report of unilateral ocular lichen planus without systemic findings. The correlation with the initiation of topical brimonidine suggests that this might be the first case of biopsy-confirmed brimonidine-induced ocular lichen planus.",
"affiliations": "Servicio de Oftalmología, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.;Servicio de Anatomía Patológica, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.;Servicio de Oftalmología, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.;Servicio de Oftalmología, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.",
"authors": "Ventura-Abreu|Nestor|N|;Fernández-Aceñero|Maria Jesus|MJ|;Narváez-Palazón|Carlos|C|;Romo-López|Angel|A|",
"chemical_list": "D000959:Antihypertensive Agents; D007166:Immunosuppressive Agents; D000068438:Brimonidine Tartrate; D016572:Cyclosporine",
"country": "Brazil",
"delete": false,
"doi": "10.5935/0004-2749.20190047",
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"issn_linking": "0004-2749",
"issue": "82(3)",
"journal": "Arquivos brasileiros de oftalmologia",
"keywords": null,
"medline_ta": "Arq Bras Oftalmol",
"mesh_terms": "D000368:Aged; D000959:Antihypertensive Agents; D001706:Biopsy; D000068438:Brimonidine Tartrate; D003228:Conjunctiva; D003229:Conjunctival Diseases; D016572:Cyclosporine; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008010:Lichen Planus",
"nlm_unique_id": "0400645",
"other_id": null,
"pages": "236-238",
"pmc": null,
"pmid": "30916215",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Brimonidine-induced unilateral ocular lichen planus: a case report.",
"title_normalized": "brimonidine induced unilateral ocular lichen planus a case report"
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"activesubstancename": "BRIMONIDINE TARTRATE"
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{
"abstract": "BACKGROUND\nNonconvulsive status epilepticus (NCSE) is a diagnosis that is often challenging and one that may progress to refractory NCSE. Ketamine is a noncompetitive N-methyl-d-aspartate antagonist that increasingly has been used to treat refractory status epilepticus. Current Neurocritical Care Society guidelines recommend intravenous (IV) ketamine infusion as an alternative treatment for refractory status epilepticus in adults. On the other hand, enteral ketamine use in NCSE has been reported in only 6 cases (1 adult and 5 pediatric) in the literature to date.\n\n\nMETHODS\nA 33-year-old woman with a history of poorly controlled epilepsy presented with generalized tonic-clonic seizures, followed by recurrent focal seizures that evolved into NCSE. This immediately recurred within 24 h of a prior episode of NCSE that was treated with IV ketamine. Considering her previous response, she was started again on an IV ketamine infusion, which successfully terminated NCSE. This time, enteral ketamine was gradually introduced while weaning off the IV formulation. Treatment with enteral ketamine was continued for 6 months and then tapered off. There was no recurrence of NCSE or seizures and no adverse events noted during the course of treatment.\n\n\nCONCLUSIONS\nThis case supports the use of enteral ketamine as a potential adjunct to IV ketamine in the treatment of NCSE, especially in cases without coma. Introduction of enteral ketamine may reduce seizure recurrence, duration of stay in ICU, and morbidity associated with intubation.",
"affiliations": "Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224 USA.;Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224 USA.;Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224 USA.;Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224 USA.;Department of Pharmacy, Mayo Clinic, Jacksonville, FL USA.;Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224 USA.",
"authors": "Pizzi|Michael A|MA|;Kamireddi|Prasuna|P|;Tatum|William O|WO|;Shih|Jerry J|JJ|;Jackson|Daniel A|DA|;Freeman|William D|WD|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40560-017-0248-6",
"fulltext": "\n==== Front\nJ Intensive CareJ Intensive CareJournal of Intensive Care2052-0492BioMed Central London 24810.1186/s40560-017-0248-6Case ReportTransition from intravenous to enteral ketamine for treatment of nonconvulsive status epilepticus Pizzi Michael A. 904-953-7103proteoglycan.mike@gmail.com 1Kamireddi Prasuna kamireddi.prasuna@mayo.edu 1Tatum William O. tatum.william@mayo.edu 1Shih Jerry J. jerryshih@ucsd.edu 13Jackson Daniel A. Jackson.Daniel1@mayo.edu 2Freeman William D. freeman.william1@mayo.edu 11 0000 0004 0443 9942grid.417467.7Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224 USA 2 0000 0004 0443 9942grid.417467.7Department of Pharmacy, Mayo Clinic, Jacksonville, FL USA 3 0000 0001 2107 4242grid.266100.3Present Address: Department of Neurology, University of California, San Diego, CA USA 8 8 2017 8 8 2017 2017 5 5426 6 2017 3 8 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nNonconvulsive status epilepticus (NCSE) is a diagnosis that is often challenging and one that may progress to refractory NCSE. Ketamine is a noncompetitive N-methyl-d-aspartate antagonist that increasingly has been used to treat refractory status epilepticus. Current Neurocritical Care Society guidelines recommend intravenous (IV) ketamine infusion as an alternative treatment for refractory status epilepticus in adults. On the other hand, enteral ketamine use in NCSE has been reported in only 6 cases (1 adult and 5 pediatric) in the literature to date.\n\nCase presentation\nA 33-year-old woman with a history of poorly controlled epilepsy presented with generalized tonic-clonic seizures, followed by recurrent focal seizures that evolved into NCSE. This immediately recurred within 24 h of a prior episode of NCSE that was treated with IV ketamine. Considering her previous response, she was started again on an IV ketamine infusion, which successfully terminated NCSE. This time, enteral ketamine was gradually introduced while weaning off the IV formulation. Treatment with enteral ketamine was continued for 6 months and then tapered off. There was no recurrence of NCSE or seizures and no adverse events noted during the course of treatment.\n\nConclusion\nThis case supports the use of enteral ketamine as a potential adjunct to IV ketamine in the treatment of NCSE, especially in cases without coma. Introduction of enteral ketamine may reduce seizure recurrence, duration of stay in ICU, and morbidity associated with intubation.\n\nKeywords\nEnteral ketamineIntravenous ketamineNonconvulsive status epilepticusRefractory status epilepticusSeizuresissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nNonconvulsive status epilepticus (NCSE) constitutes about 70% of refractory status epilepticus (SE) [1]. Due to varied presentations and dependency on continuous electroencephalography (EEG) for confirmation, diagnosis of NCSE is often delayed, leading to prolonged seizures that can become refractory to standard pharmacotherapy. Current Neurocritical Care Society guidelines and several studies recommend the use of anesthetic agents for refractory SE [2–4]. However, studies have shown poor outcomes with the use of anesthetic agents due to hypotension, respiratory suppression requiring mechanical ventilation, and infections [5–7]. Thus, their use remains controversial in the management of NCSE, particularly in patients presenting with mild confusion or focal clonic jerking [8, 9].\n\nKetamine may be a better alternative to standard anesthetic agents as it does not cause hypotension or respiratory suppression [10, 11]. Moreover, intravenous (IV) ketamine is known to control 60% of episodes of SE when used as a third- or fourth-line agent [12]. Oral ketamine has been used as an analgesic adjuvant in a variety of chronic pain syndromes [13], but its use in NCSE has been reported in only 6 cases so far, with successful outcomes and no adverse events [14, 15].\n\nWe report a case of successful control of NCSE with IV ketamine infusion and gradual transition to enteral ketamine without recurrence or adverse events. This is a potentially useful regimen for refractory NCSE, especially in patients with tenuous blood pressures and those at higher risk from intubation.\n\nCase presentation\nA 33-year-old woman with a 27-year history of poorly controlled focal seizures and focal seizures evolving to bilateral convulsions presented to our clinic. She had multiple prior hospitalizations resulting in the addition, deletion, or dose adjustments of several antiseizure drugs (ASDs). Her ASDs at the time of presentation included phenobarbital 60 mg in the morning and 90 mg at night and levetiracetam 1500 mg, topiramate 150 mg, and lacosamide 200 mg twice daily. She could not tolerate clobazam or valproate (the latter due to elevated liver functions).\n\nPrior to this episode, the patient had 2 hospitalizations in the same month. During the first, she was given propofol and midazolam to control SE, which resulted in hypotension and respiratory failure managed successfully with fluids and mechanical ventilation, respectively. During the second admission, she presented with focal seizures and was found to have NCSE on EEG successfully treated with an IV ketamine infusion of 0.5 mg/kg/h that was tapered off over 2 days. The day after discharge from that hospitalization, she had recurrence of a generalized tonic-clonic seizure at her residence, which lasted approximately 45 s. After termination of her generalized tonic-clonic seizure, she remained confused with development of unilateral facial and eye jerking. She was unresponsive for 10 min until she reached the emergency department (ED).\n\nIn the ED, the patient’s mental status was waxing and waning with a Glasgow Coma Scale score of 10. She also had subtle bilateral eye twitching with occasional left gaze deviation and left beating horizontal nystagmus. Eventually, she developed intermittent bilateral upper extremity subtle jerking movements and the Glasgow Coma Scale score improved to 14 with mild confusion.\n\nThe patient had no seizure precipitants such as infection, stress, sleep difficulties, or medication noncompliance. Her noncontrasted magnetic resonance imaging and head computed tomography were negative for structural abnormalities. Analysis of cerebrospinal fluid was negative for an infectious etiology, and her paraneoplastic panel, done during a hospitalization within the past month, was negative. Her metabolic profile was negative for any electrolyte disturbances, and her drug screen was negative. ASD levels were within the therapeutic ranges.\n\nThe patient’s STAT EEG showed rhythmic 2.0- to 2.5-Hz delta activity with occasional spike-and-wave morphology consistent with electrographic seizure (Fig. 1). The electrographic and clinical findings were consistent with NCSE, and she was admitted to the neurology intensive care unit. In view of the hypotension and respiratory failure associated with prior anesthetic medications and previous good response with ketamine, IV ketamine infusion was started and titrated to 1.25 mg/kg/h. Enteral ketamine was initiated on hospital day 2 (1 day after IV ketamine was started) and increased each day to a final dose of 250 mg twice daily. Enteral ketamine was prepared according to a previously developed protocol by the Mayo Clinic Department of Pharmacy. Ketamine infusion was decreased starting on the same day as initiation of enteral ketamine and subsequently titrated off by hospital day 5. Table 1 depicts the electrographic, clinical, and ketamine administration events from admission to discharge.Fig. 1 Onset of NCSE (thick arrow) on initial EEG after admission. This epoch of the EEG shows onset of NCSE with diffuse slowing of 2- to 2.5-Hz delta and left greater than right hemispheric spikes (thin arrows)\n\n\nTable 1 Electrographic and pharmacologic course in the ICU\n\nDay\tContinuous EEG\tClinical features\tGCS\tIV ketamine, mg/kg/h\tOral ketamine, mg BID\t\n1\t1. 9 generalized electroclinical and subclinical seizures\n2. Generalized slowing mixed delta and theta frequencies\tSlightly confused\t14\t1.25\tNot started yet\t\n2\t1. Diffuse frontal intermittent rhythmic delta activity\n2. Diffuse amplitude suppression that was bihemispheric and occasional localized slowing in the left frontal and right occipital regions\n3. No epileptiform activity or nonconvulsive status was noted during this portion of the record.\tAlert and oriented\t15\tWeaned off from 1.25 to 0.75\t50\t\n3\t1. Diffuse slowing and loss of the posterior-dominant rhythm, monorhythmic frontal delta activity\n2. Occasional sharp waves emanating from the right frontal and paracentral region\tAlert and oriented\t15\t0.75\t100\t\n4\tSame as day 3, with decreased frequency of sharp waves in the frontal region\tAlert and oriented\t15\tWeaned off from 0.75 to 0.5\t200\t\n5\tDiscontinued\tAlert and oriented\t15\tStopped\t250\t\n\nBID twice a day, EEG electroencephalography, GCS Glasgow Coma Scale score\n\n\n\n\nAfter termination of NCSE, the patient received a vagal nerve stimulator and was subsequently discharged home with enteral ketamine 250 mg twice daily, phenobarbital 60 mg in the morning and 90 mg at night, levetiracetam 1500 mg and topiramate 175 mg (increased from 150 mg) twice daily, and perampanel 2 mg at night started on day 3 of admission after discontinuation of lacosamide.\n\nFor the next 6 months, the patient had no major episodes of SE and did well except for 3 brief hospitalizations for breakthrough seizures. Her seizure frequency decreased more than 50% with the addition oral ketamine and perampanel. No adverse events or dissociative symptoms were noted. She discontinued enteral ketamine after 6 months by tapering its dosage by 50 mg over a 10-week period. As of her 14-month follow-up visit in our epilepsy clinic, she has had no further events after discontinuing oral ketamine.\n\nDiscussion\nSE is defined as 5 min or more of continuous clinical or electrographic seizure activity or recurrent seizure activity without returning to baseline between seizures [2]. As the name suggests, NCSE is SE where electrographic seizure activity is seen on EEG without any convulsions [16] and constitutes about 21 to 47% of all SE cases [17, 18].\n\nDiagnosing NCSE has always been a challenge because of its nonspecific presentation, including altered mental status, behavioral abnormalities, focal twitches, automatisms, nystagmus, and even coma, thus leaving a broad differential diagnosis [2]. EEG criteria for diagnosis of NCSE have been outlined [16], but NCSE may present with other rhythmic and periodic patterns that occur as part of the ictal-interictal continuum [2] and do not clearly meet the criteria for NCSE. Other imaging modalities like fluorodeoxyglucose-positron emission tomography [19], diffusion weighted imaging, and fluid attenuation inversion recovery [16] can support the diagnosis of NCSE, but these findings are often delayed.\n\nOur patient’s clinical course was highly suggestive of NCSE due to recurrent clinical seizures and lack of returning to baseline mental status. She presented to the ED with focal seizures and altered mental status following an episode of generalized convulsive seizures at home. This presentation could have been misdiagnosed as a postictal state, but her previous history of NCSE along with an EEG showing rhythmic 2.0- to 2.5-Hz delta meeting the Salzburg criteria [20] led to the diagnosis.\n\nOur patient’s NCSE was refractory as she was already on 4 ASDs at the time of presentation and did not respond to IV diazepam or IV levetiracetam. SE is designated to be refractory when it fails to respond to the acute administration of 2 ASDs [21]. Several investigators have described the mechanism for refractory seizures to be attributed to internalization of inhibitory γ-aminobutyric acid (GABA)-A receptors and increased expression of excitatory noncompetitive N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on the postsynaptic neuronal membranes [22]. Hence, drugs that act on GABA receptors may lose their efficacy, while drugs that inhibit NMDA (ketamine) or AMPA (perampanel) receptors may have greater efficacy in terminating SE or NCSE lasting more than 30 min. An animal study supports this mechanism by showing ketamine to be more effective in prolonged seizures lasting more than an hour, rather than administered after only 15 min of induced SE [23].\n\nCurrent guidelines and several studies support the use of anesthetic agents for refractory SE [24]. There is concern over their adverse events on respiratory suppression requiring intubation and severe hypotension. A recent prospective study [25] states that therapeutic coma in SE increases hospital length of stay and related costs. Also, there are observational studies which provide clear evidence of increased mortality and poor outcomes in patients with SE treated with IV anesthetic agents [5–9, 26].\n\nConsidering our patient’s mental status (Glasgow Coma Scale score 14), previous refractory NCSE that responded well to IV ketamine, and severe hypotension with prior use of propofol, she was immediately started on IV ketamine infusion in the neuro-ICU. Adding a ketamine infusion to her home ASD regimen allowed for control of her refractory seizures while avoiding over-sedation and subsequent intubation. Furthermore, this treatment regimen did not cause systemic hypotension.\n\nIV ketamine has been in use for a long time as an alternative drug for refractory SE, but usage of oral ketamine has been reported in only 6 patients, 1 adult and 5 pediatric patients [14, 15]. There is no commercially available oral preparation, so it was extemporaneously prepared by the hospital pharmacy (Fig. 2). Furthermore, no specific dosage recommendations are available with proven efficacy or safety profile, and published case reports served as a guide to the current regimen.Fig. 2 Extemporaneous preparation of enteral ketamine in our pharmacy\n\n\n\n\nIn the published pediatric cases, oral ketamine was started as a last resort for refractory NCSE. The enteral preparation (50 mg/ml) was given orally at a dose of 1.5 mg/kg/day in 2 divided doses. Enteral ketamine was administered for 5 days in addition to the maintenance ASD treatment and then stopped without weaning. Resolution of NCSE occurred in 24 to 48 h of starting enteral ketamine, and no adverse events were reported [14]. In the adult case, IV ketamine was first given as a bolus of 1.5 mg/kg followed by continuous infusion with gradual dose titration from 0.05 to 0.4 mg/kg/h. She was then switched to enteral ketamine 50 mg twice daily to avoid intubation due to her “Do Not Resuscitate” code status. This patient’s clinical SE and EEG improved and remained stable after a total dosage of 2000 mg of ketamine, which was then withdrawn later in the course of treatment [15]. Based on these published cases of enteral ketamine, we started our patient on enteral ketamine 50 mg twice daily (1.25 mg/kg/day in 2 divided doses), followed by increased titration based on EEG findings.\n\nWe initiated an IV ketamine infusion with titration to 1.25 mg/kg/h. Once our patient’s EEG showed resolution of electrographic seizures for 24 h, enteral ketamine 50 mg twice daily was introduced while we began weaning her off the IV ketamine infusion (Table 1). We tapered from 1.25 to 0.75 to 0.5 mg/kg/h, and eventually, it was discontinued. We simultaneously increased the enteral ketamine dosage from 50 to 100 to 200 to 250 mg twice daily, respectively. Enteral ketamine 250 mg twice daily was continued along with her other ASDs for 6 months and then tapered off over a 10-week titration schedule.\n\nThe onset of action for IV ketamine is 1 to 5 min and for enteral ketamine 15 to 30 min [27]. Moreover, enteral ketamine undergoes first pass metabolism, which decreases bioavailability and is metabolized to norketamine. This metabolite is much weaker than ketamine and is associated with fewer adverse events [13]. Therefore, IV ketamine can be used to terminate NCSE due to its rapid action and 100% bioavailability and then be transitioned to enteral ketamine with a safer profile as a maintenance therapy to prevent seizure recurrence. Several adverse events, including increased intracranial pressure, dissociative symptoms, and neurotoxicity, have been described in the literature [28], but there were no adverse events seen with any of the previously published patients treated with oral ketamine nor in our patient in spite of continuing treatment for 6 months. She also had better seizure control after discharge from the hospital, but this could be due to a combined effect of enteral ketamine, AMPA antagonist perampanel, and vagus nerve stimulation (VNS). The efficacy of perampanel for the treatment of SE has yielded mixed results in published case reports, with a small series demonstrating EEG improvements seen in 24 to 48 h after starting perampanel for SE [29, 30]. In a review of VNS for refractory SE (RSE), 76% of generalized RSE and 25% of focal RSE resolved after placement of a VNS [31].\n\nConclusion\nASD medication management of refractory NCSE is debatable and should be tailored based on the condition of the patient at the time of presentation. Ketamine could be a better choice in refractory NCSE or subtle focal SE than other anesthetic agents, and its early initiation in the course of management may be considered with additional validation from a larger population. Enteral ketamine, though not currently indicated for NCSE, was beneficial as a maintenance therapy in our patient after controlling electrographic seizures with IV ketamine. This case and successful transitional regimen requires further support from prospective, controlled studies.\n\nAbbreviations\nAMPAα-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid\n\nASDsAntiseizure drugs\n\nEEGElectroencephalography\n\nGABAγ-Aminobutyric acid\n\nIVIntravenous\n\nNCSENonconvulsive status epilepticus\n\nNMDA\nN-methyl-d-aspartate\n\nRSERefractory status epilepticus\n\nVNSVagus nerve stimulator\n\nPresented at the 46th Critical Care Congress, January 21–25, 2017, in Honolulu, Hawaii\n\nAcknowledgements\nWe acknowledge the continued outpatient care of this patient by Anteneh Feyissa, MD.\n\nFunding\nNone.\n\nAvailability of data and materials\nThe datasets during and/or analyzed during the current study are available from the corresponding author on a reasonable request.\n\nEthics approval and consent to participate\nNo ethics committee was utilized per Mayo Clinic policy for single case reports. No IRB was utilized for a single case report.\n\nAuthors’ contributions\nMP and PK wrote the manuscript and conducted the data extraction from the medical record and literature search. MP, PK, WT, JS, DJ, and WF read, edited, and approved the final manuscript.\n\nConsent for publication\nConsent was obtained from the patient to use her medical information in this manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Novy J Logroscino G Rossetti AO Refractory status epilepticus: a prospective observational study Epilepsia 2010 51 251 256 10.1111/j.1528-1167.2009.02323.x 19817823 \n2. Brophy GM Bell R Claassen J Guidelines for the evaluation and management of status epilepticus Neurocrit Care 2012 17 3 23 10.1007/s12028-012-9695-z 22528274 \n3. Meierkord H Boon P Engelsen B EFNS guideline on the management of status epilepticus in adults Eur J Neurol 2010 17 348 355 10.1111/j.1468-1331.2009.02917.x 20050893 \n4. Parviainen I Kälviäinen R Ruokonen E Propofol and barbiturates for the anesthesia of refractory convulsive status epilepticus: pros and cons Neurol Res 2007 29 667 671 10.1179/016164107X240044 18173905 \n5. Kowalski RG Ziai WC Rees RN Third-line antiepileptic therapy and outcome in status epilepticus: the impact of vasopressor use and prolonged mechanical ventilation Crit Care Med 2012 40 2677 2684 10.1097/CCM.0b013e3182591ff1 22732291 \n6. Sutter R De Marchis GM Semmlack S Anesthetics and outcome in status epilepticus: a matched two-center cohort study CNS Drugs 2017 31 65 74 10.1007/s40263-016-0389-5 27896706 \n7. Marchi NA Novy J Faouzi M Stahli C Burnand B Rossetti AO Status epilepticus: impact of therapeutic coma on outcome Crit Care Med 2015 43 1003 1009 10.1097/CCM.0000000000000881 25654177 \n8. Kaplan PW No, some types of nonconvulsive status epilepticus cause little permanent neurologic sequelae (or: « the cure may be worse than the disease ») Neurophysiol Clin 2000 30 377 382 10.1016/S0987-7053(00)00238-0 11191930 \n9. Sutter R Kaplan PW Can anesthetic treatment worsen outcome in status epilepticus? Epilepsy Behav 2015 49 294 297 10.1016/j.yebeh.2015.02.044 25819797 \n10. Dorandeu F Ketamine for the treatment of (super) refractory status epilepticus? Not quite yet Expert Rev Neurother 2017 17 419 421 10.1080/14737175.2017.1288099 28128002 \n11. Dubey D Kalita J Misra U Status epilepticus: refractory and super-refractory Neurol India 2017 65 12 17 10.4103/neuroindia.NI_990_16 \n12. Gaspard N Foreman B Judd LM Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multi-center study Epilepsia 2013 54 1498 1503 10.1111/epi.12247 23758557 \n13. Blonk MI Koder BG Bemt PMLA Huygen FJPM Use of oral ketamine in chronic pain management: a review Eur J Pain 2010 14 466 472 10.1016/j.ejpain.2009.09.005 19879174 \n14. Mewasingh LD SÉKhara T Aeby A FJC C Dan B Oral ketamine in paediatric non-convulsive status epilepticus Seizure 2003 12 483 489 10.1016/S1059-1311(03)00028-1 12967577 \n15. Yeh P-S Shen H-N Chen T-Y Oral ketamine controlled refractory nonconvulsive status epilepticus in an elderly patient Seizure 2011 20 723 726 10.1016/j.seizure.2011.06.001 21724423 \n16. Sutter R Semmlack S Kaplan PW Nonconvulsive status epilepticus in adults—insights into the invisible Nat Rev Neurol 2016 12 281 293 10.1038/nrneurol.2016.45 27063108 \n17. Laccheo I Sonmezturk H Bhatt AB Non-convulsive status epilepticus and non-convulsive seizures in neurological ICU patients Neurocrit Care 2015 22 202 211 10.1007/s12028-014-0070-0 25246236 \n18. Rudin D Grize L Schindler C Marsch S Rüegg S Sutter R High prevalence of nonconvulsive and subtle status epilepticus in an ICU of a tertiary care center: a three-year observational cohort study Epilepsy Res 2011 96 140 150 10.1016/j.eplepsyres.2011.05.018 21676592 \n19. Struck AF Westover MB Hall LT Deck GM Cole AJ Rosenthal ES Metabolic correlates of the ictal-interictal continuum: FDG-PET during continuous EEG Neurocrit Care 2016 24 324 331 10.1007/s12028-016-0245-y 27169855 \n20. Leitinger M Trinka E Gardella E Diagnostic accuracy of the Salzburg EEG criteria for non-convulsive status epilepticus: a retrospective study Lancet Neurol 2016 15 1054 1062 10.1016/S1474-4422(16)30137-5 27571157 \n21. Hocker S Wijdicks EF Rabinstein AA Refractory status epilepticus: new insights in presentation, treatment, and outcome Neurol Res 2013 35 163 168 10.1179/1743132812Y.0000000128 23336320 \n22. Chen JWY Wasterlain CG Status epilepticus: pathophysiology and management in adults Lancet Neurol 2006 5 246 256 10.1016/S1474-4422(06)70374-X 16488380 \n23. Borris DJ Bertram EH Kapur J Ketamine controls prolonged status epilepticus Epilepsy Res 2000 42 117 122 10.1016/S0920-1211(00)00175-3 11074184 \n24. Glauser T Shinnar S Gloss D Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the Guideline Committee of the American Epilepsy Society Epilepsy Curr 2016 16 48 61 10.5698/1535-7597-16.1.48 26900382 \n25. Alvarez V Lee JW Westover MB Therapeutic coma for status epilepticus: differing practices in a prospective multicenter study Neurology 2016 87 1650 1659 10.1212/WNL.0000000000003224 27664985 \n26. Sutter R Marsch S Fuhr P Kaplan PW Rüegg S Anesthetic drugs in status epilepticus: risk or rescue?: a 6-year cohort study Neurology 2014 82 656 664 10.1212/WNL.0000000000000009 24319039 \n27. Fang Y Wang X Ketamine for the treatment of refractory status epilepticus Seizure 2015 30 14 20 10.1016/j.seizure.2015.05.010 26216679 \n28. Fujikawa DG Neuroprotective effect of ketamine administered after status epilepticus onset Epilepsia 1995 36 186 195 10.1111/j.1528-1157.1995.tb00979.x 7821277 \n29. Strzelczyk A Willems LM Willig S Rosenow F Bauer S Perampanel in the treatment of focal and idiopathic generalized epilepsies and of status epilepticus Expert Rev Clin Pharmacol 2015 8 733 740 10.1586/17512433.2015.1091303 26436331 \n30. Rohracher A Hofler J Kalss G Leitinger M Kuchukhidze G Deak I Dobesberger J Novak H Pilz G Zerbs A Trinka E Perampanel in patients with refractory and super-refractory status epilepticus in a neurological intensive care unit Epilepsy Behav 2015 49 354 358 10.1016/j.yebeh.2015.04.005 25962657 \n31. Zeiler FA Zeiler KJ Teitelbaum J Gillman LM West M VNS for refractory status epilepticus Epilepsy Res 2015 112 100 113 10.1016/j.eplepsyres.2015.02.014 25847345\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2052-0492",
"issue": "5()",
"journal": "Journal of intensive care",
"keywords": "Enteral ketamine; Intravenous ketamine; Nonconvulsive status epilepticus; Refractory status epilepticus; Seizures",
"medline_ta": "J Intensive Care",
"mesh_terms": null,
"nlm_unique_id": "101627304",
"other_id": null,
"pages": "54",
"pmc": null,
"pmid": "28808577",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "28281491;19817823;25847345;25246236;23758557;18173905;26436331;12967577;7821277;27571157;24319039;23336320;16488380;11074184;19879174;25962657;28128002;27896706;26900382;21676592;21724423;26216679;22732291;27169855;27664985;27063108;22528274;25819797;25654177;11191930;20050893",
"title": "Transition from intravenous to enteral ketamine for treatment of nonconvulsive status epilepticus.",
"title_normalized": "transition from intravenous to enteral ketamine for treatment of nonconvulsive status epilepticus"
} | [
{
"companynumb": "US-LUNDBECK-DKLU2036702",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOBAZAM"
},
"drugadditional": "3",
"... |
{
"abstract": "OBJECTIVE\nTo evaluate the short-term efficacy and safety of neoadjuvant synchronous chemoradiotherapy (paclitaxel plus carboplatin regimen) in stage III adenocarcinoma of esophagogastric junction (AEG).\n\n\nMETHODS\nForty cases clinically diagnosed as stage III AEG were prospectively enrolled at the Department of Gastrointestinal Oncology Surgery, the First Affiliated Hospital of Hebei North University from December 2014 to November 2017 and then were randomly divided into paclitaxel plus carboplatin combined with synchronous radiotherapy group(neoadjuvant group) and direct operation group. Inclusion criteria was as follows:(1) AEG was diagnosed by gastroscopic biopsy and III stage was confirmed by ultrasound endoscopy and spiral CT;(2) physical strength score ≥70, and age ≤75 years old; (3) no contraindications of chemoradiotherapy and operation. Exclusion criteria was as follows:(1) patients voluntarily withdrew or refused the treatment;(2) occurrence of severe anaphylaxis; (3) uncontrollable events happened during treatment and treatment was unable to continue;(4) tumor developed obviously during treatment. Preoperative neoadjuvant synchronous chemoradiotherapy used TP regimen: paclitaxel 80 mg/m², drug concentration-time area under curve of carboplatin= 1.5 mg×ml⁻¹×min⁻¹, once per week for 9 weeks; radiotherapy began at the second week, 40 Gy/20 F, completed within 4 weeks. Operative procedure of both groups was radical resection of cardiac cancer(D2). Postoperative chemotherapy regimen was oral Tegafur(Gimeracil and Oteracil potassium). The side effects, diet situation, change of gastroscopic image after treatment in patients of neoadjuvant group were observed and efficacy evaluation of chemotherapy was performed according to solid tumor efficacy evaluation criteria of US National Cancer Institute. Operation-associated parameters, including R0 resection rate, lymph node metastasis, operative mortality and postoperative complications, were compared between two groups.\n\n\nRESULTS\nThere were no significant differences in baseline information between the two group (all P>0.05). One case in neoadjuvant group was excluded because of perforation at lesion site 7 weeks after chemotherapy. The side effects of 19 cases in neoadjuvant group were mainly alopecia (100%) and marrow inhibition (68.4%), while 3-4 degree side effects were alopecia(8/19,42.1%), leukopenia (3/19, 15.8%) and neutropenia(3/19, 15.8%). Complete remission was observed in 4 cases; partial remission was observed in 13 cases and stable disease in 2 cases, with an objective response rate of 89.5% and a disease control rate of 100%. Before neoadjuvant chemotherapy, 16 cases were difficult to take liquid diet and 3 cases received liquid diet only, while after 12 weeks of neoadjuvant chemotherapy, all the 19 cases received normal diet. Besides, after neoadjuvant chemotherapy, gastroscopic examination showed close healing of cardiac ulcer, disappearance of swelling, and renewal of normal mucosa. Compared to direct operation group, neoadjuvant group had less number of positive lymph node (4.9±3.6 vs. 8.8±2.8, P<0.05) and higher R0 resection rate (94.7% vs. 50.0%, P<0.05). Total number of harvested lymph node was not significantly different between two groups (19.1±2.5 vs. 18.6±7.0, t=0.326, P=0.746). There was no surgical death in either group. One case in direct operation group developed postoperative inflammatory obstruction. No associated complication was found in neoadjuvant group.\n\n\nCONCLUSIONS\nPaclitaxel plus carboplatin combined with synchronous radiotherapy can elevate the R0 resection rate of patients with stage III esophagogastric junction adenocarcinoma, without increasing operative mortality and postoperative complications.",
"affiliations": "Graduate School of Hebei North University, Zhangjiakou 075000, China Email:549678754@qq.com.;Endoscopy Eenter, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, China.;Department of General Surgery, First Hospital of Zhangjiakou, ZhangjiaKou 075000, China.;Graduate School of Hebei North University, Zhangjiakou 075000, China.;Graduate School of Hebei North University, Zhangjiakou 075000, China.;Graduate School of Hebei North University, Zhangjiakou 075000, China.;Department of Gastrointestinal Oncology Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, China Email: shuguangli6688@126.com.",
"authors": "Ji|Yangyang|Y|;Peng|Tao|T|;Wang|Guoqiang|G|;Zhang|Yu|Y|;Cao|Mingfu|M|;Gao|Qiang|Q|;Li|Shuguang|S|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1671-0274",
"issue": "21(9)",
"journal": "Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery",
"keywords": null,
"medline_ta": "Zhonghua Wei Chang Wai Ke Za Zhi",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D059248:Chemoradiotherapy; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D006801:Humans; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D017239:Paclitaxel; D013274:Stomach Neoplasms; D015996:Survival Rate",
"nlm_unique_id": "101177990",
"other_id": null,
"pages": "1019-1024",
"pmc": null,
"pmid": "30269322",
"pubdate": "2018-09-25",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Short-term efficacy and safety of the synchronous neoadjuvant chemoradiotherapy with paclitaxel plus carboplatin in stage III adenocarcinoma of esophagogastric junction.",
"title_normalized": "short term efficacy and safety of the synchronous neoadjuvant chemoradiotherapy with paclitaxel plus carboplatin in stage iii adenocarcinoma of esophagogastric junction"
} | [
{
"companynumb": "CN-PFIZER INC-2018422923",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nNuclear protein in testis (NUT) midline carcinomas (NMC) are characterized by rearrangements of the gene NUT. In the majority of NMCs, a translocation t(15;19), resulting in a BRD4/NUT fusion gene, is present. Nuclear protein in testis midline carcinomas is a rare, but probably underdiagnosed entity due to misdiagnosis. Most cases have been reported in the mediastinum and upper aero-digestive tract. The clinical course of a NMC is extremely aggressive, in spite of intensive chemotherapy and radiotherapy, with an average survival < 1 year.\n\n\nRESULTS\nA 32-year-old man presented with a pre-auricular swelling on the left side. After partial parotidectomy, the diagnosis of a NMC was made based on the presence of t(15;19)(q14;p13.1) and BRD4/NUT fusion gene demonstrated by fluorescence in situ hybridization (FISH). During postoperative radiotherapy, the patient developed bone metastases for which chemotherapy consisting of cisplatine, doxorubicine and ifosfamide (PAI) was initiated with remarkable clinical and radiological improvement. Nevertheless, the response was not durable.\n\n\nCONCLUSIONS\nThis case illustrates that responses to chemotherapy in the palliative treatment of a t(15;19)-translocated salivary gland carcinoma are possible but not durable.",
"affiliations": "a Department of Oncology , Integrated Cancer Center , Ghent , Belgium.;c Department of Imaging and Pathology , KU Leuven , Belgium.;d Department of Human Genetics , KU Leuven , Belgium.;c Department of Imaging and Pathology , KU Leuven , Belgium.;e Department of Radiation Oncology , UZ Leuven , Belgium.;g Department of Oral Health Sciences , KU Leuven , Belgium.;g Department of Oral Health Sciences , KU Leuven , Belgium.;h Department of Medical Oncology , Jessa Ziekenhuis , Hasselt , Belgium.;c Department of Imaging and Pathology , KU Leuven , Belgium.;b Department of General Medical Oncology , UZ Leuven , Belgium.",
"authors": "Vulsteke|Christof|C|;Lurquin|Eveline|E|;Debiec-Rychter|Maria|M|;Gheysens|Olivier|O|;Nuyts|Sandra|S|;Schoenaers|Joseph|J|;Politis|Constantinus|C|;Mebis|Jeroen|J|;Hauben|Esther|E|;Clement|Paul M|PM|",
"chemical_list": "C471990:BRD4-NUT fusion oncogene protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D004317:Doxorubicin; D002945:Cisplatin; D007069:Ifosfamide",
"country": "England",
"delete": false,
"doi": "10.1179/1973947815Y.0000000046",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-009X",
"issue": "28(3)",
"journal": "Journal of chemotherapy (Florence, Italy)",
"keywords": "BRD4/NUT fusion gene; Chemotherapy; Nut midline carcinoma",
"medline_ta": "J Chemother",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D002277:Carcinoma; D002945:Cisplatin; D004317:Doxorubicin; D006801:Humans; D007069:Ifosfamide; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D010307:Parotid Neoplasms; D011878:Radiotherapy; D016896:Treatment Outcome",
"nlm_unique_id": "8907348",
"other_id": null,
"pages": "242-6",
"pmc": null,
"pmid": "26027633",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "First evidence of treatment efficacy in metastatic carcinoma of the parotid gland with BRD4/NUT translocation.",
"title_normalized": "first evidence of treatment efficacy in metastatic carcinoma of the parotid gland with brd4 nut translocation"
} | [
{
"companynumb": "BE-PFIZER INC-2016395234",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Cetuximab is a monoclonal antibody against epidermal growth factor receptor useful in the treatment of patients with Head and Neck Squamous Cell Carcinoma combined with radiotherapy or chemotherapy. Its pharmacokinetics are not influenced by hepatic status and there are no specific warnings concerning its indication in patients with impaired hepatic function. Patients with a previous liver transplant are at risk for hepatic toxicity and use immunosupressants to avoid rejection that can interact with other drugs. We present two cases of patients with a previous liver transplant in which cetuximab was administered to treat head and neck cancer.",
"affiliations": "a Deparment of Medical Oncology, Catalan Institute of Oncology , Hospital JosepTrueta , Girona , Spain.;a Deparment of Medical Oncology, Catalan Institute of Oncology , Hospital JosepTrueta , Girona , Spain.;c Deparment of Medical Oncology, Catalan Institute of Oncology , Hospital Duran I Reynalds , L'Hospitalet de LLobregat, Barcelona , Spain.;d Deparment of Radiotherapy, Catalan Institute of Oncology , Hospital JosepTrueta , Girona , Spain.;c Deparment of Medical Oncology, Catalan Institute of Oncology , Hospital Duran I Reynalds , L'Hospitalet de LLobregat, Barcelona , Spain.;e Deparment of Otorhinolaringology , Hospital Universitari JosepTrueta , Servei Català de la Salut, Girona , Spain.;f Deparment of Otorhinolaringology , Hospital Universitari de Bellvitge, University of Barcelona , Servei Català de la Salut, Barcelona , Spain.;c Deparment of Medical Oncology, Catalan Institute of Oncology , Hospital Duran I Reynalds , L'Hospitalet de LLobregat, Barcelona , Spain.",
"authors": "Holguin|Francia|F|;Rubió-Casadevall|Jordi|J|;Saigi|Maria|M|;Marruecos|Jordi|J|;Taberna|Miren|M|;Tobed|Marc|M|;Maños|Manuel|M|;Mesía|Ricard|R|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000068818:Cetuximab",
"country": "England",
"delete": false,
"doi": "10.1080/1120009X.2016.1187360",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-009X",
"issue": "29(5)",
"journal": "Journal of chemotherapy (Florence, Italy)",
"keywords": "Cetuximab; Head and neck cancer; Immunosuppressors; Liver transplant; Tacrolimus; mTOR inhibitors",
"medline_ta": "J Chemother",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D000068818:Cetuximab; D005260:Female; D006258:Head and Neck Neoplasms; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8907348",
"other_id": null,
"pages": "310-313",
"pmc": null,
"pmid": "27380218",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cetuximab as treatment for head and neck cancer patients with a previous liver transplant: report of two cases.",
"title_normalized": "cetuximab as treatment for head and neck cancer patients with a previous liver transplant report of two cases"
} | [
{
"companynumb": "ES-ASTELLAS-2017US043288",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Although HLA-B*58:01 is a well-known risk factor for the development of allopurinol-induced severe cutaneous adverse reactions (SCARs), most of the HLA-B*58:01 carriers do not suffer from SCARs despite a long-term use of allopurinol. This suggests that there are other risk factors that determine the fate of HLA-B*58:01 carriers.\n\n\n\nThe aim of this study was to investigate the additional genetic factors that increase the risk of allopurinol-induced SCARs in HLA-B*58:01 carriers.\n\n\n\nThe incidence of allopurinol-induced SCARs was investigated according to coexisting HLA alleles in all subjects with HLA-B*58:01 who took allopurinol between 2003 and 2017. The allopurinol tolerant group was defined as a group who took allopurinol for more than 60 days without developing hypersensitivity and was compared with the allopurinol-induced SCAR group.\n\n\n\nAmong the retrospective cohort consisting of 367 HLA-B*58:01 carriers treated with allopurinol, 11 (3.0%) were diagnosed with allopurinol-induced SCARs. When HLA-B75, DR13 homozygosity, or DR14 was present, the incidence of SCARs increased up to 22.2% (odds ratio [OR], 19.568; P = .015), 20.0% (OR, 38.458; P = .001), and 10.7% (OR, 19.355; P = .004), respectively. Among the 153 HLA-B*58:01 carriers with chronic renal insufficiency (CRI), the incidence of SCARs doubled to 6.5% and further increased to 40%, 30%, and 37.5% in the presence of HLA-B75, DR13 homozygosity, or DR14, respectively.\n\n\n\nSecondary screening with HLA-B75, DR13 homozygosity, and DR14 in addition to primary screening with HLA-B*58:01 would enable a more accurate prediction of SCAR occurrence, especially in patients with CRI.",
"affiliations": "Division of Allergy and Clinical Immunology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.;Department of Immunology and Rheumatology, Nepean Hospital, Sydney, Australia; The University of Sydney, Sydney, Australia.;Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.;Division of Allergy and Clinical Immunology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.;Division of Allergy and Clinical Immunology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.;Regional Pharmacovigilance Center, Seoul National University Hospital, Seoul, Korea.;Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea.;Division of Allergy and Clinical Immunology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul National University College of Medicine, Seoul, Korea; Regional Pharmacovigilance Center, Seoul National University Hospital, Seoul, Korea.;Division of Allergy and Clinical Immunology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul National University College of Medicine, Seoul, Korea; Regional Pharmacovigilance Center, Seoul National University Hospital, Seoul, Korea. Electronic address: helenmed@snu.ac.kr.",
"authors": "Shim|Ji-Su|JS|;Yun|James|J|;Kim|Mi-Yeong|MY|;Chung|Soo Jie|SJ|;Oh|Ji Hyun|JH|;Kang|Dong-Yoon|DY|;Jung|Jae-Woo|JW|;Cho|Sang-Heon|SH|;Kang|Hye-Ryun|HR|",
"chemical_list": "D000485:Allergens; D015235:HLA-B Antigens; C500126:HLA-B*58:01 antigen; C057904:HLA-B75 antigen; D059810:HLA-DR Serological Subtypes; C097337:HLA-DR13 antigen; C052238:HLA-DR14; D000493:Allopurinol",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaip.2018.11.039",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "7(4)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Allopurinol; Drug hypersensitivity syndrome; Human leukocyte antigen; Koreans; Stevens-Johnson syndrome; Toxic epidermal necrolysis",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000328:Adult; D000485:Allergens; D000493:Allopurinol; D015331:Cohort Studies; D004342:Drug Hypersensitivity; D005260:Female; D015235:HLA-B Antigens; D059810:HLA-DR Serological Subtypes; D006720:Homozygote; D006801:Humans; D015994:Incidence; D007723:Korea; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012306:Risk; D012867:Skin",
"nlm_unique_id": "101597220",
"other_id": null,
"pages": "1261-1270",
"pmc": null,
"pmid": "30529060",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The Presence of HLA-B75, DR13 Homozygosity, or DR14 Additionally Increases the Risk of Allopurinol-Induced Severe Cutaneous Adverse Reactions in HLA-B*58:01 Carriers.",
"title_normalized": "the presence of hla b75 dr13 homozygosity or dr14 additionally increases the risk of allopurinol induced severe cutaneous adverse reactions in hla b 58 01 carriers"
} | [
{
"companynumb": "KR-NORTHSTAR HEALTHCARE HOLDINGS-KR-2018NSR000168",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALLOPURINOL"
},
"drug... |
{
"abstract": "Hemophagocytic lymfohistiocytosis (HLH) is rare, life-threatening condition, characterized by excessive activation of immune system with subsequent proinflammatory state resulting in multiorgan failure. Most frequently, it appears in infancy as a primary disorder caused by mutation of immune-regulatory genes. Increasingly, HLH is being diagnosed as a secondary - adult - form, which occurs as a result of aberrant immune response. Viral or bacterial systemic infections, malignancy with a predominance of lymphoproliferative disorders and autoimmune diseases are the most common triggers. Early diagnosis and initiation of therapy is crucial and increase the chance for recovery. HLH is usually presented as multisystem febrile illness, where an extensive differential diagnosis is needed. Diagnosis of HLH is defined by a combination of clinical and laboratory findings, eventually by a proof of specific mutation. The basic mechanism of therapy is an interruption of aberrant immune response by destruction and suppression of T-lymphocytes function. This is mostly achieved by corticosteroid and etoposide therapy. This review summarizes pathophysiology, diagnostics and therapy of HLH. Furthermore, a case-report of 22-years old patient with secondary HLH being manifested predominantly with acute respiratory failure is presented.Key words: acute respiratory failure - hemophagocytic lymphohistiocytosis - HLH-94 - macrophage activation syndrome - MODS.",
"affiliations": null,
"authors": "Šrámek|Jiří|J|;Karvunidis|Thomas|T|;Lysák|Daniel|D|;Harazim|Martin|M|;Karas|Michal|M|;Jindra|Pavel|P|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "Czech Republic",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0042-773X",
"issue": "64(3)",
"journal": "Vnitrni lekarstvi",
"keywords": null,
"medline_ta": "Vnitr Lek",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D003937:Diagnosis, Differential; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D009102:Multiple Organ Failure; D018805:Sepsis; D055815:Young Adult",
"nlm_unique_id": "0413602",
"other_id": null,
"pages": "300-307",
"pmc": null,
"pmid": "29766733",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hemophagocytic lymfohistiocytosis in adults: review and case report.",
"title_normalized": "hemophagocytic lymfohistiocytosis in adults review and case report"
} | [
{
"companynumb": "CZ-MYLANLABS-2018M1094022",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "1",
... |
{
"abstract": "Recreational ketamine use has emerged as an important health and social issue worldwide. Although ketamine is associated with biliary tract damage, the clinical and radiological profiles of ketamine-related cholangiopathy have not been well described.\n\n\n\nChinese individuals who had used ketamine recreationally at least twice per month for six months in the previous two years via a territory-wide community network of charitable organizations tackling substance abuse were recruited. Magnetic resonance cholangiography (MRC) was performed, and the findings were interpreted independently by two radiologists, with the findings analysed in association with clinical characteristics.\n\n\n\nAmong the 343 ketamine users referred, 257 (74.9%) were recruited. The mean age and ketamine exposure duration were 28.7 (±5.8) and 10.5 (±3.7) years, respectively. A total of 159 (61.9%) had biliary tract anomalies on MRC, categorized as diffuse extrahepatic dilatation (n = 73), fusiform extrahepatic dilatation (n = 64), and intrahepatic ductal changes (n = 22) with no extrahepatic involvement. Serum alkaline phosphatase (ALP) level (odds ratio [OR] 1.007; 95% CI 1.002-1.102), lack of concomitant recreational drug use (OR 1.99; 95% CI 1.11-3.58), and prior emergency attendance for urinary symptoms (OR 1.95; 95% CI 1.03-3.70) had high predictive values for biliary anomalies on MRC. Among sole ketamine users, ALP level had an AUC of 0.800 in predicting biliary anomalies, with an optimal level of ≥113 U/L having a positive predictive value of 85.4%. Cholangiographic anomalies were reversible after ketamine abstinence, whereas decompensated cirrhosis and death were possible after prolonged exposure.\n\n\n\nWe have identified distinctive MRC patterns in a large cohort of ketamine users. ALP level and lack of concomitant drug use predicted biliary anomalies, which were reversible after abstinence. The study findings may aid public health efforts in combating the growing epidemic of ketamine abuse.\n\n\n\nRecreational inhalation of ketamine is currently an important substance abuse issue worldwide, and can result in anomalies of the biliary system as demonstrated by magnetic resonance imaging. Although prolonged exposure may lead to further clinical deterioration, such biliary system anomalies might be reversible after ketamine abstinence. Clinical trial number: NCT02165488.",
"affiliations": "Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong. Electronic address: wkseto@hku.hk.;Department of Surgery, North District Hospital, Hong Kong.;Department of Diagnostic Radiology, The University of Hong Kong, Hong Kong.;Department of Diagnostic Radiology, The University of Hong Kong, Hong Kong.;Department of Surgery, North District Hospital, Hong Kong.;Department of Surgery, North District Hospital, Hong Kong.;Department of Radiology, North District Hospital, Hong Kong.;Department of Radiology, Queen Mary Hospital, Hong Kong.;Department of Psychiatry, Queen Mary Hospital, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong. Electronic address: waikleung@hku.hk.",
"authors": "Seto|Wai-Kay|WK|;Mak|Siu-King|SK|;Chiu|Keith|K|;Vardhanabhuti|Varut|V|;Wong|Ho-Fai|HF|;Leong|Heng-Tat|HT|;Lee|Paul S F|PSF|;Ho|Y C|YC|;Lee|Chi-Kei|CK|;Cheung|Ka-Shing|KS|;Yuen|Man-Fung|MF|;Leung|Wai K|WK|",
"chemical_list": "D018691:Excitatory Amino Acid Antagonists; D013287:Illicit Drugs; D007649:Ketamine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jhep.2018.03.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0168-8278",
"issue": "69(1)",
"journal": "Journal of hepatology",
"keywords": "Alkaline phosphatase; Biliary; Cholangiogram; Ketamine; Magnetic resonance cholangiography; Substance abuse",
"medline_ta": "J Hepatol",
"mesh_terms": "D000328:Adult; D001649:Bile Duct Diseases; D049448:Cholangiopancreatography, Magnetic Resonance; D004108:Dilatation, Pathologic; D055030:Drug Users; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D013287:Illicit Drugs; D007649:Ketamine; D008297:Male; D015203:Reproducibility of Results; D012189:Retrospective Studies",
"nlm_unique_id": "8503886",
"other_id": null,
"pages": "121-128",
"pmc": null,
"pmid": "29551711",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Magnetic resonance cholangiogram patterns and clinical profiles of ketamine-related cholangiopathy in drug users.",
"title_normalized": "magnetic resonance cholangiogram patterns and clinical profiles of ketamine related cholangiopathy in drug users"
} | [
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"companynumb": "HK-PFIZER INC-2018157487",
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"activesubstancename": "KETAMINE HYDROCHLORIDE"
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"abstract": "Polymyositis (PM) is an uncommon inflammatory myopathy that affects striated muscles. It causes weakness of the limb girdles, neck, and pharyngeal muscles. We are presenting a case of PM which manifested after intrauterine death (IUD). The patient was referred to our hospital for breathing difficulty, 4 days after delivery of a dead fetus. Initially, she was treated in line of puerperal sepsis and peripartum cardiomyopathy. Patient's cardiopulmonary functions improved but she had persistent high-grade fever. Gross muscle weakness was found on day 5 of admission, involving all four limbs, predominantly in proximal muscles and she had dark colored urine. Laboratory tests revealed myoglobinuria, high serum creatine phosphokinase (CPK) levels, and high lactate dehydrogenase (LDH) levels. Polymyositis diagnosed on the basis of high CPK levels, magnetic resonance imaging (MRI) of cervical spine, electromyography (EMG), and muscle biopsy findings. We question, whether the PM could be pathogenically related to the pregnancy? Literature review of the previously reported cases of PM/dermatomyositis and our case report suggests that pregnancy can trigger the new onset of PM.\nBorse MP, Sahoo TK, Anand KV, Kumar M, Panda D. Postpartum Polymyositis Following Intrauterine Fetal Death. Indian J Crit Care Med 2020;24(8):731-734.",
"affiliations": "Critical Care Department, Medanta Hospital, Ranchi, Jharkhand, India.;Critical Care Department, Medanta Hospital, Ranchi, Jharkhand, India.;Department of Neurology, Medanta Hospital, Ranchi, Jharkhand, India.;Critical Care Department, Medanta Hospital, Ranchi, Jharkhand, India.;Critical Care Department, Medanta Hospital, Ranchi, Jharkhand, India.",
"authors": "Borse|Manmohan P|MP|;Sahoo|Tapas K|TK|;Anand|Kumar V|KV|;Kumar|Manoj|M|;Panda|Debasish|D|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.5005/jp-journals-10071-23541",
"fulltext": "\n==== Front\nIndian J Crit Care Med\nIndian J Crit Care Med\nIJCCM\nIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine\n0972-5229 1998-359X Jaypee Brothers Medical Publishers \n\n10.5005/jp-journals-10071-23541\nCase Report\nPostpartum Polymyositis Following Intrauterine Fetal Death\nBorse Manmohan P 1 Sahoo Tapas K 2 Anand Kumar V 3 Kumar Manoj 4 Panda Debasish 5 1,2,4,5 Critical Care Department, Medanta Hospital, Ranchi, Jharkhand, India\n3 Department of Neurology, Medanta Hospital, Ranchi, Jharkhand, India\nTapas K Sahoo, Critical Care Department, Medanta Hospital, Ranchi, Jharkhand, India, Phone: +91-011-42252404, e-mail: tapask.sahoo@gmail.com\n8 2020 \n24 8 731 734\nCopyright © 2020; Jaypee Brothers Medical Publishers (P) Ltd.2020© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Abstract\nPolymyositis (PM) is an uncommon inflammatory myopathy that affects striated muscles. It causes weakness of the limb girdles, neck, and pharyngeal muscles. We are presenting a case of PM which manifested after intrauterine death (IUD). The patient was referred to our hospital for breathing difficulty, 4 days after delivery of a dead fetus. Initially, she was treated in line of puerperal sepsis and peripartum cardiomyopathy. Patient's cardiopulmonary functions improved but she had persistent high-grade fever. Gross muscle weakness was found on day 5 of admission, involving all four limbs, predominantly in proximal muscles and she had dark colored urine. Laboratory tests revealed myoglobinuria, high serum creatine phosphokinase (CPK) levels, and high lactate dehydrogenase (LDH) levels. Polymyositis diagnosed on the basis of high CPK levels, magnetic resonance imaging (MRI) of cervical spine, electromyography (EMG), and muscle biopsy findings. We question, whether the PM could be pathogenically related to the pregnancy? Literature review of the previously reported cases of PM/dermatomyositis and our case report suggests that pregnancy can trigger the new onset of PM.\n\nHow to cite this article\nBorse MP, Sahoo TK, Anand KV, Kumar M, Panda D. Postpartum Polymyositis Following Intrauterine Fetal Death. Indian J Crit Care Med 2020;24(8):731–734.\n\nKeywords\nCreatine phosphokinasePolymyositisPostpartum\n==== Body\nIntroduction\nPolymyositis (PM) is an idiopathic inflammatory myopathy that targets predominantly skeletal muscles. It causes symmetrical proximal muscle weakness of limbs in particular while distal muscle weakness tends to be mild. Bulbar muscle involvement can be seen in 30% of patients. The exact etiology of PM is unknown; it is thought to be an immune-mediated syndrome associated with other autoimmune systemic diseases. Evidence supports T-cell (CD8(+)T)-mediated cytotoxic process.1 Among the myositis-specific autoantibodies, antibodies against aminoacyl transfer ribonucleic acid (t-RNA) synthetases and anti-histidyl-tRNA synthetase (anti-Jo-1) antibodies are associated with PM, but the cause of their production remains unclear.2 Environmental triggers like infectious viruses [human immunodeficiency virus (HIV), human T-lymphotropic virus-1 (HTLV-1), coxsackievirus B, hepatitis B, and influenza] have been implicated.\n\nPolymyositis and pregnancy association has been reported few times, and most of them reported about the effect of myositis on pregnancy and high-risk pregnancy management in known myositis patients, but the pregnancy itself causing PM is not reported that widely.\n\nCase Description\nA 20-year-old woman, primigravida, transferred to our hospital because of breathing difficulty 4 days after delivering a dead fetus at 24 weeks of gestation. She was intubated in emergency department in view of respiratory distress and shifted to critical care department. There were no significant past medical or genetic history of patient or her family. There was no history of complications like preeclampsia, gestational diabetes, or infections during pregnancy.\n\nOn examination, patients’ Glasgow coma scale (GCS) was E4M6Vt. Her temperature was 101°F, pulse was 122 beats/minute, and blood pressure was 118/78 mm Hg. No rash was observed. Systemic examination revealed bilateral crepitations. Chest X-ray posteroanterior (PA) view showed bilateral infiltrates and echo assessment showed poor left ventricle (LV) systolic function and no right atrium (RA)/right ventricle (RV) dilatation. Patient was treated in line of pneumonia, sepsis, acute kidney injury (AKI), and peripartum cardiomyopathy. Patient's hemodynamics and cardiopulmonary-renal functions improved but she had persistent high-grade fever. Gross muscle weakness was found on day 5 of admission, involving all four limbs, predominantly in proximal muscles and she had dark colored urine. Laboratory tests revealed positive urine myoglobin, raised erythrocyte sedimentation rate (ESR) 47 mm/hour, raised serum creatine phosphokinase (CPK) levels 109,200 U/L, and raised lactate dehydrogenase (LDH) levels 460 U/L. Thyroid function tests were normal. Systemic lupus erythematosus (SLE) was ruled out based on clinical criteria, negative antinuclear antibody (ANA) and negative anti-dsDNA antibody. Initially, we thought of rhabdomyolysis as a differential diagnosis, as urine myoglobin was positive, CPK was high, but we did not find any major recovery with hemodialysis and other supportive measures. As weakness was more in proximal muscles, we decided to investigate her further.\n\nInflammatory myopathy was suspected in view of proximal muscle weakness and very high CPK levels. Magnetic resonance imaging (MRI) of cervical spine showed diffuse edema within the neck and shoulder girdle muscles on both sides. Electromyography (EMG) showed myopathic pattern, i.e., polyphasic motor unit potential of decreased amplitude and duration recorded predominantly in proximal muscles of bilateral upper limbs and lower limbs (Fig. 1). Muscle biopsy from the left thigh muscle showed an inflammatory reaction as evident by endomysial infiltration with lymphocytes along with few necrotic muscle fibers (Fig. 2). Polymyositis diagnosed based on Bohan's criteria3 and she was started on high dose of intravenous (IV) steroids for first 3 days (methylprednisolone—1 g/day) then prednisolone 60 mg/day. Tracheostomy was performed on day 10 in view of prolonged ventilation. She responded well to the steroids and other supportive measures, her limbs power recovered progressively, and CPK levels decreased from more than 1 lac to less than 20 thousands by the end of second week).\n\nShe was liberated from mechanical ventilator and decannulated on day 19 of admission, but her bulbar weakness persisted resulting in intermittent cough, intolerance to oral feeds, and retained secretions. Videolaryngoscopy was performed which confirmed dysphagia due to cricopharyngeal muscle discordance, because of that we continued to feed her through Ryles tube. She improved gradually; her CPK levels decreased to 1066 U/L. She was able to walk without support, started to take oral feeds, and was discharged on tapering dose of oral steroids. Patient was followed up after 2 weeks then monthly. Prednisone dose at 60 mg/day given for 6 weeks, then the steroid dose was tapered every week by 5 mg for 8 weeks and then tapered off by 2.5 mg every week. She was counseled to avoid to get conceive for a year at least.\n\nDiscussion\nPregnancy has been involved in eruption of various autoimmune diseases like SLE4 and associated with bad consequences in diffuse scleroderma patients.5 Diseases like myasthenia gravis6 and multiple sclerosis7 have been diagnosed or relapsed in postpartum period. Autoimmune disease may be erupted because of the change in immune function or as a repercussion of passing of fetal cells into the maternal circulation during pregnancy.8 Bianchi et al. suggested that fetal cells can remain in maternal circulation following delivery.9 Fetal microchimerism can increase the vulnerability to systemic scleroderma in postpartum.10 Katz reported aggravation of herpes gestationis in postpartum due to drop in progesterone levels; these maternal hormonal changes can trigger autoimmune disease.11 These changes in immune system and maternal hormones may justify the onset of PM in postpartum. Pinheiro et al. suggested that reduction in the humoral response to certain viral antigens explains the association between pregnancy and dermatomyositis (DM).12 Gutierrez et al. studied 18 women with PM/DM to find the potential effect of pregnancy on the disease and the effect of disease on pregnancy. They observed three patients with prior quiescent disease, which aggravated during pregnancy, their observations allowed them to think that pregnancy as a trigger factor for the onset and exacerbation of PM/DM.13\n\nSilva et al. reported 15 patients (9 DM and 6 PM) who developed the disease in antepartum and 7 patients (4 DM and 3 PM) who developed the disease in postpartum. They concluded that severity of maternal disease speculate the fetal prognosis. Severe the myopathy, greater the chance of fetal loss.14,15 Missumi et al. reported four cases of myositis (two DM and two PM) developed in postpartum. All patients responded well to steroid and other immunosuppressant drugs.16\n\nFig. 1 EMG shows myopathic pattern i.e., polyphasic motor unit potential of decreased amplitude and duration\n\nFig. 2 Muscle fibers showing increased internal nuclei with endomysial lymphocytes along with degeneration of fibers\n\nOther case reports which have reported myositis after child birth or abortion, suggesting that the fetal antigens or maternal hormonal changes precipitate disease activity during pregnancy.17–22\n\nTakei et al. reported a similar case of postpartum PM following intrauterine fetal death. They suggested PM should be considered as differential diagnosis of puerperal fever.17 Noelyn et al. reported the case of PM in a pregnancy complicated by stillbirth and placental massive perivillous fibrinoid deposition (MPFD). They suggested the possibility of role of the placenta in autoimmune disease.18 Papapetropoulos et al. reported a case of PM with three pregnancies.\n\nThey concluded that the incidence of PM during one pregnancy does not guarantee its recurrence in next pregnancy. They suggested that women should be counseled to avoid to get conceive during the active disease and regular follow-up is essential even if pregnancy occurs in remission.19\n\nKanoh et al. reported a case of DM following delivery of a healthy baby. They suggested that pregnancy can elicit the onset of DM.\n\nThey classified pregnancy-related DM into two types; type I—disease aggravated in pregnancy and tends to improve following delivery, type II—has postpartum onset.20 Lee and Yoo reported a case of postpartum DM and discussed earlier reported cases. They concluded that pregnancy can elicit the onset of DM.21 Yassaee et al. reported a case of amyopathic dermatomyositis (ADM) following a spontaneous abortion and progressed 2 years later to classic DM following the delivery of a healthy baby.22\n\nWe are reporting a case of PM which manifested following the delivery of dead fetus. The disease process could have started peripartum but it manifested first in postpartum. Postpartum PM is rare, with only few reported cases.\n\nThough our patient's initial presentation was more suggestive of pneumonia, sepsis, and peripartum cardiomyopathy, but after few days she developed myoglobinuria and had gross symmetrical proximal predominant muscle weakness. On further evaluation, definitive diagnosis of PM was established. She had excellent response to corticosteroids, as her limb muscle weakness improved in 2nd week but dysphagia which was reported in 30% of patients persisted till 7th week.\n\nConclusion\nThis case of PM which manifested following delivery indicates the possibility of new onset PM during postpartum period and it should be considered as differential diagnosis of puerperal fever. Literature review of the previously reported cases of PM/DM and our case report suggests that pregnancy can trigger the new onset of PM.\n\nConsent\nWritten informed consent was acquired from the patient prior to writing this case report.\n\nSource of support: Nil\n\nConflict of interest: None\n==== Refs\nReferences\n1. O'Hanlon TP Miller FW. Genetic risk and protective factor for the idiopathic inflammatory myopathies. Curr Rheumatol Rep 2009 11 4 287 294 DOI: 10.1007/s11926-009-0040-2 19691932 \n2. Dobloug C Garen T Bitter H Stjärne J Stenseth G Grøvle L et al. prevalence and clinical characteristics of adult polymyositis and dermatomyositis; Data from a large and unselected Norwegian cohort. Ann Rheum Dis 2015 74 8 1551 1556 DOI: 10.1136/annrheumdis-2013-205127 24695011 \n3. Bohan A. History and classification of polymyositis and dermatomyositis. Clin Dermatol 1988 6 2 3 8 DOI: 10.1016/0738-081X(88)90044-2 3293742 \n4. Khamashta MA Ruiz-Irastorza G Hughes GRV. Systemic lupus erythematosus flares during pregnancy. Rheum Dis Clin North Am 1997 23 1 15 30 DOI: 10.1016/S0889-857X(05)70312-4 9031372 \n5. Steen VD. Scleroderma and pregnancy. Rheum Dis Clin North Am 1997 23 1 133 147 DOI: 10.1016/S0889-857X(05)70319-7 9031379 \n6. Fraser D Turner JWA. Myasthenia gravis and pregnancy. Proc R Soc Med 1963 56 5 379 381 DOI: 10.1177/003591576305600523 19994245 \n7. Korn-Lubetzki I Kahana E Cooper G Abramsky O. Activity of multiple sclerosis during pregnancy and puerperium. Ann Neurol 1984 16 2 229 231 DOI: 10.1002/ana.410160211 6476794 \n8. Nelson JL. Pregnancy, immunology and autoimmune disease. J Reprod Med 1998 43 4 335 340 9583065 \n9. Bianchi DW Zickwolf GK Weil GJ Sylvester S DeMaria MA. Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proc Natl Acad Sci USA 1996 93 2 705 708 DOI: 10.1073/pnas.93.2.705 8570620 \n10. Nelson JL Furst DE Maloney S Gooley T Evans PC Smith A et al. Microchimerism and HLA compatible relationships of pregnancy in scleroderma. Lancet 1998 351 9102 559 562 DOI: 10.1016/S0140-6736(97)08357-8 9492775 \n11. Katz SI. Herpes gestationis. Fitzpatrick TB Eisen AZ Wolff K et al., Dermatology in General Medicine. 4th edn., New York McGraw-Hill 1993 626 629 \n12. Pinheiro GdaR Goldenberg J Atra E Pereira RB Camano L Schmidt B. Juvenile dermatomyositis and pregnancy: report and literature review. J Rheumatol 1992 19 11 1798 1801 1491405 \n13. Gutierrez G Dagnino R Mintz G. Polymyositis/dermatomyositis and pregnancy. Arthritis Rheum 1984 27 3 291 294 DOI: 10.1002/art.1780270307 6704192 \n14. Silva CA Sultan SM Isenberg DA. Pregnancy outcome in adult-onset idiopathic inflammatory myopathy. Rheumatology (Oxford) 2003 42 10 1168 1172 DOI: 10.1093/rheumatology/keg318 12777640 \n15. Steiner I Averbuch-Heller L Abramsky O Raz E. Postpartum idiopathic polymyositis. Lancet 1992 339 8787 256 DOI: 10.1016/0140-6736(92)90073-C \n16. Missumi LS Souza FH Andrade JQ Shinjo SK. Pregnancy outcomes in dermatomyositis and polymyositis patients. Rev Bras Reumatol 2015 55 2 95 102 DOI: 10.1016/j.rbr.2014.10.001 25577487 \n17. Takei R Suzuki S Kijima K Sawa R Yoneyama Y Asakura H et al. First presentation of polymyositis postpartum following intrauterine fetal death. Arch Gynecol Obstet 2000 264 1 47 48 DOI: 10.1007/PL00007487 10985623 \n18. Noelyn AH Christopher J Martha N Highton J. Pregnancy related polymyositis and massive perivillous fibrin deposition in the placenta: are they pathogenetically related? Arthritis Rheum 2006 55 1 154 156 DOI: 10.1002/art.21710 16463429 \n19. Papapetropoulos T Kanellakopoulou N Tsibri E Paschalis C. Polymyositis and pregnancy: report of a case with three pregnancies. J Neurol Neurosurg Psychiatry 1998 64 3 406 DOI: 10.1136/jnnp.64.3.406 \n20. Kanoh H Izumi T Seishima M Nojiri M Ichiki Y Kitajima Y. A case of dermatomyositis that developed after delivery: the involvement of pregnancy in the induction of dermatomyositis. Br J Dermatol 1999 141 5 897 900 DOI: 10.1046/j.1365-2133.1999.03165.x 10583175 \n21. Lee SI Yoo WH. Postpartum-onset dermatomyositis: case report and literature review. Mod Rheumatol 2002 12 4 362 365 DOI: 10.3109/s101650200066 24384009 \n22. Yassaee M Kovarik CL Werth VP. Pregnancy-associated dermatomyositis. Arch Dermatol 2009 145 8 952 953 19687439\n\n",
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"issn_linking": "0972-5229",
"issue": "24(8)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Creatine phosphokinase; Polymyositis; Postpartum",
"medline_ta": "Indian J Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "101208863",
"other_id": null,
"pages": "731-734",
"pmc": null,
"pmid": "33024387",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports",
"references": "19687439;1491405;19691932;6704192;25577487;6476794;9031379;9492775;3293742;24695011;8570620;10583175;9031372;24384009;19994245;9527163;12777640;16463429;1346226;9583065;10985623",
"title": "Postpartum Polymyositis Following Intrauterine Fetal Death.",
"title_normalized": "postpartum polymyositis following intrauterine fetal death"
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"abstract": "Objectives: Very few data on the incidence, predictors, and clinical outcomes of lupus-like reactions (LLRs) in patients with inflammatory bowel disease (IBD) treated with anti-TNFs have been reported. Materials and methods: All records of consecutive IBD patients who started a treatment with an anti-TNF from January 2006 to June 2018 were retrospectively reviewed. Patients were defined as having LLR by the presence of immunologic abnormalities (positivity for ANA and/or anti-ds-DNA), along with clinical features that included at least two of the following: arthralgia, fatigue, fever, cutaneous manifestations, or serositis, which had a clear temporal association with exposure to the anti-TNFs, and resolved without recurrence once the drug was discontinued. Results: 760 patients (1059 total treatments with anti-TNFs) were included. Participants contributed a total of 2863.5 person-years of follow-up, during which 16 cases of LLRs (2.1% of patients) were reported, accounting for an incidence rate of 5.6 per 1000 person-years. Female gender and being former smokers were more prevalent in the LLR group (75.0% versus 44.1%, p = .02; and 18.8% versus 5.4%, p = .037, respectively), with a hazard ratio of 4.40 (95% CI: 1.40-13.81; p = .011) and 4.87 (95% CI: 1.37-17.38; p = .015), respectively, at Cox regression analysis. All LLRs resolved following discontinuation of the drug after a mean of 8.1 ± 4.2 weeks. Ten patients required corticosteroids to control severe symptoms. Conclusions: In this large cohort of patients treated with anti-TNFs with long follow-up, LLRs were rare adverse events, more common in women and former smokers, occurring with nonspecific and insidious clinical features.",
"affiliations": "Inflammatory Bowel Disease Unit, A.O.O.R. \"Villa Sofia-Cervello\" , Palermo , Italy.;Inflammatory Bowel Disease Unit, A.O.O.R. \"Villa Sofia-Cervello\" , Palermo , Italy.;Inflammatory Bowel Disease Unit, A.O.O.R. \"Villa Sofia-Cervello\" , Palermo , Italy.;Inflammatory Bowel Disease Unit, A.O.O.R. \"Villa Sofia-Cervello\" , Palermo , Italy.;Inflammatory Bowel Disease Unit, A.O.O.R. \"Villa Sofia-Cervello\" , Palermo , Italy.;Inflammatory Bowel Disease Unit, A.O.O.R. \"Villa Sofia-Cervello\" , Palermo , Italy.",
"authors": "Macaluso|Fabio Salvatore|FS|;Sapienza|Chiara|C|;Ventimiglia|Marco|M|;Renna|Sara|S|;Cottone|Mario|M|;Orlando|Ambrogio|A|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000079424:Tumor Necrosis Factor Inhibitors",
"country": "England",
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"issue": "54(9)",
"journal": "Scandinavian journal of gastroenterology",
"keywords": "Adalimumab; biologics; infliximab; lupus like reaction; safety",
"medline_ta": "Scand J Gastroenterol",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D005260:Female; D006801:Humans; D015994:Incidence; D015212:Inflammatory Bowel Diseases; D007558:Italy; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012737:Sex Factors; D000074285:Smokers; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "0060105",
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"pages": "1102-1106",
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"pubdate": "2019-09",
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"references": null,
"title": "Lupus-like reactions in patients with inflammatory bowel disease treated with anti-TNFs are insidious adverse events: data from a large single-center cohort.",
"title_normalized": "lupus like reactions in patients with inflammatory bowel disease treated with anti tnfs are insidious adverse events data from a large single center cohort"
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"abstract": "BACKGROUND\nTacrolimus is a macrolide immunosuppressant widely used to prevent rejection after solid organ transplantation. In general, adverse events of tacrolimus occur more often as the concentration of tacrolimus in the blood increases. We report the case of a 39-year-old man who developed a variety of adverse events despite in the therapeutic level of tacrolimus in the blood.\n\n\nMETHODS\nA 39-year-old man underwent liver transplantation for liver cirrhosis due to alcoholic liver disease. The postoperative immunosuppressant consisted of tacrolimus (5 mg) and mycophenolate (500 mg) twice daily. Five months after taking tacrolimus, he presented with talkativeness, which gradually worsened. Brain magnetic resonance imaging performed 10 months after tacrolimus administration revealed a hyperintense lesion affecting the middle of the pontine tegmentum on T2WI. The blood concentration of tacrolimus was 7.2 ng/mL (therapeutic range 5-20 ng/mL). After 21 months, he exhibited postural tremor in both the hands. Twenty-four months after taking tacrolimus, he showed drowsy mentality, intention tremor, and dysdiadochokinesia. Electroencephalography presented generalized high-voltage rhythmic delta waves; therefore, tacrolimus was discontinued in suspicion of tacrolimus-induced neurotoxicity, and anticonvulsive treatment was started. The level of consciousness gradually improved, and the patient was able to walk independently with mild ataxia.\n\n\nCONCLUSIONS\nThis case shows that tacrolimus-induced neurotoxicity can occur even at normal concentrations. Therefore, if a patient taking tacrolimus exhibits psychiatric or neurologic symptoms, neurotoxicity should be considered even when the blood tacrolimus is within the therapeutic range.",
"affiliations": "Department of Neurology, School of Medicine, Dong-A University, 26, Daesingongwon-ro, Seo-gu, Busan, 49201, Korea.;Department of Neurology, School of Medicine, Dong-A University, 26, Daesingongwon-ro, Seo-gu, Busan, 49201, Korea.;Department of Neurology, School of Medicine, Dong-A University, 26, Daesingongwon-ro, Seo-gu, Busan, 49201, Korea. smcheon@dau.ac.kr.",
"authors": "Jin|Bora|B|;Kim|Ga Yeon|GY|;Cheon|Sang-Myung|SM|http://orcid.org/0000-0001-5905-2188",
"chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus",
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"doi": "10.1186/s12883-021-02479-z",
"fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377\nBioMed Central London\n\n2479\n10.1186/s12883-021-02479-z\nCase Report\nTacrolimus-induced neurotoxicity from bipolar disorder to status epilepticus under the therapeutic serum level: a case report\nJin Bora bora1128@naver.com\n\nKim Ga Yeon luckykayon@gmail.com\n\nhttp://orcid.org/0000-0001-5905-2188\nCheon Sang-Myung smcheon@dau.ac.kr\n\ngrid.255166.3 0000 0001 2218 7142 Department of Neurology, School of Medicine, Dong-A University, 26, Daesingongwon-ro, Seo-gu, Busan, 49201 Korea\n15 11 2021\n15 11 2021\n2021\n21 4489 7 2021\n3 11 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nTacrolimus is a macrolide immunosuppressant widely used to prevent rejection after solid organ transplantation. In general, adverse events of tacrolimus occur more often as the concentration of tacrolimus in the blood increases. We report the case of a 39-year-old man who developed a variety of adverse events despite in the therapeutic level of tacrolimus in the blood.\n\nCase presentation\n\nA 39-year-old man underwent liver transplantation for liver cirrhosis due to alcoholic liver disease. The postoperative immunosuppressant consisted of tacrolimus (5 mg) and mycophenolate (500 mg) twice daily. Five months after taking tacrolimus, he presented with talkativeness, which gradually worsened. Brain magnetic resonance imaging performed 10 months after tacrolimus administration revealed a hyperintense lesion affecting the middle of the pontine tegmentum on T2WI. The blood concentration of tacrolimus was 7.2 ng/mL (therapeutic range 5–20 ng/mL). After 21 months, he exhibited postural tremor in both the hands. Twenty-four months after taking tacrolimus, he showed drowsy mentality, intention tremor, and dysdiadochokinesia. Electroencephalography presented generalized high-voltage rhythmic delta waves; therefore, tacrolimus was discontinued in suspicion of tacrolimus-induced neurotoxicity, and anticonvulsive treatment was started. The level of consciousness gradually improved, and the patient was able to walk independently with mild ataxia.\n\nConclusion\n\nThis case shows that tacrolimus-induced neurotoxicity can occur even at normal concentrations. Therefore, if a patient taking tacrolimus exhibits psychiatric or neurologic symptoms, neurotoxicity should be considered even when the blood tacrolimus is within the therapeutic range.\n\nKeywords\n\nTacrolimus\nNeurotoxicity\nBipolar disorder\nAtaxia\nStatus epilepticus\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nTacrolimus is a macrolide immunosuppressant. It blocks the production of interleukin 2, which inhibits T-lymphocyte proliferation [1]. The neurological side effects of calcineurin inhibitors (cyclosporine and tacrolimus) are most commonly mild, such as headache, dysarthria, visual changes, and postural tremor [2]. Severe side effects can include psychosis, cortical blindness, and seizures [2]. Severe complications have been more frequently reported following liver and lung transplantation than with renal transplantation, which typically occur with tacrolimus concentrations consistently above the therapeutic range of 15 ng/mL [3]. Neurotoxicity commonly occurs early after the initiation of tacrolimus; however, it may occur months or even years later [2]. Here, we report a case of tacrolimus-induced neurotoxicity despite in the therapeutic blood level of tacrolimus.\n\nCase presentation\n\nA 39-year-old man underwent liver transplantation for liver cirrhosis due to alcoholic liver disease. He had no other medical history, including absence of any neuropsychiatric disorder. Postoperative immunosuppressive therapy consisted of tacrolimus (5 mg) and mycophenolate (500 mg) twice daily. Five months after taking tacrolimus, he presented with talkativeness, which gradually worsened. Three months later, he showed elated mood, grandiose delusion, talkativeness, and a decreased need for sleep, which was diagnosed of bipolar disorder. At that time, he was not taking any medication other than tacrolimus and mycophenolate mofetil. Short-term hospitalization and discharge were repeated due to poor control of these symptoms and lack of insights. Brain magnetic resonance imaging (MRI) performed 10 months after tacrolimus administration revealed a hyperintense lesion affecting the middle of the pontine tegmentum on T2 weighted images without enhancement (Fig. 1). Blood concentration of tacrolimus was 7.2 ng/mL (therapeutic range: 5–20 ng/mL). There were no laboratory abnormalities other than a slight elevation in AST levels, including electrolytes and vitamins. The score on the Positive and Negative Syndrome Scale (PANSS) for schizophrenia was 119. The introduction of antipsychotic drugs, such as lithium and quetiapine, controlled these symptoms for about a year. Twenty-one months later, he exhibited postural tremor in both hands, which was reduced with the administration of a beta-blocker. Two months later, he presented with memory disturbance and disorientation, which progressed with dysarthria and gait disturbance. He was hospitalized and referred for neurologic consultation. The score of PANSS score for schizophrenia was 72. On neurologic examination, he presented with drowsy mentality, kinetic tremor, intention tremor, dysdiadochokinesia, postural instability, and inability to stand in tandem. The International Cooperative Ataxia Rating Scale score was 39 [4]. The concentration of tacrolimus was 3.5 ng/mL. Brain MRI showed the same lesion in the pontine tegmentum. No laboratory abnormalities except for the presence of albumin-cytologic dissociation protein (64 mg/dL) in the cerebrospinal fluid were detected. No anti-neuronal or paraneoplastic autoantibodies were detected. During the examination, the patient’s level of consciousness rapidly deteriorated, and electroencephalography (EEG) showed generalized high-voltage rhythmic delta waves, which were terminated by intravenous injection of lorazepam (Fig. 2). Non-convulsive status epilepticus was diagnosed, and anticonvulsant treatment was initiated. Administration of tacrolimus was stopped in suspicion of tacrolimus-induced neurotoxicity, and the immunosuppressive regimen was changed to mycophenolate and prednisolone. Despite anticonvulsant treatment and discontinuation of tacrolimus, the ictal rhythm persisted and was eventually controlled through coma-inducing anesthesia with mechanical ventilation. Thiopental was administered, and the dose was gradually increased to achieve burst suppression in EEG, which was made 32 h later and maintained for an additional 24 h. The patient’s level of consciousness gradually improved over 2 weeks of aggressive treatment and produced normal EEG. Immunosuppressive treatment was maintained with cyclosporine instead of prednisolone. The patient was able to walk independently with mild ataxia (ataxia score 22) and showed a schizophrenia score of 61 without any psychiatric medication. The Wechsler Adult Intelligence Scale-IV score was 66, corresponding to intellectual disability at the time of discharge after 3 weeks of hospitalization. The patient was administered cyclosporine as an immunosuppressant without any other medication. Two months after discharge, the follow-up intelligence score was 91, corresponding to average level of intelligence. The follow-up brain MRI showed partial resolution of the lesion in the middle of the pons (Fig. 3). The patient did not present any neurological or psychiatric sign or symptom 8 months after discharge (Fig. 4).Fig. 1 Brain MRI at 10 months after taking tacrolimus shows a low signal intensity lesion in the middle of the pontine tegmentum on a T1 weighted image (A) and high signal intensity lesion in the same region on a T2 weighted image (B)\n\nFig. 2 Electroencephalography at 24 months after taking tacrolimus shows generalized high-voltage rhythmic delta waves\n\nFig. 3 Brain MRI at 4 months after stopping tacrolimus shows partial resolution of low signal intensity lesion in the middle of pontine tegmentum on T1WI (A) and high signal intensity in the same region on T2WI (B)\n\nFig. 4 Time course of symptoms, signs, and treatments of the patient\n\nDiscussion and conclusion\n\nThe cellular basis of neurotoxicity associated with tacrolimus has not been conclusively identified [5]. Tacrolimus mediates immune-suppressive effects via inhibition of calcineurin, which provokes a complete block off in the translocation of the cytosolic component of the nuclear factor in activated T-cells, resulting in a failure to activate the genes regulated by the nuclear factor of activated T-cells transcription factor [5]. Tacrolimus decreases the expression of p-glycoprotein as a drug efflux pump in brain endothelial cells and causes dysfunction of the blood-brain barrier, resulting in vasogenic edema [5]. In this patient, neurologic manifestation could be considered as a result of mycophenolate mofetil; however, such cases have rarely been reported and are irrelevant to the patient’s presentation. Neurotoxicity is a well-known adverse event associated with tacrolimus-mediated immunosuppression after solid organ transplantation. Approximately, 25–31% of patients who receive tacrolimus experience some form of neurotoxic adverse events [6]. They have mild neurotoxicity, including tremors (most common), insomnia, headache, dysesthesia, and mood disturbance. These adverse events generally occurred within the first 30 days following transplantation and were correlated in many instances to high plasma levels of tacrolimus [6]. Sakamoto et al. investigated the correlation between neurotoxicity and intracerebral concentration of tacrolimus in rats and demonstrated that at concentrations over a threshold value (700 ng/g of the rat brain), the intensity of the neurological event increases with the concentration of tacrolimus in the brain [7]. The recommended target concentration of tacrolimus in combination with mycophenolate is 6–10 ng/mL during the first 4 weeks following transplantation and 5–8 ng/mL thereafter [8]. A neurological event can occur at therapeutic blood concentrations [9], and even within the therapeutic range there could be a possibility of increased permeability of the blood brain barrier or decreased elimination from the brain in those patients. However, there are no reports on sudden onset of various complications appearing at once, as in our case. Of those, serious neurotoxicity such as medication-resistant status epilepticus can occur and suggests the importance of EEG for altered mentality. Prompt recognition of tacrolimus-induced neurotoxicity may be challenging. Our patient developed psychiatric symptoms 5 months after taking tacrolimus, which progressed until the brain MRI showed abnormal lesions in the pons. Such lesions could have resulted from other causes, such as myelinolysis due to hyponatremia or vitamin deficiency; however, no such events occurred during the patient’s illness. Despite these clues, the diagnosis was delayed by 2 years. Therefore, if a patient taking tacrolimus exhibits psychiatric or neurologic symptoms, neurotoxicity should be considered even within the therapeutic range of blood tacrolimus.\n\nAbbreviations\n\nPANSS Positive and Negative Syndrome Scale\n\nEEG Electroencephalography\n\nMRI Magnetic resonance imaging\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nBJ collected the clinical data and drafted the manuscript. GY collected the clinical data. SC designed and revised the paper and provided a practice consultation. All authors read and approved the final manuscript.\n\nFunding\n\nThis study was supported by the Dong-A University Research Fund.\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\nWritten informed consent was obtained from the patient for publication of this report.\n\nCompeting interests\n\nThe authors declare that there are no conflicts of interest.\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. Bechstein WO Neurotoxicity of calcineurin inhibitors: impact and clinical management Transpl Int 2000 13 313 326 10.1111/j.1432-2277.2000.tb01004.x 11052266\n2. Junna MR Rabinstein AA Tacrolimus induced leukoencephalopathy presenting with status epilepticus and prolonged coma J Neurol Neurosurg Psychiatry 2007 78 1410 1411 10.1136/jnnp.2007.121806 18024699\n3. Chegounchi M Hanna MG Neild GH Progressive neurological disease induced by tacrolimus in a renal transplant recipient: case presentation BMC Nephrol 2006 7 7 10.1186/1471-2369-7-7 16573841\n4. Trouillas P Takayanagi T Hallett M International cooperative ataxia rating scale for pharmacological assessment of the cerebellar syndrome. The Ataxia neuropharmacology Committee of the World Federation of neurology J Neurol Sci 1997 145 205 211 10.1016/S0022-510X(96)00231-6 9094050\n5. Wu G, Weng FL, Balaraman V. Tacrolimus-induced encephalopathy and polyneuropathy in a renal transplant recipient. BMJ Case Reports. 2013;2013. 10.1136/bcr-2013-201099.\n6. Eidelman BH Abu-Elmagd K Wilson J Neurologic complications of FK 506 Transplant Proc 1991 23 3175 3178 10.1136/bcr-2013-201099 1721398\n7. Sakamoto Y Makuuchi-M M Harihara Y Imamura H Sato H Correlation between neurotoxic events and intracerebral concentration of tacrolimus in rats Biol Pharm Bull 2000 23 1008 1010 10.1248/bpb.23.1008 10963314\n8. Brunet M van Gelder T Åsberg A Therapeutic drug monitoring of tacrolimus-personalized therapy: second consensus report Ther Drug Monit 2019 41 261 307 10.1097/FTD.0000000000000640 31045868\n9. Seo EH Kim SG Cho YS Yoon HJ Tuberculum sellae meningioma with possible tacrolimus neurotoxicity manifesting as manic-like psychosis after kidney transplantation Ann General Psychiatry 2019 18 18 10.1186/s12991-019-0242-6\n\n",
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"keywords": "Ataxia; Bipolar disorder; Neurotoxicity; Status epilepticus; Tacrolimus",
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"mesh_terms": "D000328:Adult; D001714:Bipolar Disorder; D006801:Humans; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D008297:Male; D013226:Status Epilepticus; D016559:Tacrolimus",
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"abstract": "Intraoperative hypotension (IOH) invariably follows the induction of general anesthesia during surgical operations. The current prevailing and predominant consensus is that IOH has immense clinical benefits such as reduced bleeding, less need for blood transfusions, and shorter surgery times. Simultaneously, it is assumed that IOH is devoid of adverse renal, hepatic and neurological consequences. Emerging new evidence and our experiences suggest a strong link between IOH and postoperative acute kidney injury (AKI). Method/Case Reports: We report on three case presentations to illustrate the impact of IOH on postoperative AKI.\n\n\n\nOur recent experiences suggest and show a link between IOH and postoperative AKI. Sun et al. (2015) recently demonstrated that postoperative AKI was associated with sustained intraoperative hypotensive periods of MAP <55 and <60 mm Hg, respectively, in a graded pattern. Our experiences and new emerging Surgery-AKI literature provide an impetus for clinical trials to be set up and completed to determine whether interventions that promptly treat IOH, or better still that prevent IOH, and that are tailored to suit individual patient physiology, would reduce the risk of AKI. We posit that IOH is a neglected cause of postoperative AKI. We call for a preventative nephrology paradigm shift and the targeting of MAP ≥ 60 mm Hg and/or SBP ≥ 90 mm Hg during surgical procedures. Particularly in sub-Saharan Africa with its paucity of renal replacement therapy options to manage kidney failure, every effort to limit AKI, SORO-ESRD and exacerbation of kidney dysfunction in general, must be vigorously applied.",
"affiliations": "Department of Nephrology, Mayo Clinic Health System, 1221 Whipple Street, Eau Claire, WI 54702, United States.;North East London NHS Foundation Trust, London, United Kingdom.",
"authors": "Onuigbo|Macaulay Amechi Chukwukadibia|MAC|;Agbasi|Nneoma|N|",
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"keywords": "Acute kidney injury; chronic kidney disease; end stage renal disease (ESRD); general anesthesia; hemodialysis; intraoperative hypotension; preventative nephrology",
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"mesh_terms": "D058186:Acute Kidney Injury; D000768:Anesthesia, General; D006801:Humans; D007022:Hypotension; D007431:Intraoperative Complications; D009398:Nephrology; D011183:Postoperative Complications",
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"title": "The Ignored Role of Intraoperative Hypotension in Producing Postoperative Acute Kidney Injury-An Obligatory Appeal for More Preventative Nephrology.",
"title_normalized": "the ignored role of intraoperative hypotension in producing postoperative acute kidney injury an obligatory appeal for more preventative nephrology"
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"abstract": "A 69-year-old female with recurrent stage IV squamous cell lung carcinoma and metastatic abdominal lymph node but not bone metastases was being treated with pembrolizumab. Four months after starting the recurrent treatment, the tumour reduced in size but she began to complain of back pain and palmar rash. A bone scan showed uptake lesions in the left sternocostal joints and vertebrae, while spine magnetic resonance imaging (MRI) showed multiple lesions in the thoracic vertebrae. Her heterogeneous lesions, such as skin and multiple bone manifestations, were comprehensively diagnosed as SAPHO syndrome by different experts. Furthermore, the SAPHO syndrome was suspected to be an immune-related adverse event induced by pembrolizumab, and pembrolizumab withdrawal and prednisolone treatment were performed. Subsequently, her symptoms improved and the follow-up imaging findings showed that the bone lesions had almost disappeared. This case demonstrates that SAPHO syndrome mimicking bone metastases developed during treatment with pembrolizumab. SAPHO syndrome is rare and bone lesions related to the disease may be misdiagnosed as bone metastases. Therefore, it is important in the future for various physicians to have a better understanding of SAPHO syndrome and to consider the potential relationship between this disease and immunotherapy.",
"affiliations": "Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan.;Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan.",
"authors": "Kubo|Yuko|Y|;Ito|Kimiteru|K|;Fujiwara|Yutaka|Y|;Yoshida|Tatsuya|T|;Kusumoto|Masahiko|M|",
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"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.679111\nMedicine\nCase Report\nCase Report: SAPHO Syndrome Mimicking Bone Metastases During Treatment With Pembrolizumab for Non-small Cell Lung Cancer\nKubo Yuko 1*\n\nIto Kimiteru 1\n\nFujiwara Yutaka 2\n\nYoshida Tatsuya 2\nKusumoto Masahiko 1\n1Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan\n2Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan\nEdited by: Laurent Pierre Nicod, University of Lausanne, Switzerland\n\nReviewed by: Konstantinos Samitas, Athens Chest Hospital Sotiria, Greece; Tomohiko Yamane, Kobe City Medical Center General Hospital, Japan; Masatoshi Hotta, University of California, Los Angeles, United States; Kazuo Kubota, Southern TOHOKU Research Institute for Neuroscience, Japan\n\n*Correspondence: Yuko Kubo yukkubo@ncc.go.jp\nThis article was submitted to Pulmonary Medicine, a section of the journal Frontiers in Medicine\n\n22 7 2021\n2021\n8 67911111 3 2021\n24 6 2021\nCopyright © 2021 Kubo, Ito, Fujiwara, Yoshida and Kusumoto.\n2021\nKubo, Ito, Fujiwara, Yoshida and Kusumoto\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.\nA 69-year-old female with recurrent stage IV squamous cell lung carcinoma and metastatic abdominal lymph node but not bone metastases was being treated with pembrolizumab. Four months after starting the recurrent treatment, the tumour reduced in size but she began to complain of back pain and palmar rash. A bone scan showed uptake lesions in the left sternocostal joints and vertebrae, while spine magnetic resonance imaging (MRI) showed multiple lesions in the thoracic vertebrae. Her heterogeneous lesions, such as skin and multiple bone manifestations, were comprehensively diagnosed as SAPHO syndrome by different experts. Furthermore, the SAPHO syndrome was suspected to be an immune-related adverse event induced by pembrolizumab, and pembrolizumab withdrawal and prednisolone treatment were performed. Subsequently, her symptoms improved and the follow-up imaging findings showed that the bone lesions had almost disappeared. This case demonstrates that SAPHO syndrome mimicking bone metastases developed during treatment with pembrolizumab. SAPHO syndrome is rare and bone lesions related to the disease may be misdiagnosed as bone metastases. Therefore, it is important in the future for various physicians to have a better understanding of SAPHO syndrome and to consider the potential relationship between this disease and immunotherapy.\n\npembrolizumab\nSAPHO syndrome\nimmune-checkpoint inhibitors\nimmune- related adverse event\nnon-small cell lung cancer\n==== Body\nIntroduction\n\nNon-small cell lung cancer (NSCLC) encompasses 85% of total lung malignancies, which remains to be the leader malignancy worldwide, accounting more than 1.8 million of deaths in 2020 (1). In the last decade, one of the major advances in the diagnosis and treatment of lung cancer has been the improved knowledge of oncogenic driver mutations and immune-checkpoint inhibitors (ICIs) that have revolutionised therapeutic strategies. Immunotherapy has been shown to induce robust responses in patients with advanced cancer (2). Accordingly, pembrolizumab, a humanised IgG4 monoclonal antibody against programmed cell death protein 1 (PD-1), showed antitumor activity in patients with advanced NSCLC by disrupting the binding of PD-1 to its ligand and impeding the inhibitory signals in T cells (3). Despite important clinical benefits, pembrolizumab has been associated with a wide spectrum of side effects termed as immune-related adverse events (irAEs) that occur as a consequence of general immunological stimulation (4). SAPHO syndrome is a rare disease of unknown aetiology, and few cases of concomitant disease during the course of lung cancer treatment have been reported (5, 6). We herein describe a case of SAPHO syndrome mimicking bone metastases during treatment with pembrolizumab in a patient with stage IV NSCLC. We present the following case in accordance with the CARE Guideline (7).\n\nCase Description\n\nThe patient was a 69-year-old woman with a history of smoking who received cisplatin and gemcitabine as first-line chemotherapy for stage IV squamous cell lung cancer with abdominal lymph node metastasis but no bone metastasis. Her cancer temporarily disappeared due to the effects of first-line chemotherapy; however, the lymph node metastasis recurred 7 months later and she received second-line chemotherapy with pembrolizumab. Timeline of computed tomography (CT) images during the therapeutic course was shown in Figure 1. Four months after starting the treatment, the tumour had reduced in size, but the patient developed severe back pain and a rash on both palms resembling pustulosis palmoplantaris (Figure 2A). A Tc-99m methylenediphosphonate bone scan was performed in suspicion that her back pain was due to bone metastasis. Accordingly, the bone scan revealed abnormal uptake in multiple vertebrae and left sternoclavicular joint (Figure 2B). Subsequently, MRI was performed to closely evaluate the vertebral lesions, showing multiple bone lesions with a hypointense area on T1-weighted images and contrast-enhancing effects on contrast T1-weighted images (Figure 3). These multiple vertebral lesions had a characteristic pattern of SAPHO syndrome showing a semi-circular pattern of contiguous vertebral body involvement localised at the anterior vertebral corners, unlike the usual bone metastases.\n\nFigure 1 Timeline of computed tomography images during the therapeutic course. (A) The initial images at the time of diagnosis, (B) The images after first-line chemotherapy showed reduction of right lower lobe lung cancer and mediastinal lymph node metastasis, (C) The images after 7 months of first-line chemotherapy showed lymph node recurrence (arrow), (D) The images after second-line chemotherapy showed reduction of mediastinal lymph node metastasis; PFS, progression-free survival.\n\nFigure 2 (A) The patient developed palmoplantar pustular skin lesions after 4 months of pembrolizumab immunotherapy, (B) Bone scan detected multiple abnormal sites of uptake at the left sternoclavicular joints and across multiple vertebrae.\n\nFigure 3 (A) Spine magnetic resonance imaging showed hypointense area on T1-weighted image, (B) abnormally enhancing effect on contrast T1-weighted image in contiguous anterior thoracic vertebral corners. These multiple vertebral lesions had a characteristic semi-circular pattern (dashed line) in contiguous vertebral body segments.\n\nIn conclusion, the patient was comprehensively diagnosed with SAPHO syndrome by different experts, including dermatologists, thoracic oncologists, and radiologists, based on the diagnostic criteria proposed by Benhamou (8, 9) because although the cancer was reduced after pembrolizumab treatment, new heterogeneous lesions such as osteoarticular manifestations with palmoplantar pustulosis were observed. Five months after the discontinuation of pembrolizumab and immunosuppression therapy with prednisolone, the follow-up MRI showed complete resolution of all previously observed multiple bone lesions (Figure 4). Follow-up Tc-99m methylenediphosphonate bone scan after 6 months showed decreased uptakes in the left sternoclavicular joint and multiple vertebras. At present, the patient has remained cancer-free, about 3 years after pembrolizumab withdrawal; however, she continues to be medicated prednisone due to joint pain.\n\nFigure 4 (A) Follow-up T1-weighted image and (B) contrast T1-weighted image after 5 months showed complete resolution of all previously noted bony lesions.\n\nDiscussion\n\nSAPHO syndrome, first identified in 1987 by Chamot et al. is a disorder of unknown aetiology that is manifested by synovitis (inflammation of the joints), acne, pustulosis (thick yellow blisters containing pus) often on the palms and soles, hyperostosis (increase in bone substance) and osteitis (inflammation of the bones) (10). There are several published diagnostic criteria for SAPHO and the presence of only one of the inclusion criteria is sufficient for diagnosis. However, the criteria suggested by Kahn and others by Benhamou (8, 9) have been applied most frequently. The clinical presentation of SAPHO syndrome is heterogeneous, so patients may be examined by different experts to reach a comprehensive diagnosis, although sometimes reaching a diagnosis is difficult and a biopsy may be needed. In this case, heterogeneous clinical presentation, such as osteoarticular manifestations with palmoplantar pustulosis, was comprehensively diagnosed by different experts, including dermatologists, thoracic oncologists and radiologists. Since the syndrome has radiological characteristics, these are useful and recognisable in diagnosis using X-ray, CT, MRI and bone scintigraphy. Uptake in the sternoclavicular region shown in bone scintigraphy is characteristic of the SAPHO syndrome (11). Previous reports have shown that SAPHO syndrome can be difficult to differentiate from multiple bone metastases associated with lung cancer (5). However, other reports have showed that the semi-circular pattern of vertebral body signal alteration and enhancement may help differentiate SAPHO syndrome from metastases, which tend to be randomly distributed throughout the spine (12). A recent review has reported that FDG PET/CT may be useful in differentiating SAPHO syndrome (13). In our case, the characteristic radiological findings on bone scintigraphy and MRI supported the diagnosis of SAPHO syndrome.\n\nPembrolizumab is a selective humanised IgG4 kappa monoclonal antibody that inhibits the PD-1 receptor, an integral component of immune-checkpoint regulation in the tumour microenvironment. PD-1 is directly involved in the peripheral tolerance of self-reactive T cells. Immune checkpoints are necessary to maintain a balance between activation and quiescence of the immune system and suppress self-reactive T cells. By blocking these checkpoints, ICIs disrupt this delicate balance, which may cause autoimmune events. A recently published multicentre retrospective analysis reported that pembrolizumab-induced irAEs occurred in approximately one-third of all cases, with cutaneous disease being the most common followed by rheumatic irAEs in 12.6% of the cases (14).\n\nThe SAPHO syndrome can affect patients of any age, and its aetiology is still unknown. The pathogenesis of SAPHO may be multifactorial, involving a combination of genetic, infectious and immunological components. One aetiology of SAPHO syndrome is thought to involve innate immunologic components (15), with a case of bacillus Calmette-Guérin vaccine immunotherapy-induced SAPHO syndrome having been documented (16). Recent literature has reported a high incidence of malignancy in SAPHO syndrome (17). However, to the best of our knowledge, no previous study has reported on SAPHO syndrome during treatment with pembrolizumab for non-small lung cancer. Furthermore, in this case, withdrawal of pembrolizumab and administration of steroids dramatically and reversibly improved the clinical findings. Thus, we considered that immunotherapy with pembrolizumab could be one of the possible aetiologies of inducing SAPHO syndrome as rheumatic irAEs (12).\n\nThis case report demonstrates that SAPHO syndrome mimicking bone metastases developed during treatment with pembrolizumab. SAPHO syndrome is a rare syndrome, with bone lesions related to the disease being misdiagnosed as bone metastases. Therefore, it is important in the future for various physicians to have a better understanding of SAPHO syndrome and to consider the potential relationship between this disease and immunotherapy.\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\nYK: conceptualisation, data curation, project administration, visualisation, investigation, writing—original draft preparation, writing—reviewing, and editing. KI: conceptualisation, visualisation, and investigation. YF and TY: data curation and supervision. MK: supervision and writing—reviewing and editing. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nYF received grants and personal fees from Astra Zeneca, grants from Abbvie, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Chugai Pharma, grants and personal fees from Daiichi Sankyo, grants from Eisai, grants from Eli Lilly, grants from Incyte, grants from Merck Serono, grants and personal fees from MSD, grants and personal fees from Novartis, personal fees from Ono Pharmaceutical, outside the submitted work. TY has received grants from Ono Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, Takeda, AMGEN, Abbvie, Daiichi-Sankyo and MSD and has received personal fees from AstraZeneca, Chugai, Novartis, Archer DX, Boehringer Ingelheim, Lilly, Bristol-Myers Squibb and MSD. MK received honoraria for lecture fees from Ono pharmaceutical Co.,Ltd, AstraZeneca K.K. and MSD K.K. MK received a research grant from Canon medical systems corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.679111/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1. Sung H Ferlay J Siegel RL Laversanne M Soerjomataram I Jemal A . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. (2020) 71 :209−49 10.3322/caac.21660 33538338\n2. Finn O . Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann oncol. (2012) 23 :viii6–viii9. 10.1093/annonc/mds256 22918931\n3. Garon EB Rizvi NA Hui R Leighl N Balmanoukian AS Eder JP . Pembrolizumab for the treatment of non–small-cell lung cancer. New Engl J Med. (2015) 372 :2018–28. 10.1056/NEJMoa1501824 25891174\n4. Abdel-Wahab N Shah M Suarez-Almazor ME . Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PLoS ONE. (2016) 11 :e0160221. 10.1371/journal.pone.0160221 27472273\n5. Shibakuki R Seto T Uematsu K Shimizu K Seki N Nakano M . Pulmonary adenocarcinoma associated with SAPHO syndrome difficult to differentiate from multiple bone metastasis. Intern Med. (2006) 45 :543–6. 10.2169/internalmedicine.45.1628 16702748\n6. Imamura K Sakata S Sakamoto Y Saeki S . Small-cell lung cancer associated with SAPHO syndrome. Internal Med. (2018) 57 :149–51. 10.2169/internalmedicine.9162-17 29033438\n7. Riley DS Barber MS Kienle GS Aronson JK von Schoen-Angerer T Tugwell P . CARE guidelines for case reports: explanation and elaboration document. J clin epidemiol. (2017) 89 :218–35. 10.1016/j.jclinepi.2017.04.026 28529185\n8. Benhamou CL Chamot AM Kahn MF . Synovitis-acne-pustulosis hyperostosis-osteomyelitis syndrome (SAPHO). A new syndrome among the spondyloarthropathies? Clin Exp Rheumatol. (1988) 6 :109–12. 2972430\n9. Rukavina I . SAPHO syndrome: a review. J Child Orthop. (2015) 9 :19–27. 10.1007/s11832-014-0627-7 25585872\n10. Chamot AM Benhamou CL Kahn MF Beraneck L Kaplan G Prost A . Acne-pustulosis-hyperostosis-osteitis syndrome. results of a national survey. 85 cases. Rev Rhum Mal Osteoartic. (1987) 54 :187–96. 2954204\n11. Sallés M Olivé A Perez-Andres R Holgado S Mateo L Riera E . The SAPHO syndrome: a clinical and imaging study. Clin rheumatol. (2011) 30 :245–9. 10.1007/s10067-010-1560-x 20878342\n12. McGauvran AM Kotsenas AL Diehn FE Wald JT Carr CM Morris JM . SAPHO syndrome: imaging findings of vertebral involvement. Am J Neuroradiol. (2016) 37 :1567–72. 10.3174/ajnr.A4736 27012293\n13. Hotta M Minamimoto R Kaneko H Yamashita H . Fluorodeoxyglucose PET/CT of arthritis in rheumatic diseases: a pictorial review. Radiographics. (2020) 40 :223–40. 10.1148/rg.2020190047 31917663\n14. Cortellini A Friedlaender A Banna GL Porzio G Bersanelli M Cappuzzo F . Immune-related adverse events of pembrolizumab in a large real-world cohort of patients with NSCLC with a PD-L1 expression ≥ 50% and their relationship with clinical outcomes. Clin Lung Cancer. (2020) 21 :498–508.e2. 10.1016/j.cllc.2020.06.010 32680806\n15. Hurtado-Nedelec M Chollet-Martin S Nicaise-Roland P Grootenboer-Mignot S Ruimy R Meyer O . Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome. Rheumatology. (2008) 47 :1160–7. 10.1093/rheumatology/ken185 18559374\n16. Matsumaru K Nagai K Murakami T Andoh K . SAPHO syndrome with bacillus calmette-guerin (BCG) immunotherapy for bladder cancer. BMJ Case Rep. (2010) 2010 :2591. 10.1136/bcr.12.2009.2591 22767524\n17. Yamada S Nagafuchi Y Kono M Hatano H Tateishi S Harada H . high incidence of malignancy in SAPHO syndrome. Clin Exp Rheumatol. (2020) 38 :805–6. 32141430\n\n",
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"title": "Case Report: SAPHO Syndrome Mimicking Bone Metastases During Treatment With Pembrolizumab for Non-small Cell Lung Cancer.",
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"abstract": ": Development of neutralizing alloantibodies in hemophilia B is a less common, but clinically challenging phenomenon. Novel therapeutics for hemophilia B have recently been developed and reports of clinical experience with these agents outside of clinical trials are needed. We report development of an inhibitor in a child with severe hemophilia B, and subsequent immune tolerance induction using an extended desensitization protocol with the addition of immunosuppression. This case highlights successful management of a rare complication in a rare bleeding disorder and the need for additional investigation into this infrequent and clinically challenging occurrence.",
"affiliations": "Bleeding & Clotting Disorders Institute.;Bleeding & Clotting Disorders Institute.;Bleeding & Clotting Disorders Institute.",
"authors": "Roberts|Jonathan C|JC|;Jesudas|Rohith|R|;Tarantino|Michael D|MD|",
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"mesh_terms": "D002648:Child; D002985:Clinical Protocols; D005164:Factor IX; D002836:Hemophilia B; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D007518:Isoantibodies",
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"title": "Development of an inhibitor in a child with severe hemophilia B: treatment with immunosuppression and an extended desensitization protocol.",
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"abstract": "Although the patient with very severe aplastic anemia might be a fit elderly receiving standard therapy, there are factors which contribute to an adverse outcome such as severity of pancytopenia, absence of minor paroxysmal nocturnal hemoglobinuria clone and infective complications of therapy.",
"affiliations": "Department of Hematology Ampang Hospital Ampang Malaysia.;Department of Hematology Ampang Hospital Ampang Malaysia.;Department of Hematology Ampang Hospital Ampang Malaysia.",
"authors": "Kasinathan|Ganesh|G|https://orcid.org/0000-0002-7489-9261;Lee|Bee Sun|BS|;Sathar|Jameela|J|",
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"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.3757\nCCR33757\nCase Report\nCase Reports\nVery severe aplastic anemia in an 80‐year‐old man\nKASINATHAN et al.\nKasinathan Ganesh https://orcid.org/0000-0002-7489-9261\n1\nLee Bee Sun 1\nSathar Jameela 1\n1 Department of Hematology Ampang Hospital Ampang Malaysia\nCorrespondence\nGanesh Kasinathan, Department of Hematology, Ampang Hospital, Jalan Mewah Utara, Pandan Mewah, 68000 Ampang, Selangor, Malaysia.\nEmail: ganeshkasinathan11@hotmail.com\n\n18 1 2021\n3 2021\n9 3 10.1002/ccr3.v9.3 13301333\n18 7 2020\n05 6 2020\n20 10 2020\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nThis 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.\n\nAbstract\n\nAlthough the patient with very severe aplastic anemia might be a fit elderly receiving standard therapy, there are factors which contribute to an adverse outcome such as severity of pancytopenia, absence of minor paroxysmal nocturnal hemoglobinuria clone and infective complications of therapy.\n\nAlthough the patient with very severe aplastic anemia might be a fit elderly receiving standard therapy, there are factors which contribute to an adverse outcome such as severity of pancytopenia, absence of minor paroxysmal nocturnal hemoglobinuria clone, and infective complications of therapy.\n\nsource-schema-version-number2.0\ncover-dateMarch 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.0 mode:remove_FC converted:21.03.2021\nKasinathan G , Lee BS , Sathar J . Very severe aplastic anemia in an 80‐year‐old man. Clin Case Rep. 2021;9 :1330–1333. 10.1002/ccr3.3757\n==== Body\n1 INTRODUCTION\n\nAn 80‐year‐old gentleman with very severe aplastic anemia was treated with standard combination therapy of equine antithymocyte globulin and cyclosporine A. His death shortly after treatment could be attributed to his advanced age, severe pancytopenia at diagnosis, absence of minor paroxysmal nocturnal hemoglobinuria clone, and immunosuppressive therapy‐related complications.\n\nAplastic anemia (AA) is an acquired bone marrow failure syndrome characterized by fatty replacement and diminished production of hematopoietic precursor stem cells of the bone marrow. Immune‐mediated destruction of hematopoietic stem cell precursors in AA is triggered by the activated cytotoxic T cells which express a variety of inhibitory cytokines such as interferon‐gamma through the Fas‐dependent apoptosis pathway. 1 AA demonstrates a bimodal age distribution in which, it occurs most frequently in those aged between 20 and 30 and over 60. 2 AA has an annual incidence of 2 per 1 000 000 population in the West, but it is higher in Asia. 2 The common causes for aplastic anemia are exposure to toxic chemicals such as benzene, certain drugs such as chloramphenicol, ionizing radiation, history of cytotoxic chemotherapy, viral infections, and autoimmune diseases. 3 Most AA diagnosed in the elderly are idiopathic, and they do not exhibit any underlying secondary etiology. 4 Age over 60 years is an important independent risk factor for mortality in AA. 4 One should consider other possibilities such as hypoplastic myelodysplastic syndrome(h‐MDS), paroxysmal nocturnal hemoglobinuria (PNH), nutritional deficiency, late onset telomeropathy, and delayed onset inherited bone marrow failure syndromes when diagnosing AA in the elderly. Here, we describe a case of idiopathic very severe aplastic anemia in an 80‐year‐old man who was treated with standard first‐line therapy but subsequently succumbed to severe infection.\n\n2 CASE PRESENTATION\n\nAn 80‐year‐old Chinese gentleman with no known prior medical illness presented to the department of hematology with lethargy, reduced effort tolerance, easy bruising, anorexia, and loss of weight for the past 6 weeks. He has no significant family history. He is a nonsmoker and a teetotaler and does not consume any recreational or therapy‐related drugs. He worked as a bank clerk previously. He is married with 5 children, whom are all healthy.\n\nOn examination, he was alert with a body weight of 75 kilograms. He demonstrated a Charlson comorbidity index (CCI) score of 4 (low risk) with an Eastern Cooperative Oncology group (ECOG) performance status of 0 (fully active). His blood pressure was 140/70 with a pulse rate of 96 beats per minute. He was afebrile. Visible cutaneous bruising was evident. His cardiovascular and respiratory system examinations were unremarkable. There was no palpable organomegaly or lymphadenopathy.\n\nA complete blood count revealed severe pancytopenia. The blood parameters are tabulated in Table 1.\n\nTABLE 1 Tabulation of parameters\n\nBlood parameters\tValue (normal range with SI unit)\t\nHemoglobin\t5.5 (1.3‐16.5 g/dL)\t\nTotal White Cell count\t0.9 (4‐10 × 109/L)\t\nAbsolute neutrophil count (ANC)\t0.1 (2‐7 × 109/L)\t\nPlatelet\t15 (150‐400 × 109/L)\t\nLactate Dehydrogenase (LDH)\t150 (140‐280 U/L)\t\nCreatinine\t65 (60‐90 umol/L)\t\nAlanine Transaminase\t26 (0‐40 U/L)\t\nB12\t350 (200‐600 ng/mL)\t\nFolate\t12 (2‐10 ng/mL)\t\nCytomegalovirus IgM/IgG\tNot detected\t\nEpstein Barr IgM/IgG\tNot detected\t\nParvovirus IgM/IgG\tNot detected\t\nHepBsAg\tNot reactive\t\nAnti‐HepC\tNot reactive\t\nAnti‐HIV‐1,2\tNot reactive\t\nAntinuclear antibody (ANA)\tNot reactive\t\nJohn Wiley & Sons, Ltd\n\nThe peripheral blood film revealed erythrocyte anisopoikilocytosis and severe pancytopenia. The bone marrow aspiration (Figure 1A) was aparticulate and markedly hypocellular. No abnormal cells were seen. The bone marrow trephine biopsy (Figure 1B) revealed a hypocellular marrow which was replaced mainly with nonhematopoietic tissue such as fat. Flow cytometry analysis did not show any evidence of leukemia. Cytogenetic studies using Giemsa banding technique revealed ‐Y and trisomy 8 abnormalities. Multiparameter flow cytometry and Fluorescent aerolysin (FLAER) of erythrocytes, polymorphonuclear neutrophils, and monocytes did not detect any paroxysmal nocturnal hemoglobinuria (PNH) clone. Whole‐body CT imaging did not reveal any organomegaly or lymphadenopathy.\n\nFIGURE 1 (A) Bone marrow aspiration is aparticulate and markedly hypocellular. No abnormal cells were seen. (B) Bone marrow trephine biopsy shows a hypocellular marrow which was replaced mainly with nonhematopoietic tissue such as fat\n\nHe was diagnosed with very severe idiopathic aplastic anemia (based on Camitta criteria, 1976).\n\nIn view of his advanced age, he was not suitable for an allogeneic stem cell transplant. He was treated with triple therapy consisting of Intravenous equine Antithymocyte globulin (ATGAM) 40 mg/kg for 4 days, oral ciclosporin A (CsA) 75 mg twice daily (total daily dose of 2 mg/kg per body weight) and concomitant upfront subcutaneous granulocyte‐colony stimulating factor (G‐CSF) 300 mcg once daily. Serum sickness prophylaxis in the form of intravenous methylprednisolone 1 mg/kg 30 minutes before and after the ATGAM was also administered. The oral CsA was titrated slowly to a maximum of 125 mg twice daily (total daily dose of 3 mg/kg per body weight) in view of the patient's age and risk of nephrotoxicity in the elderly. He was also given a thrombopoietin receptor agonist, oral eltrombopag 50 mg once daily, and triple antimicrobial prophylaxis (acyclovir, trimethoprim/sulfamethoxazole, and fluconazole). However, he developed severe pneumonia and sepsis on Day 8 of ATGAM therapy which necessitated oxygen support. The chest radiograph (Figure 2) showed diffuse bilateral interstitial and nodular consolidation. The family opted for palliation. He succumbed to his illness on Day 10 of treatment.\n\nFIGURE 2 Chest radiograph shows diffuse bilateral interstitial and nodular consolidation\n\n3 DISCUSSION\n\nWe describe an interesting case of idiopathic very severe aplastic anemia (VSAA) in an 80‐year‐old man who did not have any obvious secondary risk factors. VSAA is defined as bone marrow hypoplasia < 30% on a bone marrow trephine biopsy AND two of the three following criteria: polymorphonuclear neutrophils < 0.2 × 109/L, platelets < 20 × 109/L, or absolute reticulocyte count < 20 × 109/L. 5 Over the age of 60 AA, 6 in 10 patients are women as opposed to a higher male incidence in the younger age‐group. 6\n\nAA in the elderly may demonstrate a variety of molecular mutations. Next‐generation sequencing (NGS) by Yoshizato et al on 439 patients with AA demonstrated no significant relationship between the presence of molecular mutations and response to IST. 7 However, on individual gene assessment, molecular mutations in BCOR, BCORL1, and PIGA were associated with a better response to IST while mutations in DNMT3A and ASXL1 were linked to an adverse outcome. 7\n\nCytogenetic abnormalities are seen in 4%‐5% of aplastic anemia patients over the age of 60. 8 A French nationwide survey study of 88 aplastic anemia patients over the age of 60 demonstrated 8% of these patients had cytogenetic abnormalities. The common cytogenetic abnormalities encountered were Y deletions, trisomy 8, 13p deletion, 4q deletion, chromosome 14 aberrations, and one split of IgH locus. 9 Our patient in this case revealed ‐Y and trisomy 8 cytogenetic abnormalities which were consistent with findings found in the literature.\n\nHigh frequency of HLA‐DR2 and its serologic spilt HLA‐DR15 are overexpressed in AA and hypoplastic MDS. Saunthararajah et al studied two cohorts at the National Institute of Health (NIH) which consisted of 148 patients with severe AA in cohort 1 and 2609 patients with severe AA who received allogenic SCT in cohort 2. Thirty‐two of forty‐seven HLA‐DR15 positive AA and thirty‐one of fifty‐two HLA‐DR15 negative AA patients responded to the combination ATG‐CsA therapy. 10 Hence, the presence of HLA‐DR15 overexpression does not predict a response to IST in AA. 10\n\nSeveral other biomarkers may contribute to responsiveness of immunosuppressive therapy (IST) in elderly AA. Shorter duration of AA, younger age at diagnosis, a higher absolute neutrophil count, a higher absolute lymphocyte count, a higher baseline platelet count, higher CsA levels during the first 2 weeks of commencement of IST, longer telomere length, positive minor PNH clone, lower thrombopoietin (TPO) levels, and increased IFN‐gamma expression in the bone marrow indicate better response to IST. 11\n\nTelomere shortens with age and is a marker of an aging process. Significant abnormal shortening of telomeres of bone marrow nucleated cells have been seen in elderly AA. 12 Telomeres are structures with tandem DNA repeats of 5’‐TTAGGG‐3’. 12 Increased oxidative and hematopoietic stress contributes to the abnormal shortening of telomeres which in turn lead to genomic instability in AA. 12\n\nThe Dutch Society of Hematology national guidelines recommends a combination of equine ATG 40mg/kg daily for 4 days, oral CsA therapy, and subcutaneous G‐CSF as first‐line therapy in patients with severe AA not suitable for allogeneic hematopoietic stem cell transplantation. 13 , 14 This combination incorporating G‐CSF is efficacious as it allows quick neutrophil recovery and identifies early nonresponders. The use of G‐CSF was not associated with any increase in clonal transformation. 13 The overall survival (OS) at 6 and 12 months in elderly patients (aged 60 years and above) treated with ATG‐CsA combination therapy was 96% and 88%, respectively, as compared to only 35% with CsA alone, 22% with eltrombopag alone, and 21% with androgen alone. 14 , 15 The overall response rates (ORR) in patients over 70 years receiving ATG‐CsA was 81%. 15 Patients aged more than 70 receiving ATG‐CsA did not appear to suffer from any additional complications than the younger age group and tolerated the treatment well. 15 Among the common complications seen in this subgroup of elderly AA patients (>70 years old) who received ATG‐CsA combination therapy were infections (88%), followed by acute kidney injury (50%), cardiovascular complications (31%), hemorrhagic manifestations (19%), and neurological complications (13%). 15 Reducing the dose of ATG without administering CsA in elderly AA was associated with a lower risk of treatment toxicity but the response was dismal as only 1 out of the 14 elderly patients achieved a partial hematological response in a British multicentre study. 16 It is interesting to note that the addition of oral eltrombopag at a median maximum dose of 150 mg daily (50‐300 mg) to standard ATG‐CsA combination therapy in newly diagnosed severe AA with a median age of 47 (19‐66), produced an ORR of 90% (trilineage response: 60%, neutrophil response: 20%, platelet response: 30%) at 12 weeks of therapy. 17 Eltrombopag is well tolerated in the elderly. Besides, sex hormones such as oral testosterone 40 mg/day for 5 days per week demonstrated a 59% ORR in patients with persistent cytopenia after ATG‐CsA therapy. 18 Combination of CsA and androgens would be the treatment of choice for frail patients above the age of 70 who are not suitable for the more intensive ATG‐CsA therapy. 18\n\n4 CONCLUSION\n\nIn summary, we report a case of very severe aplastic anemia in an 80‐year‐old man who had a poor outcome with standard treatment. His adverse risk factors which contributed to his poor disease outcome were probably advanced age, severe pancytopenia at diagnosis, delay in seeking treatment, absence of a minor PNH clone, and therapy‐related complications. Age on its own should not be a contraindication to treat fit elderly severe AA patients with combination ATG‐CsA therapy.\n\n5 GUARANTOR\n\nGanesh Kasinathan is the guarantor of this manuscript.\n\nCONSENT\n\nWritten informed consent was obtained from the patient for publication of this case report and the accompanying images.\n\nCONFLICT OF INTEREST\n\nThe authors declare there are no conflicting interests.\n\nAUTHOR CONTRIBUTIONS\n\nGK: analyzed the data, designed the paper, and contributed to the writing of the manuscript. LBS and J.S: made critical revisions and approved the final manuscript.\n\nETHICAL APPROVAL\n\nEthical approval is not required as this is not a clinical trial.\n\nDATA AVAILABILITY STATEMENT\n\nThe data used and analyzed during this study are available from the corresponding author on request.\n==== Refs\nREFERENCES\n\n1 Risitano AM , Maciejewski JP , Green S , et al. In‐vivo dominant immune responses in aplastic anemia: molecular tracking of putatively pathogenetic T‐cell clones by TCR beta‐CDR3 sequencing. Lancet. 2004;364 :355‐364.15276395\n2 Issaragrisil S . Thai Aplastic Anemia Study Group. Epidemiology of aplastic anemia in Thailand. Int J Hematol. 1999;70 :137‐140.10561905\n3 Young NS . Aplastic anemia. The N Eng J Med. 2018;379 (17 ):1643‐1656.\n4 Montane E , Ibanez L , Vidal X , et al. Epidemiology of aplastic anemia: a prospective multicenter study. Haematologica. 2008;93 (4 ):518‐523.18322256\n5 Camitta BM , Thomas ED , Nathan DG , et al. Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood. 1976;48 (1 ):63‐70.779871\n6 Tichelli A , Marsh J . Treatment of aplastic anemia in elderly patients aged > 60 years. Bone Marrow Transplant. 2013;48 :180‐182.23178542\n7 Yoshizato T , Dumitriu B , Hosokawa K , et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Eng J Med. 2015;373 (1 ):35‐47.\n8 Kim SY , Lee JW , Lee SE , et al. The characteristics and clinical outcome of adult patients with aplastic anemia and abnormal cytogenetics at diagnosis. Genes Chromosomes Cancer. 2010;49 (9 ):844‐850.20540166\n9 Maciejewski JP , Risitano A , Sloand EM , et al. Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood. 2002;99 :3129‐3135.11964274\n10 Saunthararajah Y , Nakamura R , Nam JM , et al. HLA‐DR15 (DR2) is overexpressed in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood. 2002;100 (5 ):1570‐1574.12176872\n11 Narita A , Kojima S . Biomarkers for predicting clinical response to immunosuppressive therapy in aplastic anemia. Int J Haematol. 2016;104 :153‐158.\n12 Wang C , Zhang T , Wang Y , et al. The shortening telomere length of T‐lymphocytes maybe associated with hyper‐function in severe aplastic anemia. Mol Med Rep. 2018;17 (1 ):1015‐1021.29115638\n13 Tichelli A , Schrezenmeier H , Socie G , et al. A randomised controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G‐CSF: a study of the SAA Working Party of the European Group for Blood and Marrow transplantation. Blood. 2011;117 (17 ):4434‐4441.21233311\n14 Tjon JM‐L , de Groot MR , Sypkens Smit SMA , et al. Short‐term efficacy and safety of antithymocyte globulin treatment in elderly patients with acquired aplastic anemia. Br J haematol. 2016;180 (3 ):459‐462.27714765\n15 Contejean A , Resche‐Rigon M , Tamburini J , et al. Aplastic anemia in the elderly: a nationwide survey on behalf of the French Reference Center for Aplastic Anemia. Haematologica. 2018;104 (2 ):256‐262.30262561\n16 Killick SB , Cavenagh JD , Davies JK , et al. Low dose antithymocyte globulin for the treatment of older patients with aplastic anemia. Leuk Res. 2006;30 (12 ):1517‐1520.16530266\n17 Hwang YY , Harinder G , Chan TSY , et al. Eltrombopag in the management of aplastic anemia: real world experience in a non‐trial setting. Hematology. 2018;23 (7 ):399‐404.29303047\n18 Bacigalupo A . How I treat aplastic anemia. Blood. 2017;129 (11 ):1428‐1436.28096088\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "9(3)",
"journal": "Clinical case reports",
"keywords": null,
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "1330-1333",
"pmc": null,
"pmid": "33768838",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": "28096088;27714765;30262561;15276395;779871;18322256;21233311;10561905;20540166;16530266;29115638;27091471;26132940;11964274;23178542;12176872;30354958;29303047",
"title": "Very severe aplastic anemia in an 80-year-old man.",
"title_normalized": "very severe aplastic anemia in an 80 year old man"
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"companynumb": "MY-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-302008",
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"activesubstancename": "FLUCONAZOLE"
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"abstract": "OBJECTIVE\nTo report the occurrence of acute posterior multifocal placoid pigment epitheliopathy (APMPPE)-like posterior uveitis as part of the ocular manifestation of tubulointerstitial nephritis and uveitis (TINU) syndrome.\n\n\nMETHODS\nA 54-year-old previously healthy woman received oral ibuprofen and dipirone because of high fever and malaise. Three days after being started on this treatment, she developed bilateral posterior uveitis resembling APMPPE accompanied by anterior segment inflammation in the context of acute renal nephritis and maculopapular skin rash probably related to drug exposure.\n\n\nRESULTS\nThe patient was hospitalized because of acute renal failure and received support therapy and topical steroids in both eyes. A renal biopsy was not performed (based on good clinical response), but she fulfilled the clinical criteria of acute interstitial nephritis and TINU. Although her renal and ocular functions improved in the first week, she needed to be readmitted days later because of fever and generalized edema and received steroid pulse therapy. Fluorescein angiography was consistent with an APMPPE-like pattern and optical coherence tomography showed neither macular edema nor subretinal fluid. The ocular picture improved during the following weeks with fundus changes resembling those of APMPPE.\n\n\nCONCLUSIONS\nAlthough anterior uveitis is considered the typical ocular component of TINU syndrome, posterior uveitis resembling APMPPE may also be its ocular manifestation.",
"affiliations": "From the *Department of Ophthalmology, Hospital Universitario Austral, Pilar; and †Instituto de la Visión, Buenos Aires, Argentina.",
"authors": "Julián|Lilian K|LK|;Martínez-Cartier|Mauricio D|MD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0b013e31818faa0a",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "4(1)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": null,
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "40-3",
"pmc": null,
"pmid": "25390118",
"pubdate": "2010",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Drug-induced tubulointerstitial nephritis and uveitis syndrome with posterior uveitis resembling acute posterior multifocal placoid pigment epitheliopathy.",
"title_normalized": "drug induced tubulointerstitial nephritis and uveitis syndrome with posterior uveitis resembling acute posterior multifocal placoid pigment epitheliopathy"
} | [
{
"companynumb": "AR-STRIDES ARCOLAB LIMITED-2016SP016620",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
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"activesubstancename": "METAMIZOLE SODIUM"
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"abstract": "OBJECTIVE\nThe case of a patient with multiple medication hypersensitivity reactions and a methicillin-resistant Staphylococcus aureus (MRSA) infection who underwent desensitization to ceftaroline is reported.\n\n\nCONCLUSIONS\nA 32-year-old Caucasian woman with asthma, gastroesophageal reflux disease, heart murmur, and major depression was admitted for MRSA cellulitis with a subcutaneous abscess along the left sternomanubrial joint and clavicular osteomyelitis secondary to port placement after gastric bypass surgery. The patient had an extensive history of hypersensitivity reactions. Pertinent documented allergies were as follows: penicillin (anaphylaxis), daptomycin (anaphylaxis), vancomycin (hives), linezolid (hives), ertapenem (rash), ciprofloxacin (rash), and tigecycline (rash). The patient also reported previous reactions to aztreonam (unknown) and gentamicin (hives). The pharmacy was consulted to develop a desensitization protocol for ceftaroline. The desensitization protocol used three serial dilutions of ceftaroline to make 14 sequential infusions with escalating doses. Intramuscular epinephrine, i.v. diphenhydramine, and i.v. methylprednisolone were ordered as needed for the development of immediate hypersensitivity reactions during or after administration of ceftaroline. The cumulative dose (574.94 mg) was administered intravenously over 225 minutes with no breakthrough symptoms reported during or after the desensitization protocol. Ceftaroline fosamil 600 mg i.v. every 12 hours was continued for six weeks.\n\n\nCONCLUSIONS\nDesensitization to ceftaroline was conducted for a patient with extensive history of hypersensitivity reactions to other drugs, including penicillin-induced anaphylaxis. Desensitization and subsequent treatment with full doses of ceftaroline were accomplished without apparent adverse effects.",
"affiliations": "Justin M. Jones, Pharm.D., is Postgraduate Year 1 Pharmacy Resident; Lisa M. Richter, Pharm.D., BCPS, is Postgraduate Year 1 Pharmacy Residency Director; Augusto Alonto, M.D., is Infectious Disease Physician, Division of Infectious Diseases; and David D. Leedahl, Pharm.D., BCPS, is Clinical Pharmacy Manager, Sanford Medical Center, Fargo, ND.;Justin M. Jones, Pharm.D., is Postgraduate Year 1 Pharmacy Resident; Lisa M. Richter, Pharm.D., BCPS, is Postgraduate Year 1 Pharmacy Residency Director; Augusto Alonto, M.D., is Infectious Disease Physician, Division of Infectious Diseases; and David D. Leedahl, Pharm.D., BCPS, is Clinical Pharmacy Manager, Sanford Medical Center, Fargo, ND.;Justin M. Jones, Pharm.D., is Postgraduate Year 1 Pharmacy Resident; Lisa M. Richter, Pharm.D., BCPS, is Postgraduate Year 1 Pharmacy Residency Director; Augusto Alonto, M.D., is Infectious Disease Physician, Division of Infectious Diseases; and David D. Leedahl, Pharm.D., BCPS, is Clinical Pharmacy Manager, Sanford Medical Center, Fargo, ND.;Justin M. Jones, Pharm.D., is Postgraduate Year 1 Pharmacy Resident; Lisa M. Richter, Pharm.D., BCPS, is Postgraduate Year 1 Pharmacy Residency Director; Augusto Alonto, M.D., is Infectious Disease Physician, Division of Infectious Diseases; and David D. Leedahl, Pharm.D., BCPS, is Clinical Pharmacy Manager, Sanford Medical Center, Fargo, ND. david.leedahl@sanfordhealth.org.",
"authors": "Jones|Justin M|JM|;Richter|Lisa M|LM|;Alonto|Augusto|A|;Leedahl|David D|DD|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C515501:ceftaroline fosamil",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp140151",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "72(3)",
"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": "D000328:Adult; D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D003888:Desensitization, Immunologic; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus; D013203:Staphylococcal Infections",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "198-202",
"pmc": null,
"pmid": "25596602",
"pubdate": "2015-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Desensitization to ceftaroline in a patient with multiple medication hypersensitivity reactions.",
"title_normalized": "desensitization to ceftaroline in a patient with multiple medication hypersensitivity reactions"
} | [
{
"companynumb": "US-PFIZER INC-2015025589",
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"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TIGECYCLINE"
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"drugadditional": null,
... |
{
"abstract": "Noonan syndrome is a genetic disorder caused by mutations in the RAS/MAPK pathway. Multiple giant cell lesions are a rare sequelae of disruptions in this pathway, termed Noonan-like multiple giant cell lesions (NL/MGCLs). Medical management of these tumors rather than surgical intervention is preferential as the lesions are benign but locally destructive and recurring. This case series describes four male pediatric patients with Noonan syndrome and multiple giant cell lesions of the jaw treated with denosumab, a monoclonal antibody to receptor activator of nuclear factor kappa B ligand (RANKL), which has been approved for the treatment of malignant giant cell tumors in adults but not evaluated for safety or efficacy in children. All four pediatric patients responded clinically and radiographically to the treatment. Adverse events occurred in a predictable pattern and included hypocalcemia and joint pain during the initiation of treatment and symptomatic hypercalcemia after the cessation of treatment. Growth was not significantly impaired in these skeletally immature patients. This case series demonstrates how a weight-adjusted denosumab dose can effectively treat NL/MGCLs and provides laboratory data for consideration of the timing of monitoring for known side effects.",
"affiliations": "Department of Pediatrics, Division of Genetics, Alfred I. duPont Hospital for Children, Wilmington, DE, United States.;Department of Oral and Maxillofacial Surgery, John H. Jr, Stroger Hospital of Cook County, Chicago, IL, United States.;Division of Endocrinology, Children Mercy Kansas City, University of Missouri- Kansas City, School of Medicine, Kansas City, MO, United States.;Department of Pediatrics, Division of Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.;Department of Oral and Maxillofacial Surgery, University of Maryland School of Dentistry, Baltimore, MD, United States.;Division of Plastic and Reconstructive Surgery, Childrens Hospital of Philadelphia, Philadelphia, PA, United States.;Department of Pediatrics, Division of Orthogenetics, Alfred I. duPont Hospital for Children, Wilmington, DE, United States.;Department of Pediatrics, Division of Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.",
"authors": "Ferriero|Kristen|K|;Shah|Biraj|B|;Yan|Yun|Y|;Khatri|Surya|S|;Caccamese|John|J|;Napoli|Joseph A|JA|;Bober|Michael B|MB|;Crane|Janet L|JL|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fped.2020.00515",
"fulltext": "\n==== Front\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360 Frontiers Media S.A. \n\n10.3389/fped.2020.00515\nPediatrics\nCase Report\nCase Report: Safety and Efficacy of Denosumab in Four Children With Noonan Syndrome With Multiple Giant Cell Lesions of the Jaw\nFerriero Kristen 1 Shah Biraj 2 Yan Yun 3 Khatri Surya 4 Caccamese John 5 Napoli Joseph A. 6 Bober Michael B. 7 Crane Janet L. 4* 1Department of Pediatrics, Division of Genetics, Alfred I. duPont Hospital for Children, Wilmington, DE, United States\n2Department of Oral and Maxillofacial Surgery, John H. Jr, Stroger Hospital of Cook County, Chicago, IL, United States\n3Division of Endocrinology, Children Mercy Kansas City, University of Missouri- Kansas City, School of Medicine, Kansas City, MO, United States\n4Department of Pediatrics, Division of Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD, United States\n5Department of Oral and Maxillofacial Surgery, University of Maryland School of Dentistry, Baltimore, MD, United States\n6Division of Plastic and Reconstructive Surgery, Childrens Hospital of Philadelphia, Philadelphia, PA, United States\n7Department of Pediatrics, Division of Orthogenetics, Alfred I. duPont Hospital for Children, Wilmington, DE, United States\nEdited by: Fabrizio Barbetti, University of Rome Tor Vergata, Italy\n\nReviewed by: Raja Padidela, Royal Manchester Children's Hospital, United Kingdom; Maria G. Vogiatzi, University of Pennsylvania, United States\n\n*Correspondence: Janet L. Crane jcrane2@jhmi.eduThis article was submitted to Pediatric Endocrinology, a section of the journal Frontiers in Pediatrics\n\n\n18 9 2020 \n2020 \n8 51505 5 2020 21 7 2020 Copyright © 2020 Ferriero, Shah, Yan, Khatri, Caccamese, Napoli, Bober and Crane.2020Ferriero, Shah, Yan, Khatri, Caccamese, Napoli, Bober and CraneThis 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.Noonan syndrome is a genetic disorder caused by mutations in the RAS/MAPK pathway. Multiple giant cell lesions are a rare sequelae of disruptions in this pathway, termed Noonan-like multiple giant cell lesions (NL/MGCLs). Medical management of these tumors rather than surgical intervention is preferential as the lesions are benign but locally destructive and recurring. This case series describes four male pediatric patients with Noonan syndrome and multiple giant cell lesions of the jaw treated with denosumab, a monoclonal antibody to receptor activator of nuclear factor kappa B ligand (RANKL), which has been approved for the treatment of malignant giant cell tumors in adults but not evaluated for safety or efficacy in children. All four pediatric patients responded clinically and radiographically to the treatment. Adverse events occurred in a predictable pattern and included hypocalcemia and joint pain during the initiation of treatment and symptomatic hypercalcemia after the cessation of treatment. Growth was not significantly impaired in these skeletally immature patients. This case series demonstrates how a weight-adjusted denosumab dose can effectively treat NL/MGCLs and provides laboratory data for consideration of the timing of monitoring for known side effects.\n\nNoonan syndromemultiple giant cell lesionsdenosumabjawchildNational Institute of Arthritis and Musculoskeletal and Skin Diseases10.13039/100000069\n==== Body\nIntroduction\nNoonan syndrome is a relatively common genetic syndrome occurring in an estimated 1 in 1,000–2,500 live births (1). Mutations in the Ras/mitogen-activated protein kinase (RAS/MAPK) pathway, which regulates cell growth, differentiation, senescence, and death, have been identified in Noonan syndrome. Multiple giant cell lesions (MGCLs), also known as central giant cell lesions or giant cell granulomas, are non-neoplastic lesions characterized by a proliferation of granulation tissue containing multinucleated giant cells embedded in a fibrous stroma (2). MGCL is a rare but typical complication of a dysregulated RAS/MAPK pathway, including Noonan syndrome, termed NL/MGCLS, and shares phenotypic characteristics of cherubism (3, 4). The underlying genetic mutations and sequelae distinguish the two. Mutations in PTPN11 (5, 6) and SOS1 (2, 7, 8) have been reported in people with NL/MGCLS, whereas mutations in SH3BP2 are associated with cherubism (9). Giant cell lesions in cherubism tend to spontaneously resolve, whereas those observed in NL/MGCLS can have aggressive signs and symptoms (10–12). MGCLs most commonly occur in the jaw and joints (pigmented villonodular synovitis) (2).\n\nMGCLs, as opposed to giant cell tumors of the bone, are benign but locally aggressive tumors that cause osteolytic destruction of bone (13). Multiple medical treatments have been explored with variable efficacy (11, 12). Surgical resection, similar to the tumor itself, often leads to disfigurement, especially in cases with jaw involvement. Enucleation and curettage has also been used but is associated with a high recurrence rate and does not completely avoid the morbidity associated with resection (14). An effective medical treatment option would be preferential. Both MGCLs and giant cell tumors are composed of osteoclast-like giant cells that express the receptor activator of nuclear factor kappa B (RANK) and mononuclear stromal cells that express RANK ligand (RANKL) (15), leading to osteoclast activation (16). Denosumab, a RANKL monoclonal antibody that inhibits osteolytic activation, is approved for malignant giant cell tumors in adults (16). Safety and efficacy of denosumab in MGCLs is limited to case reports, which have demonstrated successful avoidance of surgery and radiologic improvement with denosumab treatment. Only one case in an adult with Noonan syndrome has been published to date (17). Further data are needed, particularly in the pediatric population, to understand the efficacy and potential side effects on the growing skeleton.\n\nCase Description\nThis retrospective case series describes the safety and efficacy of denosumab treatment in four children (3, 17, 8, and 13 years old) with NL/MGCLs of the jaw. The diagnosis of Noonan syndrome was based on clinical phenotype in three of the patients, whereas one patient was recognized only after genetic testing for MGCLs. All patients had symptomatic lesions affecting tooth positioning, chewing, and/or facial disfigurement. Surgical and medical options were discussed, including surgical curettage, calcitonin, bisphosphonate, interferon, and denosumab. After discussions between the care team and families, the decision was made to try denosumab. Baseline labs and Dual-energy X-ray absorptiometry (DXA) were obtained. Weight-based dosing was calculated by using the approved adult dose (120 mg per month) and dividing by an average adult weight of 70 kg. Legal guardians of all patients signed written informed consent for inclusion in this report. Baseline characteristics of the four patients are shown in Table 1. NL/MGCLs improved grossly and radiographically within 6 months (Figure 1). Complications of treatment included joint pain, hypocalcemia, and hypercalcemia when initiating and discontinuing denosumab, respectively (Figure 2).\n\nTable 1 Basic patient characteristics.\n\n\tCase 1\tCase 2\tCase 3\tCase 4\t\nNoonan mutation\tSOS1 heterozygous c.2536G>A (p.Glu846Lys), Exon 16, SOS1, pathogenic, de novo\tND\tPTPN11 gene, heterozygous, p.Asn200Tyr, c.598 A>T, likely pathogenic\tSOS1 heterozygous disease-associated missense mutation in exon 10 of the SOS1 gene, c.1310T>C (p.Ile437Thr)\t\nAge at Presentation\t3 yo\t17 yo\t8 yo\t13 yo\t\nPhysical features of Noonan syndrome\tPtosis, downslanting palpebral fissures, posteriorly angulated ears, cryptorchidism, and pectus excavatum\tDownslanting palpebral fissures, rounded eyebrows, posterior rotation of ears with thickened helices, low hairline, wide neck, pulmonary stenosis and ASD, cryptorchidism, and short stature\tBilateral epicanthal folds, and slightly posteriorly rotated ears\tSlightly increased inner canthal distance. Down slanting palpebral fissures. Rounded eyebrows.\n Posterior rotation of ears with thickened helices.\n Depressed nasal bridge. Slightly wide nasal tip.\n High, widely spaced peaks of the vermillion border. High palate.\n Low hairline.\n Upper pectus carinatum with lower pectus excavatum.\t\nLaterality\tBilateral\tCentral\tBilateral\tBilateral\t\nNumber of Lesions\t5\t3\t2\t2\t\nSize of Lesions\tLeft Mandible: 4.95 cm × 1.9 cm × 3.2 cm. Right Mandible: 4.0 cm × 1.42 cm × 2.6 cm. Right Maxilla: 2.6 cm × 1.7 cm × 1.5 cm. Left Maxilla: 1.65 cm × 2.15 cm × 0.98 cm. Anterior Left Maxilla: 1.1 cm × 1.1 cm × 2.2 cm\tAnterior Mandible: 2.4 cm × 4.2 cm.\n Right Mandible: 5.0 cm × 4.3 cm.\n Left Mandible: 4.0 cm × 7.3 cm\tRight Mandible: 3.6 cm × 6.0 cm × 4.2 cm. Left Mandible: 2.6 cm × 3.4 cm × 3.9 cm\tRight Mandible: 2.5 cm × 1.5 cm × 5.6 cm SI.\n Left Mandible: 2.3 cm × 1.6 cm × 3.6\t\nFigure 1 Radiography before and after denosumab in four children with Noonan-like/multiple giant cell lesions (NL/MGCLs). (A–H) Case 1 baseline images (A–D) of 3-dimensional (3D) computed tomography (CT) reconstruction of frontal (A) and profile (B) views, axial CT without contrast (C), and axial magnetic resonance imaging (MRI) (D) at the level of mandibular molars relative to post-denosumab (E–H) 3D CT reconstruction of frontal (E) and profile (F) views, axial CT without contrast (G) 8 months after initial denosumab treatment, and axial magnetic resonance imaging (MRI) (F) at the level of mandibular molars 15 months after second denosumab treatment. (I–L) Case 2 dental orthopantomogram at baseline (I) and after on denosumab for 6 (J), 12 (K), and 18 (L) months. (M, N) Case 3: dental orthopantomogram at baseline (M) and after on denosumab for 5 months (N). (O,P) Case 4: baseline axial (O) and coronal (P) CT without contrast at level of mandibular molars. Red arrows and circles denote NL/MGCLs.\n\nFigure 2 Laboratory assessment in relation to denosumab pre-treatment, during treatment, and post-treatment in four children with Noonan-like/multiple giant cell lesions (NL/MGCLs). (A) Serum calcium. (B) Serum phosphorus. (C) Parathyroid hormone (PTH). (D) Alkaline Phosphatase. (E) Serum carboxy-terminal telopeptide (C-Telopeptide), marker of bone resorption. (F) Osteocalcin, marker of bone formation. Normal ranges for calcium and phosphorus are indicated by dashed line.\n\nCase 1\nA 3-year-old male with Noonan syndrome (SOS1 mutation) presented with asymptomatic jaw swelling and was found to have NL/MGCLs of the jaw bilaterally (Figure 1). He was started on denosumab 25 mg subcutaneously every 4 weeks. During treatment, calcium levels remained within normal limits without need for calcium or vitamin D supplementation. Response to treatment was monitored by MRI and physical exam. After four doses, the NL/MGCLs had significantly decreased in size. He received four additional monthly treatments. Denosumab was discontinued as his MRI showed stabilization of the lesions (Figure 1) and his bone mineral density (BMD) had increased (Table 2). About 2 months after discontinuation of denosumab, he refused to walk and was found to be hypercalcemic to 13.6 mg/dL. He was treated with hyperhydration, furosemide, calcitonin, and ultimately pamidronate (0.5 mg/kg/dose). X-rays of long bones showed dense bands in metaphyses consistent with anti-resorptive use (Supplemental Figure 1). He was able to bear weight as his calcium normalized. He was re-hospitalized for hypercalcemia (peak calcium 15.5 mg/dL) another 2 weeks later. Treatment included hyperhydration, calcitonin, and pamidronate, which decreased the serum calcium significantly prior to discharge. He had stable disease until about 2 years off treatment, when an MRI showed an enlargement of his NL/MGCLs, although not as large as in the initial presentation. Although his BMD had increased above the normal range after 8 months of denosumab, DXA prior to the start of the second treatment showed normalization of BMD (Table 2 and Supplemental Table 1). During this second round of denosumab, he was started on calcium supplementation (500 mg twice daily) due to reported poor dietary calcium intake. Denosumab dose was adjusted for weight gain to a maximum dose of 36 mg. Calcium and phosphorus levels remained within normal limits during treatment (Figure 2). Follow-up MRIs obtained 6 and 12 months after the re-initiation of treatment showed interval decrease in size and remineralization of the lesions. Denosumab was discontinued after 15 months as MRI showed stabilization of the lesions without continued improvement (Figure 1). He developed rebound hypercalcemia (peak calcium 15 mg/dL) requiring hospitalization and treatment with hyperhydration and pamidronate almost 4 months later.\n\nTable 2 Treatment details.\n\n\tCase 1\tCase 2\tCase 3\tCase 4\t\nDose\t1.7 mg/kg (25–36 mg)\t1.3–1.7 mg/kg (60 mg)\t1.5–1.7 mg/kg (35 mg)\t1.7 mg/kg (60 mg)\t\nTreatment Frequency\tMonthly\t0, 7, 14, and 28 days for initiation, then every 4 weeks × 1 year, then every 3–4 months × 1 year\tMonthly\tMonthly\t\nTreatment Duration\t4/2015–12/2015. 4/2018–8/2019\t07/2016–08/2018\t05/2017–01/2018\t09/2018–03/2019\t\nHeight z-score Pre-Treatment\t−2.38; −2.64\t−2.2\t+0.1\t−1.68\t\nHeight z-score Post-Treatment\t−2.19; −3.01\t−1.2\t0.0\t−1.44\t\nBaseline Bone Mineral Density Height-adjusted Z-Scores\t4/2015:\n Spine +0.26;\n 4/2018: Spine +0.86\t8/2016:\n Spine −2.5;\n Total Body −3.4\t1/2017:\n Spine −1.7;\n TBLH −1.3\t8/2018:\n Spine +0.5\t\nBone Mineral Density Height-adjusted Z-Scores Post-Treatment\t12/2015:\n Spine +2.8; 5/2019:\n Spine +2.9\t2/2017:\n Spine −1.6;\n Total Body −2.6;\n TBLH −1.3\t2/2018:\n Spine: +0.3;\n TBLH +1.0\t3/2019:\n Spine +2.2\t\nNotable Labs\tHypercalcemia (2/2016–3/2016 and 11/2019-12/2019)\tHypocalcemia (11/2016), hypercalcemia (5/2018)\tHypercalcemia (3/2018)\tHypocalcemia (12/2018),\n Hypercalcemia (7/2019)\t\nAdverse Events\tHospital admission × 4 for pamidronate\tNo hospitalizations\tHospital admission × 1 for zoledronate\tKnee pain during treatment course.\n Hands and toe aching in addition to worsened knee pain with difficulty walking 6 weeks after the injection was discontinued\t\nCase 2\nA 17-year-old male with Noonan syndrome (diagnosed clinically in infancy) presented with recurrent NL/MGCLs of the jaw, status-post two surgical resections, 3 and 2 years prior. He had two benign lesions in the mandibular rami and one aggressive lesion in the symphysis. He reported alterations with eating secondary to loose teeth. After the correction of vitamin D deficiency, he was started on denosumab 60 mg, given at 0, 7, 14, and 28 days, then every 4 weeks for 1 year. He was advised to also take elemental calcium 500 mg three times daily. Dental orthopantomogram X-rays were taken approximately every 6 months (Figure 1). X-rays showed increasing radiopacity of the ramus lesions in response to denosumab, suggestive of increased calcification, and formation of normal bony trabeculation. Treatment did not prevent the loss of the two mandibular central incisors, but his other teeth solidified and he was able to eat food without pain. The bone resorption marker, carboxy-terminal collagen telopeptide (CTX), was elevated pre-treatment and suppressed to the normal range. The bone formation marker osteocalcin showed a similar pattern, elevated early in treatment that suppressed to normal range throughout the treatment phase (Figure 2). By 2 months of treatment, he developed symptomatic hypocalcemia (5.3 mg/dL). Parathyroid hormone levels were appropriately elevated. Calcium improved initially with increasing calcium and cholecalciferol supplementation. Calcitriol (0.25 mg daily) was started with recurrent hypocalcemia with waning supplementation compliance, which stabilized calcium. After 1 year of monthly denosumab, frequency was extended to every 3 months. Delay beyond 3 months resulted in symptomatic hypercalcemia (peak 11.5 mg/dL) and coincided with elevations in CTX, indicative of rebound hypercalcemia secondary to bone resorption. Symptoms, including unbearable knee and shoulder pain and mild elbow pain, resolved within 3 days after denosumab. To stop denosumab while reducing the risk of rebound hypercalcemia, he was started on alendronate (35 mg by mouth weekly for 1 month) 2.5 months after last denosumab injection. Calcium remained normal 24 weeks after the last denosumab injection. Of note, he was treated with growth hormone for short stature prior to and continued (17–19 years of age) while on denosumab. His height increased from a z-score of −2.15 to a z-score of −1.2 (Table 2). Bone age X-rays showed sclerotic bands in metaphyses (Supplemental Figure 1).\n\nCase 3\nAn 8-year-old male presented for a concern of mandibular MGCLs, initially noted at 5 years of age and monitored conservatively. By 8 years of age, he was noted to have facial disfigurement, with an expansion of two benign lesions of the mandible bilaterally, giving rise to a cherub-appearing face. He had mild pain associated with the contour and bulkiness of the lesions, which made chewing uncomfortable. Genetic workup revealed a PTPN11 mutation consistent with Noonan syndrome. He was started on denosumab 35 mg subcutaneously every 4 weeks. Baseline labs and DXA were obtained (Figure 2 and Table 2). Cholecalciferol was prescribed to optimize 25-OH vitamin D. He received six denosumab doses over the course of 7.5 months. There was an unintentional gap of 2.5 months between the third and fourth dose. Serum calcium 4 days after initial denosumab dose and prior to the fourth dose was normal (Figure 2). CTX was elevated pre-treatment and suppressed to the normal range, while osteocalcin was suppressed below normal throughout the treatment phase. Within 5 months, he reported improvement in pain, including while eating. On physical exam, the mandible shape had normalized. Dental orthopantomogram X-rays showed improvement in radiodensity, suggesting improved calcification and bony trabeculation (Figure 2). There was also improvement in the path of eruption of the mandibular right first molar and left second molar, suggestive of resolving mandibular lesions. BMD by DXA increased but remained within the normal range for age. Densoumab frequency was extended. Two months between doses, calcium remained normal. However, further extension between doses resulted in symptomatic hypercalcemia (peak calcium 14.6 mg/dL) with arm and leg pain and abnormal gait after 10 weeks. X-rays of the extremities were normal, with the exception of a subcortical lucency of the distal metaphyses (Supplemental Figure 1). Serum CTX was elevated, indicative of increased bone resorption. He was given hyperhydration and zoledronate (0.0125 mg/kg). Calcium reached a nadir (7.9 mg/dL) ~48 h after zoledronate. Thereafter, calcium remained normal. Twenty-one months after the last denosumab, he denied any jaw pain or problems chewing but acknowledged intermittent leg pain associated with exercise. Physical exam showed normal jaw contour. Long bone x-rays remained normal (Supplemental Figure 1).\n\nCase 4\nA 13-year-old male with Noonan syndrome (SOS1 mutation) presented with expanding mandibular NL/MGCLs, noted 4 years prior, but were now causing jaw pain and physical deformity with a cherub-appearing face. CT scan revealed bilateral mandibular, expansile cysts with cortical thinning (Figure 1). No disruption to teeth was noted, but he had required two dental procedures for tooth extractions. He was started on denosumab 60 mg monthly. After 6 months, physical exam revealed decreased jaw asymmetry and facial deformity. Radiographically, there was evidence of the consolidation of the cystic masses. Complications during his treatment course included throbbing pain in his knees 1 week after denosumab. Knee pain became less severe with subsequent injections. Calcium levels were slightly low (8.4 mg/dL); therefore, he was advised to take calcium and vitamin D3 supplements (Figure 2). After 6 months of treatment, BMD by DXA increased above the normal range in the spine (Table 2) but remained within the normal range for age at the distal femur (Supplemental Table 1). Therefore, the denosumab frequency was extended. At 6 weeks, 25-OH vitamin D was slightly low (19 ng/mL) with elevated PTH (175 pg/mL); calcium was normal (9.8 mg/dL). He was restarted on vitamin D3 and calcium supplements, and then discontinued, when at 10 weeks post-treatment, calcium was in the upper end of normal (10.3 mg/dL). He reported difficulty walking secondary to pain all over his body, but worse in hands, toes, and knees. By 12 weeks, pain persisted, and calcium had increased to 10.7 mg/dL with elevated urine calcium to creatinine ratio (580 mg Ca/g Cr). He was given one additional dose of denosumab 30 mg, which provided some pain relief and improvement in urinary calcium to creatinine ratio (20 mg Ca/g Cr). Eight weeks later, calcium was again elevated (11.3 mg/dL), and he was started on alendronate (35 mg by mouth weekly, increased to 70 mg when calcium did not decrease). Pain significantly worsened with a peak calcium of 13.2 mg/dL requiring hospitalization and treatment with hyperhydration and zoledronate (0.0125 mg/kg). Calcium nadir (8.9 mg/dL) occurred ~36 h after zoledronate. Two weeks later, hypercalcemia returned and was successfully managed with oral alendronate (70 mg by mouth 1 weekly for 2 months). Knee and bone age X-rays performed throughout treatment were remarkable for dense sclerotic metaphyseal bands and widening of the growth plates (Supplemental Figure 1).\n\nDiscussion\nThere is significant phenotypic heterogeneity in Noonan syndrome among our patients. Cardinal features include short stature, cardiovascular defects, broad or webbed neck, pectus deformity, developmental delay, cryptorchidism, and characteristic facies (18). In our cohort, three of the four patients had an established diagnosis of Noonan's syndrome prior to development of MGCLs, whereas the Noonan phenotype was not overtly obvious and diagnosis was not made until presentation with MGCLs in one of the four. Although rare, giant cell tumors of the jaw, which can arise from dysregulation of RAS/MAPK pathways, should also be considered part of the phenotypic presentation of Noonan syndrome (7). Given the differing clinical courses and potential additional systems that may be affected, genetic testing should be considered in children presenting with giant cell tumors of the jaw with specific testing for mutations in PTPN11, SOS1, and SH3BP2 (2, 5–9).\n\nGiant cell tumors are composed of osteoclast-like giant cells that have formed secondary to stromal cell expression of RANKL. Denosumab, a monoclonal antibody against RANKL, has been approved by the United States Food and Drug Administration and by the European Medicines Agency following a clinical study evaluating the efficacy for malignant giant cell tumors in skeletally mature adults and adolescents (19). Given the unknown and unstudied effects of denosumab on growing bones, the use of denosumab in children has been limited. To date, we have found reports of 17 children and adolescents in the literature who have been treated with denosumab for various indications, including osteogenesis imperfecta type VI (20), juvenile Paget's disease (21), giant cell tumors (22–26), fibrous dysplasia (27), osteoglyphonic dysplasia (28), cherubism (17), and non-syndromic giant cell lesions of the jaw (17, 26). The use of denosumab in NL/MGCL has been reported in one adult (17). The safety and efficacy in non-skeletally mature people with NL/MGCL have not previously been reported.\n\nAll of our patients showed resolution of symptoms associated with their mandibular NL/MGCLs, likely because of the regression of MGCLs within the mandible. In all cases, the MRI, CT scans, and dental orthopantograms showed regression of the MGCLs and improvement in the radiographic appearance of mandibular bone. As shown in Figure 2, there was a significant increase in the radiodensity of the mandibular bone. The improved radiographic appearance of these lesions is suggestive of normalization of mandibular bony architecture; however, this cannot be concluded without a biopsy of the newly formed bone within the previous lesions. We achieved very similar results with denosumab in our patients with NL/MGCLs relative to patients with non-syndromic central giant cell lesions (17, 26). Using denosumab, we were able to avoid drastic surgical interventions, which risk extensive facial disfigurement, damage to developing teeth, injury to inferior alveolar nerve, and altered growth of the mandible. Although imaging studies showed improvement of the bone density in the lesions, the bony expansion caused by these lesions did not reduce. Some patients may require recontouring of the facial bone to provide improved esthetics.\n\nObserved side effects were similar as previously described, including hypocalcemia during treatment and rebound hypercalcemia with discontinuation (17, 20–27). Namely, three of the four patients experienced hypocalcemia with the initiation of denosumab, noted within 1 week after medication administration, which was corrected with calcium supplementation. One patient who had non-adherence to calcium supplementation had more severe protracted hypocalcemia, which improved with the addition of calcitriol. None required hospitalization for hypocalcemia. All four cases experienced rebound hypercalcemia when discontinuing denosumab. The timing of hypercalcemia occurred between 67 and 80 days after the last monthly denosumab dose (Figure 2A). Two of four patients were treated with additional doses of denosumab, which quickly resolved the hypercalcemia, but recurred again 57–90 days later. All four patients required treatment with a bisphosphonate. Three had significant enough hypercalcemia to warrant hospitalization and treatment with bisphosphonate infusion, whereas hypercalcemia was prevented in one case by using alendronate orally preemptively beginning about 50 days after the last denosumab dose and continuing for 1 full month. One case had further hypercalcemia after zoledronate, which was managed with alendronate 70 mg weekly orally. No patient developed osteonecrosis of the jaw.\n\nAs the effect of denosumab on the growing skeleton remains unknown, extreme caution was utilized in monitoring for potential skeletal side effects. All four cases were skeletally immature during the denosumab treatment course. Height z-score remained stable (Case 1 and 3) or increased (Case 2 and 4). Height z-score increase (+1 standard deviation score) in Case 2 was attributed to concurrent treatment with growth hormone. At baseline, BMD assessed by DXA was low in two of four cases, and although within the normal range, below the 50th percentile for the other two cases. BMD increased in all patients but did not exceed the normal range. All four cases experienced extremity/joint pain coinciding with hypercalcemia. One case also reported extremity/joint pain during treatment with denosumab that was most intense in the week following injections and improved within 10 days. X-rays were obtained in three of the four cases and were all notable for metaphyseal sclerosis and widening of the growth plates, similar to the bone changes observed in children treated with bisphosphonates (29) (Supplemental Figure 1). Noonan syndrome is also associated with pigmented villonodular synovitis, a benign proliferative disorder of the large synovial joints or of the tendon sheath of small joints. Presenting symptoms including painless swelling of the joints (30). The resolution of symptoms within a few days of each case did not warrant tissue biopsy to evaluate for this but may be a unique risk factor in the NL/MGCL population.\n\nOsteonecrosis of the jaw (ONJ) has been noted to occur in up to 1% of adults receiving denosumab treatment for giant cell tumors (19), and one case has been described in the literature describing ONJ in a child (25). To reduce risk of ONJ, all patients were counseled on good dental hygiene. They were instructed to continue with routine dental care, including brushing and flossing twice a day, and encouraged to set up regular checkups with their dentist for routine cleanings and necessary care. In this case series, none of the patients developed ONJ, even with the targeted lesions being within the jaw. There is suspicion that the risk of ONJ may be associated with a cumulative dose. In the Uday case, the patient who developed ONJ had an unresectable sacral giant cell tumor that was treated with denosumab, 120 mg loading, then monthly for a total of 46 doses, with a total treatment dose of 5,520 mg. In comparison, cases 1–4 received a total denosumab dose of 460, 1,080, 210, and 390 mg, respectively, which is significantly less. In NL/MGCLs, dosing denosumab using a weight-based dose may help reduce risk of adverse effects while still maintaining efficacy.\n\nWe report that a weight-adjusted denosumab dose improved NL/MGCLs. There is limited information in the literature regarding the medical treatment of NL-MGCLs, and there are no randomized clinical trials comparing or showing efficacy of specific medical treatment for NL-MGCLs. In this case series, denosumab treatment has shown excellent results. Alternatively intra-lesional injection of corticosteroids, systemic calcitonin, and interferon has been reported for the treatment of central giant cell granulomas of the jaw; but, they have shown variable results (31, 32). More recently, oral imatinib has been used for treatment of isolated central giant cell lesions and those associated with cherubism (33); however, the data are limited to case reports and small series. The patients with NL/MGCLs in this study have shown excellent response in regression of the tumor with minimal side effects using denosumab. Strengths of the study include usage of a uniform dose among cases for a minimum of 6 months. Limitations of the study include limited sample size, lack of control for comparison, and variation in monitoring for safety and efficacy. Despite the limitations, all four patients demonstrated a significant improvement in NL/MGCLs and were able to avoid further surgery.\n\nInterdisciplinary care, including genetics, oral surgery, and endocrinology, was an important factor in monitoring both safety and efficacy. To avoid hypocalcemia while on denosumab, laboratory data support the optimization of 25-OH vitamin D status prior to and supplementation with calcium if history elicits a calcium deficient diet. At the cessation of denosumab therapy, hypercalcemia occurred within a finite window of 10–11 weeks after the last dose with delay of hypercalcemia noted with preemptive treatment strategies. Based on our collective knowledge gained in these four cases, a proposed treatment regimen for further long-term studies to evaluate safety and efficacy of denosumab in NL/MGCLs would include monthly subcutaneous denosumab 1.7 mg/kg for 6 months. Serum calcium should be monitored periodically throughout treatment and at least 4 months after cessation. Monitoring urine calcium to creatinine ratio may be useful after the cessation of therapy as well as hypercalcemia appears to occur after renal calcium excretion capacity is exceeded. Administration of a bisphosphonate (either orally or intravenously) 8–10 weeks after cessation of denosumab may help prevent rebound hypercalcemia. On-going monitoring of NL/MGCLs continues and is necessary to assess for disease recurrence.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Johns Hopkins Institutional Review Board, Baltimore, MD 21205. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nKF, BS, YY, and JLC wrote the manuscript. KF, BS, JC, and JLC collected the data, KF and SK organized and data, and KF, YY, JC, JN, MB, and JLC followed up the case. MB and JLC supervised the management and follow up of the case. All authors revised and approved the final manuscript and agreed to be accountable for the content of the work.\n\nConflict of Interest\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 would like to thank the patients and their families. Written informed consent was obtained from the patients' parent for publication and accompanying images.\n\nFunding. JLC received funding support from the US National Institutes of Health (AR073939).\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fped.2020.00515/full#supplementary-material\n\nClick here for additional data file.\n\n Click here for additional data file.\n\n Click here for additional data file.\n==== Refs\nReferences\n1. Allen MJ Sharma S \nNoonan Syndrome . Treasure Island, FL : StatPearls (2020 ).\n2. Beneteau C Cave H Moncla A Dorison N Munnich A Verloes A . SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions\n. Eur J Hum Genet. (2009 ) 17 :1216 –21\n. 10.1038/ejhg.2009.44 19352411 \n3. Dunlap C Neville B Vickers RA O'Neil D Barker B . The Noonan syndrome/cherubism association\n. Oral Surg Oral Med Oral Pathol. (1989 ) 67 :698 –705\n. 10.1016/0030-4220(89)90012-1 2740093 \n4. Cohen MM JrGorlin RJ . Noonan-like/multiple giant cell lesion syndrome\n. 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(2018 ) 2018 :7698052 . 10.1155/2018/7698052 30631623 \n31. Chrcanovic BR Gomes CC Gomez RS . Central giant cell lesion of the jaws: an updated analysis of 2270 cases reported in the literature\n. J Oral Pathol Med. (2018 ) 47 :731 –9\n. 10.1111/jop.12730 29751369 \n32. Chrcanovic BR Guimaraes LM Gomes CC Gomez RS . Cherubism: a systematic literature review of clinical and molecular aspects\n. Int J Oral Maxillofac Surg. (2020 ) 10.1016/j.ijom.2020.05.021 32620450 \n33. Ricalde P Ahson I Schaefer ST . A paradigm shift in the management of cherubism? A preliminary report using imatinib\n. J Oral Maxillofac Surg. (2019 ) 77 :1278 e1 –e7\n. 10.1016/j.joms.2019.02.021 30880133\n\n",
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"issn_linking": "2296-2360",
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"journal": "Frontiers in pediatrics",
"keywords": "Noonan syndrome; child; denosumab; jaw; multiple giant cell lesions",
"medline_ta": "Front Pediatr",
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"nlm_unique_id": "101615492",
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"pages": "515",
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"pmid": "33042901",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "20305546;19352411;17606790;2740093;29035698;12378481;30631623;29211870;25556556;18854871;29504582;10535540;30283883;22711702;17222357;25262402;30998511;29751369;30880133;31353534;26056018;11381256;23788687;11704759;15689434;23867211;16462511;1897569;31667453;22431375;3462363;32620450",
"title": "Case Report: Safety and Efficacy of Denosumab in Four Children With Noonan Syndrome With Multiple Giant Cell Lesions of the Jaw.",
"title_normalized": "case report safety and efficacy of denosumab in four children with noonan syndrome with multiple giant cell lesions of the jaw"
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"abstract": "OBJECTIVE\nTo assess the effect of metformin and to compare it with insulin treatment in patients with type 2 diabetes in pregnancy in terms of perinatal outcome, maternal complications, additional insulin requirement, and treatment acceptability.\n\n\nMETHODS\nIn this randomized, open label study, 206 patients with type 2 diabetes in pregnancy who met the eligibility criteria were selected from the antenatal clinics. Insulin was added to metformin treatment when required, to maintain the target glycemic control. The patients were followed up till delivery. Maternal, and perinatal outcomes and pharmacotherapeutic characteristics were recorded on a proforma.\n\n\nRESULTS\nMaternal characteristics were comparable in metformin and insulin treated group. 84.9% patients in metformin group required add-on insulin therapy at mean gestational age of 26.58 ± 3.85 weeks. Less maternal weight gain (P < 0.001) and pregnancy induced hypertension (P = 0.029) were observed in metformin treated group. Small for date babies were more in metformin group (P < 0.01). Neonatal hypoglycemia was significantly less and so was NICU stay of >24 hours in metformin group (P < 0.01). Significant reduction in cost of treatment was found in metformin group.\n\n\nCONCLUSIONS\nMetformin alone or with add-on insulin is an effective and cheap treatment option for patients with type 2 diabetes in pregnancy. This trial is registered with clinical trial registration number: Clinical trials.gov NCT01855763.",
"affiliations": "Department of Obstetrics and Gynecology, Dow University of Health Sciences, Karachi 74400, Pakistan.;Department of Pharmacology, Medical and Dental College, Bahria University, Karachi 75500, Pakistan.;School of Public Health, Dow University of Health Sciences, Karachi 75300, Pakistan.;Department of Community Health Sciences, United Medical and Dental College, Karachi 74900, Pakistan.;Department of Obstetrics and Gynecology, Hamdard University Hospital, Karachi 74400, Pakistan.",
"authors": "Ainuddin|Jahan Ara|JA|;Karim|Nasim|N|;Zaheer|Sidra|S|;Ali|Syed Sanwer|SS|;Hasan|Anjum Ara|AA|",
"chemical_list": "D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin",
"country": "England",
"delete": false,
"doi": "10.1155/2015/325851",
"fulltext": "\n==== Front\nJ Diabetes ResJ Diabetes ResJDRJournal of Diabetes Research2314-67452314-6753Hindawi Publishing Corporation 10.1155/2015/325851Research ArticleMetformin Treatment in Type 2 Diabetes in Pregnancy: An Active Controlled, Parallel-Group, Randomized, Open Label Study in Patients with Type 2 Diabetes in Pregnancy Ainuddin Jahan Ara \n1\n\n*\nKarim Nasim \n2\nZaheer Sidra \n3\nAli Syed Sanwer \n4\nHasan Anjum Ara \n5\n1Department of Obstetrics and Gynecology, Dow University of Health Sciences, Karachi 74400, Pakistan2Department of Pharmacology, Medical and Dental College, Bahria University, Karachi 75500, Pakistan3School of Public Health, Dow University of Health Sciences, Karachi 75300, Pakistan4Department of Community Health Sciences, United Medical and Dental College, Karachi 74900, Pakistan5Department of Obstetrics and Gynecology, Hamdard University Hospital, Karachi 74400, Pakistan*Jahan Ara Ainuddin: jahanaraainuddin@yahoo.comAcademic Editor: Vipin Gupta\n\n2015 22 3 2015 2015 32585114 12 2014 12 2 2015 20 2 2015 Copyright © 2015 Jahan Ara Ainuddin et al.2015This 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.\nAims. To assess the effect of metformin and to compare it with insulin treatment in patients with type 2 diabetes in pregnancy in terms of perinatal outcome, maternal complications, additional insulin requirement, and treatment acceptability. Methods. In this randomized, open label study, 206 patients with type 2 diabetes in pregnancy who met the eligibility criteria were selected from the antenatal clinics. Insulin was added to metformin treatment when required, to maintain the target glycemic control. The patients were followed up till delivery. Maternal, and perinatal outcomes and pharmacotherapeutic characteristics were recorded on a proforma. Results. Maternal characteristics were comparable in metformin and insulin treated group. 84.9% patients in metformin group required add-on insulin therapy at mean gestational age of 26.58 ± 3.85 weeks. Less maternal weight gain (P < 0.001) and pregnancy induced hypertension (P = 0.029) were observed in metformin treated group. Small for date babies were more in metformin group (P < 0.01). Neonatal hypoglycemia was significantly less and so was NICU stay of >24 hours in metformin group (P < 0.01). Significant reduction in cost of treatment was found in metformin group. Conclusion. Metformin alone or with add-on insulin is an effective and cheap treatment option for patients with type 2 diabetes in pregnancy. This trial is registered with clinical trial registration number: Clinical trials.gov NCT01855763.\n==== Body\n1. Introduction\nDiabetes in pregnancy is becoming more common worldwide especially in South Asian countries like Pakistan. This is attributed to an increase in incidence of obesity and type 2 diabetes. Type 2 diabetes is a metabolic disorder characterized by hyperglycemia resulting from progressive deterioration in pancreatic insulin secretion, insulin resistance in tissues, and inadequate suppression of glucagon production [1]. Treatment of diabetes in pregnancy reduces serious perinatal morbidity, improves women's health related quality of life, and decreases maternal complications [2]. The increasing prevalence of type 2 diabetes in pregnancy brings with it specific challenges in terms of management. One such challenge that needs to be answered is, should metformin, an antihyperglycemic agent, be used in pregnancy with diabetes? Metformin is recommended as first-line treatment for patients with type 2 diabetes by American Diabetes Association [3]. However, metformin is not yet accepted as treatment for gestational diabetes and type 2 diabetes in pregnancy. Metformin offers a logical alternative to insulin in gestational diabetes and type 2 diabetes in pregnancy as it produces euglycemia by reducing insulin resistance, improving insulin sensitivity, reducing hepatic gluconeogenesis, and increasing peripheral glucose uptake and utilization. It also increases markers of endothelial activation which are intimately associated with insulin resistance [4–6]. Metformin, a category B drug, is not associated with fetal anomalies. Recent trial evidences support its safety and efficacy in pregnancy with gestational diabetes [7]. However as metformin crosses the placental barrier, fetal effects need to be considered [8]. Women with polycystic ovarian syndrome who continued on metformin throughout pregnancy showed decreased risk of miscarriages, preeclampsia, and gestational diabetes with better pregnancy outcomes and no increase in risk of congenital anomalies in newborns [9, 10]. There is paucity of data in terms of clinical trials relating specifically to metformin treatment in women with type 2 diabetes in pregnancy. We have a population that brings specific challenges in terms of marked insulin resistance, poor compliance to insulin treatment, and lack of financial resources. Metformin instead of conventional insulin might be an alternative, effective, and cheap treatment option for women with type 2 diabetes in pregnancy in our population. The present study was aimed at evaluating the effects of metformin therapy in type 2 diabetes in pregnancy and comparing it with standard treatment insulin.\n\n2. Patients and Methods\n2.1. Study Design\nThis trial was a randomized open labeled clinical phase III study (NCT01855763) with parallel assignment to patients comparing metformin with insulin treatment in type 2 diabetes in pregnancy. The study was conducted at hospitals affiliated with Dow University of Health Sciences, Karachi, Pakistan, from January 2009 till January 2014. Institutional review board and ethics committee of the university approved the study and all participants gave informed written consent.\n\nPatients with prepregnancy diagnosed type 2 diabetes and cases of newly diagnosed overt diabetes in pregnancy (IADPSG criteria: FBS: ≥ 7.0 mmol/lit (126 mg/dL), RBS: ≥ 11.1 mmol/lit (200 mg/dL), and HbA1C ≥ 6.5%) were selected from antenatal clinics after taking informed consent. They belonged to all five major ethnic groups living in urban and rural areas of four provinces in Pakistan but now settled in urban Karachi. Women included in the study were between 20 and 48 years of age, having a singleton pregnancy continued beyond first trimester. The exclusion criteria were women who have contraindications or intolerance to metformin intake like gastrointestinal side effects and altered liver functions with or without jaundice or had hypersensitivity with the drug and women who were diagnosed as gestational diabetes or had type 1 or type 2 diabetes and were already on insulin treatment, ultrasound showing a recognized fetal anomaly, ruptured membranes in second trimester, presence of any other medical disorder, and diabetes related complications.\n\nRandomization was done as the eligible patients enter the study with odd number assigned to metformin treatment and even number for insulin treatment irrespective of body weight and previous obstetrical history. Blinding was not possible because of different routes of administration of drugs.\n\n2.2. Study Treatment\nPatients were advised for dietary modifications and nutritional instructions of three meals and three snacks daily with predesigned diets according to body weight. Metformin, (Glucophage) (Merck, Pakistan) was started at dose of 500 mg/day orally and increased up to 2500 mg in three divided doses as tolerated by the patient and till glycemic control was achieved. Target blood glucose levels for glycemic control were taken as fasting blood glucose (FBS) ≤ 100 mg/dL (5.5 mmol/lit) and postprandial blood glucose levels (1.5 hours after meals) of ≤126 mg/dL (7 mmor/lit) (Diabetic Association of Pakistan). If desired, target blood glucose levels were not maintained anytime during treatment even after maximum dose of metformin; insulin was added as supplementary treatment with metformin.\n\nInsulin (Humulin R, Humulin N (Lilly)) was prescribed as a combination of short acting and intermediate acting human insulin as twice daily injections before meals in morning (before breakfast) and in evening (before dinner) to cover for the three meals and three snacks a day or as multiple injections of short acting insulin before meals and intermediate acting insulin at bedtime depending on individual patient requirement, in order to achieve the desired glycemic targets. Dose of insulin was calculated according to body weight and gestational age. A 24-hour total insulin dose was calculated using 0.6 units/kg body weight in 1st trimester, 0.7 units/kg body weight in 2nd trimester, 0.8 units/kg body weight from 28 to 32 weeks of gestation, 0.9 units/kg body weight from 32 to 36 weeks of gestation, and 1 unit/kg body weight from 36 weeks onwards.\n\nPatients were followed up in antenatal clinics. Iron, calcium, vitamin B12, and folic acid supplements were given to all patients. They were taught self, blood glucose monitoring using home glucose monitors and were advised to maintain a written or electronic record of blood glucose levels. Patients who could not monitor and record their blood glucose levels were tested using glucose monitors at each visit in antenatal clinic or they were admitted in day care ward for blood glucose monitoring when required. Fasting and three postprandial blood glucose levels 1.5 hours after breakfast, lunch, and dinner were recorded. Dose adjustments of drugs were made at each antenatal visit weekly or fortnightly till 36 weeks and then weekly till term or delivery. Routine obstetric care was provided at the antenatal clinics. HbAIC was done at study entry and at 36/37 weeks of pregnancy. Ultrasound was done at first visit (dating scan) then at 16–19 weeks (anomaly scan) and then monthly after 28 weeks (fetal well-being scan). Mode and time of delivery were decided at 37/38 weeks of pregnancy. Maternal and neonatal outcomes were recorded on a predesigned proforma.\n\n3. Study Outcome Measures\nThe primary outcome measures were alive baby, neonatal hypoglycemia requiring intravenous dextrose therapy (blood glucose <25 mg/dL or <1.4 mmol/lit), and NICU admissions >24 hours.\n\nThe secondary outcome measures included birth weight, LGA/macrosomia (birth weight > 90 centile for gestational age or birth weight > 4 kg), SGA (birth weight < 10th centile for gestational age or birth weight < 2.5 kg), neonatal morbidity like transient tachypnea of newborn, respiratory distress syndrome, prematurity, sepsis, jaundice, and birth trauma, maternal glycemic control reported as mean fasting (FBS) and postprandial blood glucose levels (RBS) and HbAIC levels at 36/37 weeks of pregnancy, weight gain in pregnancy, maternal hypertensive complications including pregnancy induced hypertension (gestational hypertension) and preeclampsia (defined as B.P ≥ 140/90 on two occasions with significant proteinuria), and treatment compliance, dose, and cost of metformin and insulin treatment.\n\n4. Statistical Analysis\n4.1. Sample Size\nIt was estimated using the method of sample size estimation for comparing two means on www.openepi.com with mean and standard deviation of neonatal outcomes, hypoglycemia, and NICU admissions with an expected difference of 30% reduction in NICU stay and 5–10% reduction in neonatal hypoglycemia between metformin and insulin treated groups from a study done in South Asian country [11] with 5% margin of error and 95% confidence interval. We worked on 206 samples. Using PASS version 11 Chi-square for proportion with 95% CI, sample size of 206, and effect size of 0.233 with 2 degrees of freedom the power of study calculated is 0.86 from primary outcome measure, neonatal hypoglycemia, and for NICU admissions, the power of study calculated is 0.99 using effect size of 0.396.\n\n5. Data Analysis\nData was analyzed using IBM SPSS version 22; the frequencies and percentages were reported for all categorical variables. Mean with SD was reported for all continuous variables. The analysis was performed to compare the metformin alone group with metformin plus insulin group and insulin alone group using two-sample independent student t-test and Mann-Whitney U test for continuous data. Chi square, Fisher Exact test, and Mann-Whitney U test were used for categorical data. Two-tailed tests were used for all analysis and statistical significance was considered at P ≤ 0.05.\n\n6. Results\nThe overall design and subject flow through the study is illustrated in Figure 1. A total of 297 patients with type 2 diabetes in pregnancy were enrolled for the study. Of these 250 met the inclusion criteria and were randomized to treatment with metformin or insulin. 205 patients were already known cases of type 2 diabetes and were controlled on diet only or were on oral hypoglycemic agents. 45 patients were newly diagnosed cases and were classified as overt diabetes in pregnancy according to IADPSG criteria. 206 participants completed the study and their data was finally analyzed, with 106 patients in metformin group and 100 patients in insulin group (Figure 1). 84.9% patients in metformin group needed supplementary insulin treatment in varying doses to maintain glycemic control. The base line characteristics between the groups were not significantly different in metformin plus insulin and insulin alone groups; however patients in metformin alone group were younger and were of less parity (Table 1).\n\n6.1. BMI and Weight Gain\nBMI in early pregnancy was less in metformin alone group as compared to metformin plus insulin and insulin group (28.25 Kg/m2 versus 33.59 Kg/m2 versus 32.96 Kg/m2), P ≤0.01. Total weight gain in pregnancy was 10.38 ± 1.2 kg in metformin alone group, 10.52 ± 1.14 kg in metformin plus insulin group, and 11.80 ± 0.86 kg in insulin alone group indicating significantly less weight gain in metformin treated group, P ≤0.01 (Table 1).\n\n6.2. Glycemic Profiles\nFasting, postprandial blood glucose levels and HbAIC levels were statistically comparable in three groups. Glycemic targets were achieved in all three groups within one week of starting treatment and maintained throughout pregnancy in the target range with no statistical difference in three groups (Table 1).\n\n6.3. Maternal Outcomes\nPregnancy induced hypertension was found significantly less in metformin alone and metformin plus insulin group as compared to insulin alone group (6.2% versus 23.3% versus 36%), P = 0.020. However the rates of preeclampsia in three groups were 25% versus 10% versus 17%, P = 0.184. All women who developed preeclampsia in metformin alone group were primigravidae. Gestational age at enrolment and at delivery was not significantly different in three groups. More women delivered vaginally in metformin plus insulin group. Vaginal delivery rates were 18.8% in metformin alone, 47.8% in metformin plus insulin group, and 18% in insulin group, P ≤ 0.01. Cesarean section rate was 81.2% in metformin group, 52.2% in metformin plus insulin group, and 82% in insulin group showing significant reduction in cesarean section rate in metformin plus insulin group, P ≤ 0.01 (Table 2).\n\n6.4. Neonatal Outcomes\nThere were no perinatal deaths and all babies were born alive in three groups. Mean birth weights was statistically the same in all groups. Significantly more small for gestational age babies were found in metformin treated groups as compared to insulin alone group (31.2% versus 14.4% versus 2%), P ≤ 0.01. Incidence of macrosomia was statistically the same in three groups (12.5% versus 33.3% versus 27%), P = 0.208. Transient tachypnea of newborn was found in 12.5% versus 6.66% versus 18% in metformin alone, metformin plus insulin, and insulin alone group, P = 0.063. Comparable rates of RDS were found in three groups with no statistical difference but lower rates in metformin plus insulin group (12.5% versus 5.6% versus 11%), P = 0.355. 10% neonates in insulin alone group developed neonatal sepsis as compared to 3.3% in metformin plus insulin group, P = 0.094. Two newborns in metformin alone group and 2 in insulin group had birth trauma with clavicle fracture in two neonates and cephalhematoma associated with vacuum delivery in other 2 neonates; all of them had birth weight of > 4 kg. NICU stay was significantly less in metformin alone and metformin plus insulin group as compared to insulin alone group, P ≤ 0.01 (Table 3).\n\nSignificantly less neonatal jaundice was observed in metformin alone and metformin plus insulin group as compared to insulin group, P = 0.021. Apgar scores at 5 minutes of birth were statistically comparable in 3 groups. Significantly less neonatal hypoglycemia was found in metformin plus insulin group, P ≤ 0.01, and mean blood glucose levels at birth were also better in metformin plus insulin group (Table 3).\n\n6.5. Pharmacotherapeutic Characteristics\nTreatment compliance was good with oral metformin treatment than with insulin injections (see Supplementary Table in Supplementary Material available online at http://dx.doi.org/10.1155/2015/325851). Mean dose of metformin throughout pregnancy was 2.21 ± 0.63 in metformin alone group and 2.291 ± 0.63 grams per day in metformin plus insulin group, P = 0.665. 84.9% patients required additional insulin in metformin group to maintain glycemic targets in mean dose of 23.64 ± 4.61 units per day. Mean dose of insulin required in insulin alone group was 77.62 ± 12.69 units per day which was significantly higher than that required in metformin group as add-on therapy, P ≤ 0.01. Mean gestational age at which insulin was add-on in metformin group was 26.58 ± 3.8 weeks of pregnancy while insulin was started at mean gestational age of 9.55 ± 5.2 weeks in insulin group, P ≤ 0.01. Cost of treatment was significantly less in metformin alone and metformin plus insulin group as compared to insulin alone group, P ≤ 0.01 (Table 4).\n\n6.6. Maternal and Neonatal Outcomes Adjusted for BMI\nOut of 206 patients 50 had BMI < 30 and 156 had BMI > 30 indicating association of obesity with type 2 diabetes. Total weight gain in pregnancy was less in metformin alone group with BMI > 30, P ≤ 0.01. Mean dose of add-on insulin was 27.63 ± 6.03 units in women with BMI < 30 and 22.84 ± 3.78 in women with BMI > 30, P = 0.519, indicating no statistical difference in insulin dose, in groups stratified according to BMI. However mean gestational age at which insulin started was earlier in women with BMI > 30 as compared to women with BMI < 30, P ≤ 0.01. Similarly pregnancy induced hypertension was less in women with BMI < 30 as compared to women with BMI > 30, P = 0.011. There were no statistical differences in NICU stay and neonatal hypoglycemia in two groups stratified according to BMI, P = 0.249 and P = 0.699, respectively (Table 5).\n\n7. Discussion\nThis randomized clinical study reports the results of metformin versus insulin treatment in women with type 2 diabetes in pregnancy. The study was conducted in a population setting with high prevalence of diabetes to meet the needs in a background of low economic resources where health facilities especially medicines are not always available free of cost. Patients with type 2 diabetes in pregnancy were selected with strict inclusion criteria; that is, they were not on insulin treatment and did not have complications associated with diabetes. Although duration of diabetes was not taken into account, the study patients, either had newly diagnosed overt diabetes detected in this pregnancy or were known cases of type 2 diabetes, who were on diet control or on oral antihyperglycemic agents, with duration of diabetes not more than 5 years.\n\nIn mean age and BMI the difference was statistically insignificant in metformin and insulin treated groups but patients in metformin alone group were younger and most had BMI < 30. Older age and multiparity with BMI > 30 were also observed in previous studies as in our study [12–14]. Total weight gain in pregnancy was significantly less in metformin treated patients than in insulin treated patients. Similar results were reported by Rowan et al. [7, 15–17]. This effect of less weight gain was observed more in women with BMI > 30 in our study. Glycemic targets were achieved within one week of starting treatment and maintained throughout pregnancy. Similar findings were reported by Rowan et al., Hickman, Tertti, and others [7, 11, 18–20] indicating metformin to be effective in achieving diabetes control.\n\nWe found significantly less pregnancy induced hypertension in metformin group as compared to insulin group, these findings being related to the effect of metformin on reducing endothelial activation and maternal inflammatory response to insulin resistance [21]. However more preeclampsia was found in elderly obese primigravidae in metformin alone group. No differences in rates of maternal hypertensive complications were found in other studies [7, 14, 16, 22, 23]. However, higher incidence of preeclampsia was reported by Hellmuth et al. in metformin treated patients [24]. Patients with BMI > 30 were found to have more pregnancy induced hypertension than patients with BMI < 30. Metformin treatment however is associated with significantly less occurrence of pregnancy induced hypertension in women with BMI > 30 in our study.\n\nPatients were enrolled for study at around 10 weeks of gestation with a viable pregnancy. Mean gestational age at delivery was nearly the same around 37 weeks. More women delivered vaginally in metformin plus insulin group as compared to insulin alone group (47.77% versus 18%) and similarly cesarean section rate was statistically lower in metformin treated group. No differences in cesarean section and vaginal delivery rates were reported in other studies [7, 13, 15, 24]. However, 81.25% patients required cesarean section in metformin alone group mainly because of association with preeclampsia and intrauterine growth retardation.\n\nNo perinatal deaths occurred partly because congenital anomalies were excluded from the study and tight glycemic control was maintained, besides keeping a low threshold for cesarean section in cases of presumed fetal compromise. There was no difference in neonatal outcomes like birth weight, Apgar scores, large for gestational age infants, and respiratory distress syndrome in three groups. However significantly more small for gestational age infants were found in metformin group as compared to insulin group; association of preterm delivery before 37 weeks and birth weight < 10th centile for gestational age were contributing factors in metformin group. Rowan et al. reported more spontaneous preterm births in metformin group than in insulin treated group but same number of small for date infants in both groups in MIG trial [7]. Neonatal complications like transient tachypnea of newborn, neonatal sepsis, neonatal intensive care unit stay, and neonatal hypoglycemia were found significantly less in metformin treated group when compared with insulin group. Similar results were reported in other studies [7, 12, 13, 15, 18, 19, 23]. Women with BMI > 30 had more neonatal complications in insulin treated group as compared to metformin treated group indicating protective effect of metformin in reducing neonatal hypoglycemia and thus NICU admissions.\n\nPatients achieved adequate glycemic control with mean dose of 2.5 grams of metformin, and few required dose limitation due to gastrointestinal side effects. These were those who required early add-on insulin therapy. Mean gestational age at which insulin started in metformin treated group was 26 weeks in our study. 84.9% patients in metformin group required add-on insulin therapy in our study. Patients with BMI > 30 required add-on insulin earlier than those with BMI < 30 in metformin treated group. BMI appeared to be a predictor for need of add-on insulin in metformin treated group, as patients who were controlled on metformin alone had mean BMI of less than 30. Insulin was add-on with metformin to maintain glycemic control when insulin resistance increases in pregnancy that is around 26–28 weeks of pregnancy. In metformin treated group, patients with early pregnancy BMI of < 30 did not require add-on insulin or required add-on insulin at a later gestational age in our study. Ijas et al. reported similar results in their study [23]. Other studies in gestational diabetes show varying figures in terms of supplemental insulin requirement. Rowan et al. reported 46.3%, Viollet et al. 18%, and Moore et al. 34.7% [7, 21, 25]. Coetzee and Jackson reported that 28.6% patients with type 2 diabetes in pregnancy required supplemental insulin with metformin [26]. Mohammed et al. in a retrospective analysis, however, reported that 95% patients with type 2 diabetes in pregnancy required additional insulin to maintain glycemic control [14]. These disparities in need for add-on insulin with metformin may be explained by differences in populations studied because diabetes and its control vary widely in different populations related to their genetic and phenotypic makeup. WHO ranks Pakistan as a high prevalent area for diabetes with patients exhibiting high insulin resistance and obesity [27]. This explains the reason of failure of metformin alone to achieve glycemic control in these patients. Mean dose of add-on insulin was significantly less in metformin group as compared to insulin group and so the financial benefit achieved was significant in metformin group. This financial benefit is also shown in gestational diabetes part of this study [28].\n\n8. Conclusion\nMetformin is an effective treatment option for women with type 2 diabetes in pregnancy with or without add-on insulin who require pharmacological treatment for glycemic control in our resource poor setting.\n\nMetformin has advantages over insulin such as less maternal weight gain, no maternal hypoglycemia, being cheap, being oral therapy, and requiring no vigorous monitoring and frequent hospital admissions with good compliance and acceptability. Metformin treatment when compared with insulin treatment showed less maternal hypertensive complications and less risk of neonatal hypoglycemia with few neonatal intensive care admissions. Metformin treatment is suitable for nonobese type 2 diabetes patients in pregnancy without complications. Metformin treatment in type 2 diabetes in pregnancy required lower dose of add-on insulin, at a later gestational age for maintaining glycemic control when compared with insulin treatment.\n\nStudy limitations included duration of diabetes that was not taken into account in the present study; besides congenital anomalies were excluded from the study and longer infant follow-up was not carried out.\n\nThe findings of the trial are important in recommending metformin for treatment of type 2 diabetes in pregnancy in a selected population.\n\nSupplementary Material\nPatients in metformin group had good treatment compliance when compared to insulin group P<0.01. Only six patients had gastro intestinal side effects resulting in dose limitation in metformin group. 92.4% patients opted for metformin treatment in next pregnancy while all patients in metformin group considered metformin treatment as easy and cheap. Doing finger pricks for blood glucose monitoring was considered as the most difficult part of treatment in both groups.\n\n Acknowledgments\nThe authors thank the study participants for their cooperation and regular follow-ups. The authors acknowledge the help of management of Mamji hospital and Dr. Khadim medical superintendent of Lyari General Hospital and their support in providing necessary equipment and medicines for the trial. Thanks are due to Dr. Ayesha Kamran, Dr. Lubna Rehman, Dr. Moneeza, Dr. Tayyaba Anbareen, Dr. M. Yaqoob, and Dr. Kashif Abbas for their help in patient recruitment, data collection, and neonatal management.\n\nConflict of Interests\nThe authors have no conflict of interests relevant to this paper.\n\nAuthors' Contribution\nJahan Ara Ainuddin designed and researched the study and wrote the paper. Nasim Karim wrote, reviewed, and edited the paper. Sidra Zaheer and Syed Sanwer Ali contributed to statistical analysis and edited the paper. Anjum Ara Hasan codesigned the study and edited the paper. Jahan Ara Ainuddin is the guarantor of this work, had full access of data in the study, and takes the responsibility for integrity and accuracy of data analysis.\n\nFigure 1 Flow diagram of study enrollment.\n\nTable 1 Baseline demographic and maternal characteristics in treatment groups (n = 206).\n\nParameters\tGroup\tMean ± SD\t\nP valuea\n\t\nP valueb\n\t\nP valuec\n\t\nAge (years)\tMetformin alone\t31.75 ± 2.82\t0.05*\n\t \t \t\nMetformin + insulin\t34.09 ± 3.51\t \t0.07\t \t\nInsulin alone\t33.73 ± 2.95\t \t \t0.956\t\n\n\n\t\nParity\tMetformin alone\t2.56 ± 1.15\t0.550\t \t \t\nMetformin + insulin\t2.83 ± 1.18\t \t0.038*\n\t \t\nInsulin alone\t3.18 ± 1.15\t \t \t0.025*\n\t\n\n\n\t\nBMI-early pregnancy (kg/m2)\tMetformin alone\t28.25 ± 1.98\t<0.01*\n\t \t \t\nMetformin + insulin\t33.59 ± 3.97\t \t<0.01*\n\t \t\nInsulin alone\t32.96 ± 4.04\t \t \t0.171\t\n\n\n\t\nBMI-late pregnancy (kg/m2)\tMetformin alone\t32.47 ± 2.19\t<0.01*\n\t \t \t\nMetformin + insulin\t38.09 ± 4.26\t \t<0.01*\n\t \t\nInsulin alone\t38.01 ± 4.18\t \t \t0.714\t\n\n\n\t\nTotal weight gain in pregnancy (Kg)\tMetformin alone\t10.38 ± 1.20\t0.868\t \t \t\nMetformin + insulin\t10.52 ± 1.14\t \t<0.01*\n\t \t\nInsulin alone\t11.80 ± 0.86\t \t \t<0.01*\n\t\n\n\n\t\nFBS at starting treatment (mg/dl)\tMetformin alone\t138.06 ± 45.58\t0.304\t \t \t\nMetformin + insulin\t144.14 ± 29.64\t \t0.877\t \t\nInsulin alone\t139.85 ± 29.43\t \t \t0.155\t\n\n\n\t\nRBS at starting treatment (mg/dl)\tMetformin alone\t192.88 ± 25.56\t0.326\t \t \t\nMetformin + insulin\t195.03 ± 21.69\t \t0.041*\n\t \t\nInsulin alone\t201.21 ± 16.78\t \t \t0.158\t\n\n\n\t\nMean FBS throughout pregnancy (mg/dl)\tMetformin alone\t97.87 ± 3.83\t0.586\t \t \t\nMetformin + insulin\t97.50 ± 3.35\t \t0.672\t \t\nInsulin alone\t97.55 ± 3.29\t \t \t0.962\t\n\n\n\t\nMean RBS throughout pregnancy (mg/dl)\tMetformin alone\t136.79 ± 5.34\t0.176\t \t \t\nMetformin + insulin\t134.79 ± 5.69\t \t0.237\t \t\nInsulin alone\t135.31 ± 4.64\t \t \t0.944\t\n\nP value calculated by using independent t-test∖Mann-Whitney U test.\n\n\naComparison between means of metformin alone and metformin + insulin groups.\n\n\nbComparison between means of metformin alone and insulin alone.\n\n\ncComparison between means of metformin + insulin and insulin alone.\n\n\n*Significant level ≤0.05.\n\nFBS: fasting blood glucose.\n\nRBS: random blood glucose.\n\nTable 2 Maternal outcomes in treatment groups (n = 206).\n\nParameters\tMetformin alone\tMetformin + insulin\tInsulin alone\t\nP value\t\n\nn = 16\t\nn = 90\t\nn = 100\t\n\nn (%)\t\nn (%)\t\nn (%)\t\nMaternal hypertensive complications in pregnancy\t\nPregnancy induced hypertension\t \t \t \t \t\n Yes\t1 (6.2)\t21 (23.3)\t36 (36.0)\t0.020*\n\t\n No\t15 (93.8)\t69 (76.7)\t64 (64.0)\t\nPreeclampsia\t \t \t \t \t\n Yes\t4 (25.0)\t9 (10.0)\t17 (17.0)\t0.184\t\n No\t12 (75.0)\t81 (90.0)\t83 (83.0)\t\n\n\n\t\nLabor outcomes\t\nNormal vaginal delivery\t \t \t \t \t\n Yes\t3 (18.8)\t43 (47.8)\t18 (18.0)\t<0.01*\n\t\n No\t13 (81.2)\t47 (52.2)\t82 (82.0)\t\nLSCS\t \t \t \t \t\n Yes\t13 (81.2)\t47 (52.2)\t82 (82.0)\t<0.01*\n\t\n No\t3 (18.8)\t43 (47.8)\t18 (18.0)\t\n\n\n\t\nObstetric outcomes \t\n \tMean ± SD\t\nP valuea\n\t\nP valueb\n\t\nP valuec\n\t\n\n\n\t\nGestational age at enrolment (weeks)\t \t \t \t \t\n Metformin alone\t10.75 ± 5.98\t0.876\t \t \t\n Metformin + insulin\t10.09 ± 4.86\t \t0.601\t \t\n Insulin alone\t9.57 ± 5.20\t \t \t0.661\t\nGestational age at delivery (weeks)\t \t \t \t \t\n Metformin alone\t36.19 ± 1.68\t0.409\t \t \t\n Metformin + insulin\t36.86 ± 1.35\t \t0.134\t \t\n Insulin alone\t37.06 ± 1.22\t \t \t0.465\t\n\nP value calculated by using Chi-square test∖Mann-Whitney U test.\n\n\naComparison between means of metformin alone and metformin + insulin groups.\n\n\nbComparison between means of metformin alone and insulin alone groups.\n\n\ncComparison between means of metformin + insulin and insulin alone groups.\n\n\n*Significant level ≤0.05.\n\nTable 3 Neonatal outcomes in treatment groups (n = 206).\n\nParameters\tMetformin alone\tMetformin + insulin\tInsulin alone\t\nP value\t\n\nn = 16\t\nn = 90\t\nn = 100\t\n\nn (%)\t\nn (%)\t\nn (%)\t\nBorn alive\t \t \t \t \t\n Yes\t16 (100)\t90 (100)\t100 (100)\tN/A\t\n No\t—\t—\t—\t\nSmall for gestational\t \t \t \t \t\n Yes\t5 (31.2)\t13 (14.4)\t2 (2.0)\t<0.01*\n\t\n No\t11 (68.8)\t77 (85.6)\t98 (98.0)\t\nLarge for gestational\t \t \t \t \t\n Yes\t2 (12.5)\t30 (33.3)\t27 (27.0)\t0.208\t\n No\t14 (87.5)\t60 (66.7)\t73 (73.0)\t\nBirth trauma\t \t \t \t \t\n Yes\t2 (12.5)\t0 (0)\t2 (2.0)\t0.016*\n\t\n No\t14 (87.5)\t90 (100)\t98 (98.0)\t\nNICU stay\t \t \t \t \t\n Yes\t7 (43.8)\t21 (23.3)\t69 (69.0)\t<0.01*\n\t\n No\t9 (56.2)\t69 (76.7)\t31 (31.0)\t\nNeonatal jaundice\t \t \t \t \t\n Yes\t2 (12.5)\t9 (10.0)\t25 (25.0)\t0.021*\n\t\n No\t14 (87.5)\t81 (90.0)\t75 (75.0)\t\nTTN\t \t \t \t \t\n Yes\t2 (12.5)\t6 (6.7)\t18 (18.0)\t0.063\t\n No\t14 (87.5)\t84 (93.3)\t82 (82.0)\t\nRDS\t \t \t \t \t\n Yes\t2 (12.5)\t5 (5.6)\t11 (11.0)\t0.355\t\n No\t14 (87.5)\t85 (94.4)\t89 (89.0)\t\nNeonatal sepsis\t \t \t \t \t\n Yes\t0 (0)\t3 (3.3)\t10 (10.0)\t0.094\t\n No\t16 (100)\t87 (96.7)\t90 (90.0)\t\nNeonatal hypoglycemia\t \t \t \t \t\n Yes\t4 (25.0)\t7 (7.8)\t30 (30.0)\t<0.01*\n\t\n No\t12 (75.0)\t83 (92.2)\t70 (70.0)\t\n\n\n\t\nContinuous measure outcomes\t\n \tMean ± SD\t\nP valuea\n\t\nP valueb\n\t\nP valuec\n\t\n\n\n\t\nBirth weight (kg)\t \t \t \t \t\n Metformin alone\t3.03 ± 0.65\t0.305\t \t \t\n Metformin + insulin\t3.34 ± 0.68\t \t0.345\t \t\n Insulin alone\t3.41 ± 0.56\t \t \t0.985\t\nMean blood glucose level at birth (mg/dl)\t \t \t \t \t\n Metformin alone\t39.25 ± 9.32\t0.062\t \t \t\n Metformin + insulin\t45.41 ± 7.94\t \t0.335\t \t\n Insulin alone\t40.91 ± 14.81\t \t \t0.282\t\nApgar score at 5 minutes\t \t \t \t \t\n Metformin alone\t8.31 ± 1.01\t0.929\t \t \t\n Metformin + insulin\t8.27 ± 0.94\t \t0.228\t \t\n Insulin alone\t8.05 ± 0.90\t \t \t0.048*\n\t\n\nP value calculated by using Chi-square∖Fisher Exact∖Mann-Whitney U test.\n\n\naComparison between means of metformin alone and metformin + insulin groups.\n\n\nbComparison between means of metformin alone and insulin alone groups.\n\n\ncComparison between means of metformin + insulin and insulin alone groups.\n\n\n*Significant level ≤0.05.\n\nTTN: transient tachypnea of newborn.\n\nRDS: respiratory distress syndrome.\n\nNICU: neonatal intensive care unit.\n\nTable 4 Pharmacotherapeutic characteristics in treatment groups (n = 206).\n\nParameters\tGroup\tMean ± SD\t\nP valuea\n\t\nP valueb\n\t\nP valuec\n\t\nDose of drug\t\nMetformin: mean dose grams/day\tMetformin alone\t2.21 ± 0.63\t0.665\t \t \t\nMetformin + insulin\t2.29 ± 0.64\t \t—\t \t\nInsulin alone\t—\t \t \t—\t\nInsulin: mean dose units/day\tMetformin alone\t—\t—\t \t \t\nMetformin + insulin\t23.69 ± 4.61\t \t—\t \t\nInsulin alone\t77.62 ± 12.69\t \t \t<0.01*\n\t\nMean gestational age when insulin started (weeks)\tMetformin alone\t—\t—\t \t \t\nMetformin + insulin\t26.58 ± 3.85\t \t—\t \t\nInsulin alone\t9.55 ± 5.21\t \t \t<0.01*\n\t\n\n\n\t\nFinancial benefits\t\nTotal cost throughout pregnancy (PKR)\tMetformin alone\t448 ± 131\t<0.01*\n\t \t \t\nMetformin + insulin\t5004 ± 754\t \t<0.01*\n\t \t\nInsulin alone\t10976 ± 6339\t \t \t<0.01*\n\t\nTotal cost throughout pregnancy (USD)\n\n\tMetformin alone\t4.39 ± 1.01\t<0.01*\n\t \t \t\nMetformin + insulin\t49.05 ± 7.39\t \t<0.01*\n\t \t\nInsulin alone\t107.60 ± 62.14\t \t \t<0.01*\n\t\n\nP value calculated by using Mann-Whitney U test.\n\n\naComparison between means of metformin alone and metformin + insulin groups.\n\n\nbComparison between means of metformin alone and insulin alone groups.\n\n\ncComparison between means of metformin + insulin and insulin alone groups.\n\n\n*Significant level ≤0.05.\n\nPKR: Pakistani rupee.\n\nUSD: US dollar.\n\nTable 5 Maternal and neonatal characteristics in treatment groups adjusted for BMI (n = 206).\n\nParameters\tNormal (BMI ≤ 30), n = 50\tObese (BMI > 30), n = 156\t\nP valued\n\t\n Group\tMean ± SD\t\nP valuea\n\t\nP valueb\n\t\nP valuec\n\tMean ± SD\t\nP valuea\n\t\nP valueb\n\t\nP valuec\n\t\nTotal weight gain in pregnancy (Kg)\t \t \t \t \t \t \t \t \t<0.01*\n\t\n Metformin alone\t10.53 ± 0.87\t0.031*\n\t \t \t9.66 ± 2.30\t0.664\t \t \t \t\n Metformin + insulin\t9.12 ± 1.31\t \t<0.01*\n\t \t10.82 ± 0.84\t \t0.011*\n\t \t \t\n Insulin alone\t11.71 ± 0.95\t \t \t<0.01*\n\t11.82 ± 0.84\t \t \t<0.01*\n\t \t\n\n\n\t\nPharmacotherapeutic characteristics\t \t\nInsulin: mean dose units/day\t \t \t \t \t \t \t \t \t0.519\t\n Metformin alone\t—\t—\t \t \t—\t—\t \t \t \t\n Metformin + insulin\t27.63 ± 6.03\t \t—\t \t22.84 ± 3.78\t \t—\t \t \t\n Insulin alone\t75.52 ± 14.93\t \t \t<0.01*\n\t78.18 ± 12.06\t \t \t<0.01*\n\t \t\nMean gestational age when insulin started (weeks)\t \t \t \t \t \t \t \t \t<0.01*\n\t\n Metformin alone\t—\t—\t \t \t—\t—\t \t \t \t\n Metformin + insulin\t28.31 ± 1.95\t \t—\t \t26.20 ± 4.06\t \t—\t \t \t\n Insulin alone\t8.48 ± 2.50\t \t \t<0.01*\n\t9.84 ± 5.69\t \t \t<0.01*\n\t \t\n\n\n\t\n \tMetformin alone\tMetformin + insulin\tInsulin alone\t\nP value\tMetformin alone\tMetformin + insulin\tInsulin alone\t\nP value\t \t\n \t(n = 13)\t(n = 16)\t(n = 21)\t(n = 3)\t(n = 74)\t(n = 79)\t \t\n\n\n\t\nMaternal characteristics\t \t\nPregnancy Induced Hypertension\t \t \t \t \t \t \t \t \t0.011*\n\t\n Yes\t1 (7.7)\t1 (6.2)\t5 (23.8)\t0.238\t0 (0)\t20 (27.0)\t31 (39.2)\t0.035*\n\t \t\n No\t12 (92.3)\t15 (93.8)\t16 (76.2)\t \t3 (100)\t54 (73.0)\t48 (60.8)\t \t \t\n\n\n\t\nNeonatal characteristics\t \t\nNICU stay\t \t \t \t \t \t \t \t \t0.249\t\n Yes\t7 (53.8)\t2 (12.5)\t11 (52.4)\t0.029*\n\t0 (0)\t19 (25.7)\t58 (73.4)\t<0.01*\n\t \t\n No\t6 (46.2)\t14 (87.5)\t10 (47.6)\t3 (100)\t55 (74.3)\t21 (26.6)\t \t\nNeonatal hypoglycemia\t \t \t \t \t \t \t \t \t0.699\t\n Yes\t4 (30.8)\t0 (0)\t5 (23.8)\t0.066\t0 (0)\t7 (9.5)\t25 (31.6)\t<0.01*\n\t \t\n No\t9 (69.2)\t16 (100)\t16 (76.2)\t3 (100)\t67 (90.5)\t54 (68.4)\t \t\n\nP value calculated by using Mann-Whitney U test∖Chi-square∖Fisher Exact test.\n\n\naComparison between means of metformin alone and metformin + insulin groups.\n\n\nbComparison between means of metformin alone and insulin alone groups.\n\n\ncComparison between means of metformin + insulin and insulin alone groups.\n\n\ndComparison between BMI with parameters only.\n\n\n*Significant level ≤0.05.\n==== Refs\n1 Spellman C. W. Pathophysiology of type 2 diabetes: targeting islet cell dysfunction The Journal of the American Osteopathic Association 2010 110 3 S2 S7 2-s2.0-77955873660 \n2 Crawther C. A. Hiller J. E. Moss R. J. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes The New England Journal of Medicine 2005 352 24 2477 2486 15951574 \n3 Inzucchi S. E. Bergenstal R. M. Buse J. B. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the study of diabetes (EASD) Diabetologia 2012 55 6 1577 1597 2-s2.0-84864285795 22526604 \n4 Hawthorne G. Metformin use and diabetic pregnancy—has its time come? Diabetic Medicine 2006 23 3 223 227 10.1111/j.1464-5491.2006.01856.x 2-s2.0-33645075725 16492202 \n5 Caballero A. E. Delgado A. Aguilar-Salinas C. A. The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial Journal of Clinical Endocrinology and Metabolism 2004 89 8 3943 3948 10.1210/jc.2004-0019 2-s2.0-4043162976 15292331 \n6 Kirpichikov D. McFarlane S. I. Sowers J. R. Metformin: an update Annals of Internal Medicine 2002 63 1879 1894 \n7 Rowan J. A. Hague W. M. Gao W. Battin M. R. Moore M. P. Metformin versus insulin for the treatment of gestational diabetes The New England Journal of Medicine 2008 358 19 2003 2015 10.1056/nejmoa0707193 2-s2.0-43249092553 18463376 \n8 Hague W. M. Davoren P. M. McIntyre D. Norris R. Xiaonian X. Charles B. G. Metformin crosses the placenta Proceedings of the Medicine and Pregnancy October 2003 Fremantle, Australia Novo Nordisk \n9 Glueck C. J. Goldenberg N. Pranicoff J. Loftspring M. Sieve L. Wang P. Height, weight, and motor—social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy Human Reproduction 2004 19 6 1323 1330 10.1093/humrep/deh263 2-s2.0-3042685726 15117896 \n10 Harborne L. Fleming R. Lyall H. Norman J. Sattar N. Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome The Lancet 2003 361 9372 1894 1901 2-s2.0-0038392806 10.1016/s0140-6736(03)13493-9 \n11 Waheed S. Malik F. P. Mazhar S. B. Efficacy of metformin versus insulin in the management of pregnancy with diabetes Journal of the College of Physicians and Surgeons Pakistan 2013 23 12 866 869 2-s2.0-84890020589 24304990 \n12 Hughes R. C. E. Rowan J. A. Pregnancy in women with type 2 diabetes: who takes metformin and what is the outcome? Diabetic Medicine 2006 23 3 318 322 10.1111/j.1464-5491.2006.01750.x 2-s2.0-33645049852 16492217 \n13 Ekpebegh C. O. Coetzee E. J. van der Merwe L. Levitt N. S. A 10-year retrospective analysis of pregnancy outcome in pregestational Type 2 diabetes: comparison of insulin and oral glucose-lowering agents Diabetic Medicine 2007 24 3 253 258 10.1111/j.1464-5491.2007.02053.x 2-s2.0-33846943354 17305787 \n14 Mohammed M. A. Abdelmonem A. M. Abdullah M. A. El Sayed A. A. Oral hypoglycemic as attractive alternative to insulin for the management of diabetes mellitus during pregnancy Gynecology & Obstetrics 2014 4 1, article 193 10.4172/2161-0932.1000193 \n15 Balani J. Hyer S. L. Rodin D. A. Shehata H. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case-control study Diabetic Medicine 2009 26 8 798 802 10.1111/j.1464-5491.2009.02780.x 2-s2.0-68149114084 19709150 \n16 Spaulonci C. P. Bernardes L. S. Trindade T. C. Zugaib M. Francisco R. P. V. Randomized trial of metformin vs insulin in the management of gestational diabetes American Journal of Obstetrics and Gynecology 2013 209 1 34.e1 34.e7 10.1016/j.ajog.2013.03.022 2-s2.0-84880135912 23524173 \n17 Rai L. Meenakshi D. Kamath A. Metformin—a convenient alternative to insulin for Indian women with diabetes in pregnancy Indian Journal of Medical Sciences 2009 63 11 491 497 2-s2.0-76549102255 10.4103/0019-5359.58878 20075550 \n18 Hickman M. A. McBride R. Boggess K. A. Strauss R. Metformin compared with insulin in the treatment of pregnant women with overt diabetes: a randomized controlled trial The American Journal of Perinatology 2013 30 6 483 489 10.1055/s-0032-1326994 2-s2.0-84879165197 23096052 \n19 Tertti K. Ekblad U. Vahlberg T. Rönnemaa T. Comparison of metformin and insulin in the treatment of gestational diabetes: a retrospective, case-control study Review of Diabetic Studies 2008 5 2 95 101 10.1900/rds.2008.5.95 2-s2.0-65749112267 18795211 \n20 Ibrahim M. I. Hamdy A. Shafik A. Taha S. Anwar M. Faris M. The role of adding metformin in insulin-resistant diabetic pregnant women: a randomized controlled trial Archives of Gynecology and Obstetrics 2014 289 5 959 965 10.1007/s00404-013-3090-7 2-s2.0-84900817346 24217938 \n21 Viollet B. Guigas B. Garcia N. S. Leclerc J. Foretz M. Andreelli F. Cellular and molecular mechanisms of metformin: an overview Clinical Science 2012 122 6 253 270 10.1042/cs20110386 2-s2.0-84855603512 22117616 \n22 Swaminathan K. Howlett H. C. S. Campbell I. W. Metformin in diabetic pregnancy Journal of the Royal College of Physicians of Edinburgh 2009 39 1 10 14 2-s2.0-70349640900 \n23 Ijas H. Vaarasmaki M. Morinpaunen L. Metfromin should be considered in the treatment of gestational diabetes: a prospective randomized study BJOG 2010 10 \n24 Hellmuth E. Damm P. Mølsted-Pedersen L. Oral hypoglycaemic agents in 118 diabetic pregnancies Diabetic Medicine 2000 17 7 507 511 10.1046/j.1464-5491.2000.00314.x 2-s2.0-0033848295 10972579 \n25 Moore L. E. Brieny G. I. Clokey D. Metformin and insulin in the management of gestational diabetes mellitus The Journal of Reproductive Medicine 2007 52 1011 1015 18161398 \n26 Coetzee E. J. Jackson W. P. U. Pregnancy in established non-insulin-dependent diabetics. A five-and-a-half year study at Groote Schuur Hospital South African Medical Journal 1980 58 20 795 802 2-s2.0-0019220834 6777880 \n27 Clinical Guidelines Task Force Global Guidelines for Type 2 Diabetes 2009 http://www.idf.org/ \n28 Ainuddin J. Karim N. Hasan A. A. Naqvi S. A. Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country. A randomized control trial Diabetes Research and Clinical Practice 2015 107 2 290 299 10.1016/j.diabres.2014.10.001 25467617\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2015()",
"journal": "Journal of diabetes research",
"keywords": null,
"medline_ta": "J Diabetes Res",
"mesh_terms": "D000328:Adult; D001786:Blood Glucose; D048909:Diabetes Complications; D003924:Diabetes Mellitus, Type 2; D005260:Female; D005865:Gestational Age; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D016896:Treatment Outcome; D015430:Weight Gain",
"nlm_unique_id": "101605237",
"other_id": null,
"pages": "325851",
"pmc": null,
"pmid": "25874236",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "18795211;19709150;15951574;15117896;20075550;12788588;22526604;16492217;22117616;24217938;10972579;23096052;25467617;17305787;15292331;23524173;18463376;24304990;20382838;16492202;21083860;6777880;18161398",
"title": "Metformin treatment in type 2 diabetes in pregnancy: an active controlled, parallel-group, randomized, open label study in patients with type 2 diabetes in pregnancy.",
"title_normalized": "metformin treatment in type 2 diabetes in pregnancy an active controlled parallel group randomized open label study in patients with type 2 diabetes in pregnancy"
} | [
{
"companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2021-05259",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "Lesch-Nyhan syndrome is a genetic metabolic disorder often involving dystonia and self-mutilating behavior. This case report describes a 13-year-old boy with Lesch-Nyhan syndrome and self-mutilating behavior who received botulinum toxin injections to his bilateral masseter muscles after failing multiple other treatments. Following injections, the patient had reduction in self-biting, along with improvements in speech, mastication and feeding observed in speech therapy. Botulinum toxin injections to the masseters may help to improve oromotor function and reduce self-mutilating behaviors in children with Lesch-Nyhan syndrome who have failed more conservative treatments, providing opportunity for improved functional status and patient safety. Further investigation is indicated to establish optimal dosing. Additionally, the mechanism for the reduction of self-mutilating behavior is unclear and justifies additional investigation.",
"affiliations": "Rutgers New Jersey Medical School, Department of Physical Medicine and Rehabilitation, Newark, NJ, USA.;North Jersey Elks Developmental Disabilities Agency, Clifton, NJ, USA.;Rutgers New Jersey Medical School, Department of Physical Medicine and Rehabilitation, Newark, NJ, USA.",
"authors": "Gilbert|Courtney|C|;Sauer|Michelle|M|;Cheng|JenFu|J|",
"chemical_list": "D001905:Botulinum Toxins",
"country": "Netherlands",
"delete": false,
"doi": "10.3233/PRM-200729",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1874-5393",
"issue": "14(1)",
"journal": "Journal of pediatric rehabilitation medicine",
"keywords": "Lesch-Nyhan; botulinum; masseter; self-mutilation",
"medline_ta": "J Pediatr Rehabil Med",
"mesh_terms": "D000293:Adolescent; D001905:Botulinum Toxins; D002648:Child; D004421:Dystonia; D006801:Humans; D007926:Lesch-Nyhan Syndrome; D008297:Male; D012652:Self Mutilation",
"nlm_unique_id": "101490944",
"other_id": null,
"pages": "133-136",
"pmc": null,
"pmid": "33720862",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reduction of self-mutilating behavior and improved oromotor function in a patient with Lesch-Nyhan syndrome following botulinum toxin injection: A case report.",
"title_normalized": "reduction of self mutilating behavior and improved oromotor function in a patient with lesch nyhan syndrome following botulinum toxin injection a case report"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-311621",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugad... |
{
"abstract": "BACKGROUND\nExtensive off-label use may affect the safety profile of tigecycline. Tigecycline-associated hypofibrinogenemia is potentially life threatening, although the frequency of life-threatening reactions is unknown and their incidence is easily overlooked. We report a case of 2 instances of treatment with high-dose tigecycline, each of which presented with hypofibrinogenemia.\nAn 86-year-old male patient was treated twice with high-dose tigecycline and presented with hypofibrinogenemia both times. The decrease in fibrinogen occurred within 3 to 7 days of tigecycline treatment. Other coagulation parameters had slightly prolonged values.\nCoagulopathy and hypofibrinogenemia.\n\n\nMETHODS\nWe discontinued the tigecycline.\n\n\nRESULTS\nThe fibrinogen level normalized within 5 days after the withdrawal of tigecycline. Following 80 days of hospitalization, the patient was transferred to the rehabilitation hospital for further treatment.\n\n\nCONCLUSIONS\nWe suggest routine strict monitoring of coagulation parameters, particularly fibrinogen. Attention should be paid to below-normal fibrinogen levels due to increased bleeding risk and severity of reaction at fibrinogen levels below 1 g/L.",
"affiliations": "Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.",
"authors": "Fan|Qiaomei|Q|;Huang|Wei|W|;Weng|Yayun|Y|;Xie|Xianze|X|;Shi|Zheng|Z|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D005340:Fibrinogen",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000022638",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD \n\nMD-D-19-08955\n10.1097/MD.0000000000022638\n22638\n4900\nResearch Article\nClinical Case Report\nHypofibrinogenemia induced by high-dose tigecycline—case report and review of literature\nFan Qiaomei MM Huang Wei MM Weng Yayun MS Xie Xianze MS Shi Zheng MM∗ Saranathan. Maya Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.\n∗ Correspondence: Zheng Shi, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang, China (e-mail: frysz@163.com).\n23 10 2020 \n23 10 2020 \n99 43 e226389 12 2019 19 7 2020 9 9 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nExtensive off-label use may affect the safety profile of tigecycline. Tigecycline-associated hypofibrinogenemia is potentially life threatening, although the frequency of life-threatening reactions is unknown and their incidence is easily overlooked. We report a case of 2 instances of treatment with high-dose tigecycline, each of which presented with hypofibrinogenemia.\n\nPatient concerns:\nAn 86-year-old male patient was treated twice with high-dose tigecycline and presented with hypofibrinogenemia both times. The decrease in fibrinogen occurred within 3 to 7 days of tigecycline treatment. Other coagulation parameters had slightly prolonged values.\n\nDiagnoses:\nCoagulopathy and hypofibrinogenemia.\n\nInterventions:\nWe discontinued the tigecycline.\n\nOutcomes:\nThe fibrinogen level normalized within 5 days after the withdrawal of tigecycline. Following 80 days of hospitalization, the patient was transferred to the rehabilitation hospital for further treatment.\n\nLessons:\nWe suggest routine strict monitoring of coagulation parameters, particularly fibrinogen. Attention should be paid to below-normal fibrinogen levels due to increased bleeding risk and severity of reaction at fibrinogen levels below 1 g/L.\n\nKeywords\nadverse eventhigh-dosehypofibrinogenemiatigecyclineOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nTigecycline, the first member of the glycylcycline antibiotics group, has positive in vitro activity against most gram-positive and gram-negative microbes and anaerobic organisms.[1] It is active against carbapenem-resistant Enterobacteriaceae[2] and multidrug-resistant (MDR) Acinetobacter baumannii.[2,3] Tigecycline is a bacteriostatic agent that inhibits protein synthesis by binding to the 30S ribosomal subunit and preventing aminoacylated tRNA from entering the A site of the ribosome.[4] It was approved for the treatment of complicated intra-abdominal infections, complicated skin and skin-structure infections, and community-acquired bacterial pneumonia (CAP) at a dose of 50 mg twice daily, following a 100 mg loading dose. Due to the scarcity of antimicrobials effective against resistant bacteria, tigecycline has historically been utilized for off-label indications, frequently in combination with other agents; such off-label uses are increasing globally.[5] However, extensive off-label use may affect the safety profile of tigecycline.\n\nCurrent data suggest that tigecycline may be useful at higher doses, but the safety of these applications remains in question.[6] The Food and Drugs Administration issued a warning of increased mortality risk associated with the use of intravenous tigecycline, the cause of which was unclear. The most common adverse effects of tigecycline are gastrointestinal disorders (nausea 26% and vomiting 18%).[7] A user-reported adverse event profile study using data from the Food and Drugs Administration adverse event reports database from 2004 to 2009 indicated a relatively high incidence of nausea, vomiting, pancreatitis, and increased hepatic function; an infrequent increase in International Normalized Ratio (INR) was also reported.[8] Coagulopathy was rarely reported in initial studies. In a retrospective study analyzing the adverse events of 145 patients with ventilator-associated pneumonia who were treated with tigecycline, 5 patients with abnormal coagulation were observed, three of whom received a combined treatment with cefoperazone/sulbactam.[9] The concomitant antibiotic was associated with coagulopathy.\n\nThe manufacturer's prescribing information for tigecycline suggests a relatively high incidence of activated partial thromboplastin time (APTT) and prothrombin time (PT) prolongation. However, the incidence of hypofibrinogenemia is unknown, and clinicians often ignore this adverse reaction. Here, we present a case of hypofibrinogenemia in a patient treated with high-dose tigecycline. Although severe coagulopathy and hypofibrinogenemia have been previously reported during tigecycline treatment,[10–15] our patient was treated with tigecycline twice and in both instances presented with hypofibrinogenemia, which normalized following withdrawal. We reviewed the literature to discuss the characteristics of the adverse reaction. This study followed the Case Report Guidelines (CARE guidelines)[16] with the patient's informed consent.\n\n2 Case report\nAn 86-year-old male patient was intubated and admitted to the intensive care unit (ICU) because of respiratory failure following a traffic accident. He had a history of hypertension and chronic kidney disease, had no history of blood transfusion, and had no hepatitis B infection. He was unconscious and displayed pinpoint-sized bilateral pupils at admission. CT indicated cerebral hemorrhage in the right frontal lobe, and the white matter area and basal ganglia area of both cerebral hemispheres were thought to be ischemic because of cerebral infarction. On day 3 of hospitalization, the patient was weakly responsive to external stimulation and began to open his eyes in response to verbal command. However, he developed an infection, displaying C-reactive protein of 161 mg/L and a temperature of 38.9°C. Cefoperazone/sulbactam was administered empirically, following which his markers of systemic inflammation decreased and his general condition improved. After 20 days of treatment, the patient was awake and able to open his eyes autonomously.\n\nNew onset fever occurred on day 28 of hospitalization, and ventilator-associated pneumonia was diagnosed. Sputum cultures identified MDR Acinetobacter baumannii that was sensitive only to tigecycline. The patient was prescribed a new antibacterial regimen of high-dose tigecycline (initiated with a 200 mg loading dose, followed by 100 mg every 12 hour) in combination with cefoperazone/sulbactam. Fever subsided 2 days after the antibacterial regimen change, but the patient's fibrinogen levels continued to decline. After 7 days of antibiotic treatment with tigecycline and cefoperazone/sulbactam, his fibrinogen concentration had decreased below the normal level (1.79 g/L). We discontinued tigecycline on day 14 of therapy. Fibrinogen eventually decreased to 1.18 g/L. Notably, no signs of hepatic dysfunction as reflected by liver enzymes and liver function tests were detected before or after beginning tigecycline treatment. Serum alanine transaminase (ALT) level was 14 U/L, serum aspartate transaminase (AST) level was 24 U/L, alkaline phosphatase level was 171 U/L, and total bilirubin level was 13.0 μmol/L. No clinically significant bleeding event was detected at that time. The antimicrobial regimen was then switched to ceftizoxime as signs of inflammation improved. After discontinuation of tigecycline and cefoperazone/sulbactam, fibrinogen levels normalized within 5 days.\n\nThe patient was transferred from the ICU to the department of neurology on day 41 of hospitalization. He presented with myasthenia of limbs because of the cerebrovascular accident and displayed a mild fever. After 9 days of antibiotic treatment with ceftizoxime, the patient's condition suddenly deteriorated, with symptoms of hypotension and respiratory failure. The patient was transferred to the ICU and reintubated and given norepinephrine to maintain blood pressure. Concurrently, ceftizoxime was treatment was stopped, and the anti-infective regimen was switched back to high-dose tigecycline (100 mg q12 hours) and cefoperazone/sulbactam. At this time, the coagulation parameters were normal with the exception of the slightly elevated fibrinogen level (4.9 g/L).\n\nAfter 7 days, a slow but progressive decline in fibrinogen was noted, with concurrently elevated PT and INR. We suspected that cefoperazone/sulbactam had an effect on coagulation function, and the antibiotic was, therefore, switched to piperacillin/tazobactam; tigecycline was continued. On day 18 following the start of tigecycline, progressive worsening of hypofibrinogenemia (0.66 g/L) was noted, and prolonged APTT, INR, PT, and thrombin time were observed. The fecal occult blood test was strongly positive. No changes in ALT, AST, and alkaline phosphatase levels were noted, and signs of inflammation were improving (decreased from 104–10 mg/dL). At this point, we strongly suspected an association of fibrinogen decline with the use of tigecycline, and we discontinued the drug. Fibrinogen then improved, and baseline levels were restored (normalized within 5 days, Fig. 1). The patient was transferred to the rehabilitation hospital for further treatment.\n\nFigure 1 Trends in coagulation lab results during hospitalization. Please note the marked decrease in fibrinogen on days 29 to 40 following tigecycline administration, reversed by its discontinuation (days 41–49). Other coagulation parameters (activated partial thromboplastin time, international normalized ratio, and prothrombin time) had slightly prolonged values. After the second administration of tigecycline during days 50 to 69, coagulation parameters deteriorated again, and fibrinogen level continued to decline.\n\nThis study was approved by the Ethics Committee and institutional review board of The First Affiliated Hospital of Zhejiang Chinese Medical University. Written and informed consent was obtained from the patient for publication of this report.\n\n3 Discussion\nTigecycline has a broad spectrum of antibacterial activity. It appears to overcome the major mechanisms conferring resistance to tetracyclines (ribosomal protection and efflux pumps) due to the steric hindrance afforded by its large 9-t-butyl-glycylamido side chain.[1] Bacterial resistance to currently available antibiotics is spreading, but tigecycline remains potently active against MDR bacteria. According to 2018 China Antimicrobial Surveillance Network (CHINET) data, 5% of Acinetobacter baumannii isolates were found to be resistant to tigecycline; however, 73.9% were resistant to meropenem. Tigecycline has a long half-life and post-antibiotic effect. The area under the inhibitory curve (AUC/MIC) is considered to most accurately describe the pharmacokinetic and pharmacodynamic properties of a drug[17]; accordingly, some authors have found that as dosage increased, tigecycline showed positive pharmacokinetic characteristics and better clinical outcomes.[18,19] A high-dose tigecycline regimen consisting of a 200 mg loading dose and a maintenance dose of 100 mg every 12 hours has been proposed for treating severe infections due to MDR bacteria.[20] Data reported to date suggest that high-dose tigecycline is associated with better outcomes and is well tolerated in the treatment of critically ill patients.[21]\n\nThe most common adverse effects of tigecycline (nausea and vomiting) had little effect on critically ill patients who were sedated and mechanically ventilated. Instead, clinicians should be alert to the development of hepatic and coagulation dysfunction. Few reports in the literature address tigecycline-associated coagulopathy and hypofibrinogenemia (Table 1).[10–15] The first case report described a patient with end-stage renal disease who received prolonged tigecycline therapy while experiencing a life-threatening coagulation disorder.[10] After 35 days of tigecycline treatment, fibrinogen levels decreased to 0.38 g/L. This may have occurred due to a lack of regular follow up. Fibrinogen recovered within 5 days after tigecycline withdrawal. In addition to a few case reports, four small clinical studies have addressed tigecycline-associated coagulopathy and hypofibrinogenemia.[22–25] Karaiskos et al[22] found that 10% of patients developed hypofibrinogenemia during treatment with standard dose tigecycline, with a median onset of 8 days of treatment. Routsi et al[23] described decreased fibrinogen levels in ICU patients following high-dose tigecycline treatment. Zhang et al[24] evaluated 20 patients treated with tigecycline and found a reduction in fibrinogen levels that was proportional to the dose, not to age. In contrast, Leng et al[25] found that the level of fibrinogen was not significantly influenced by dosage, but patients with more severe illnesses in the ICU were not included in their study.\n\nTable 1 Cases regarding tigecycline-associated hypofibrinogenemia that have been reported.\n\nIn our case, the patient received high-dose tigecycline therapy, which was prescribed off label. Before the initiation of tigecycline therapy, fibrinogen level was slightly elevated. On day 7 following the start of tigecycline, a marked progressive worsening of hypofibrinogenemia (0.66 g/L) was noted. The fibrinogen level recovered to within the normal range of 2 to 4 g/L 5 days after tigecycline was discontinued. A similar pattern was observed with the second use of tigecycline. Fibrinogen levels continued to deteriorate as cefoperazone/sulbactam was replaced by piperacillin/tazobactam. However, sepsis contributed to the development of coagulopathy.[26] It is notable, however, that the general condition of the patient and his inflammatory markers were improving at the time of onset of the coagulation disorder. The Naranjo Adverse Drug Reaction Probability Scale[27] score of 10 points categorizes this adverse drug reaction as definite (Table 2), indicating with certainty that tigecycline caused the severe hypofibrinogenemia.\n\nTable 2 Naranjo Adverse Drug Reaction Probability Scale.\n\nTigecycline causes coagulation disorders and hypofibrinogenemia, and these adverse reactions display common characteristics. The decrease in fibrinogen generally occurred within 3 to 7 days of tigecycline treatment, and the decrease was sustained throughout the course of the day. The half-life of circulating fibrinogen is approximately 3 to 4 days.[28] Fibrinogen is involved in several important physiological functions, including triggering of platelet adhesion and forming of fibrin polymers in hemostasis and thrombosis. Fibrinogen levels normalized within 5 days after tigecycline withdrawal. Other coagulation parameter abnormalities, including prolongation of APTT and PT, were not consistent with the reduction of fibrinogen, and there was no change in AST, ALT, total bilirubin, or creatinine levels. Therefore, hepatic and renal function could not be correlated with fibrinogen reduction. The influence of tigecycline dosage on fibrinogen levels is still controversial, and both the standard dose and high-dose tigecycline can result in a reduction in fibrinogen levels. A prospective study or a larger sample retrospective study is needed to identify the specific risks inherent to reduction in fibrinogen level.\n\nThe main mechanism by which tigecycline induces hypofibrinogenemia is ambiguous. Vitamin K deficiency due to antimicrobial effects on the flora of the intestine is a possible mechanism underlying coagulation disorders, but this can be excluded in some patients who received vitamin K supplementation.[10,11] Fibrinogen is a hexamer composed of 3 polypeptide chains (Aα, Bβ, and γ) that are centrally connected by disulfide bonds.[29] All three polypeptides are synthesized by hepatocytes and assembled into fibrinogen in the liver.[30] Fibrinogen circulates in the plasma at a concentration of approximately 2 to 4 g/L.[31] Reduced synthesis should be examined as a cause of fibrinogen decrease. An impairment in hepatic fibrinogen synthesis can cause reduced levels of fibrinogen, and hypofibrinogenemia has been reported in association with medications that impair the synthetic functions of the liver (eg, L-asparaginase, valproic acid, and possibly allopurinol).[32–35] However, hepatic dysfunction was not implicated in this patient because transaminase and other liver tests were normal; regardless, fibrinogen synthesis is controlled at the transcription level.[36] As an acute-phase reactant, fibrinogen biosynthesis is increased by interleukin (IL)-6-mediated increases in the transcription of the fibrinogen mRNA[37]; IL-1 and tumor necrosis factor-alpha suppress fibrinogen synthesis.[38] There is, however, room for speculation that tigecycline may interfere with the production of fibrinogen by influencing the level of cytokines or by directly influencing the transcription of fibrinogen mRNA.\n\nIn conclusion, tigecycline may induce coagulation disorders and hypofibrinogenemia. Further study is needed to identify the risks of reduced fibrinogen levels. In light of the increased use of tigecycline due to the emergence of MDR bacteria, we suggest routine, strict monitoring of coagulation parameters, particularly fibrinogen levels. Attention should be paid to below-normal fibrinogen levels because fibrinogen levels below 1 g/L are associated with increased risk and severity of bleeding.\n\nAuthor contributions\nData curation: Xianze Xie.\n\nInvestigation: Qiaomei Fan.\n\nWriting – original draft: Qiaomei Fan, Wei Huang, Yayun Weng.\n\nWriting – review & editing: Zheng Shi.\n\nAbbreviations: APTT = activated partial thromboplastin time, ALT = alanine transaminase, AST = serum aspartate transaminase, ALC = advanced liver cirrhosis, ICU = intensive care unit, INR = International Normalized Ratio, MDR = multidrug-resistant, PT = prothrombin time.\n\nHow to cite this article: Fan Q, Huang W, Weng Y, Xie X, Shi Z. Hypofibrinogenemia induced by high-dose tigecycline—case report and review of literature. Medicine. 2020;99:43(e22638).\n\nThe authors have no conflicts of interests to disclose.\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\n==== Refs\nReferences\n[1] Mckeage K Keating GM \nTigecycline\n. Drugs \n2008 ;68 :2633 –44\n.19093704 \n[2] Fritzenwanker M Imirzalioglu C Herold S \nTreatment options for carbapenem- resistant gram-negative infections\n. DtschArztebl Int \n2018 ;115 :345 –52\n.\n[3] Karageorgopoulos DE Kelesidis T Kelesidis I \nTigecycline for the treatment of multidrug-resistant (including carbapenem-resistant) Acinetobacter infections: a review of the scientific evidence\n. J Antimicrob Chemother \n2008 ;62 :45 –55\n.18436554 \n[4] Pankey GA \nTigecycline\n. J Antimicrob Chemother \n2005 ;56 :470 –80\n.16040625 \n[5] Conde-Estévez D Grau S Horcajada JP \nOff-label prescription of tigecycline: clinical and microbiological characteristics and outcomes\n. Int J Antimicrob Agents \n2010 ;36 :471 –2\n.20828992 \n[6] Falagas ME Vardakas KZ Tsiveriotis KP \nEffectiveness and safety of high-dose tigecycline-containing regimens for the treatment of severe bacterial infections\n. Int J Antimicrob Agents \n2014 ;44 :1 –7\n.24602499 \n[7] Kaewpoowat Q Ostrosky-Zeichner L \nTigecycline: a critical safety review\n. Expert Opinion on Drug Safety \n2015 ;14 :335 –42\n.25539800 \n[8] Kadoyama K Sakaeda T Tamon A \nAdverse event profile of tigecycline: data mining of the public version of the U.S. Food and Drug Administration adverse event reporting system\n. Biol Pharm Bull \n2012 ;35 :967 –70\n.22687540 \n[9] Chen Z Shi X \nAdverse events of high-dose tigecycline in the treatment of ventilator-associated pneumonia due to multidrug-resistant pathogens\n. Medicine (Baltimore) \n2018 ;97 :1 –7\n.\n[10] Pieringer H Schmekal B Biesenbach G \nSevere coagulation disorder with hypofibrinogenemia associated with the use of tigecycline\n. Ann Hematol \n2010 ;89 :1063 –4\n.20174923 \n[11] Rossitto G Piano S Rosi S \nLife-threatening coagulopathy and hypofibrinogenaemia induced by tigecycline in a patient with advanced liver cirrhosis\n. Eur J Gastroenterol Hepatol \n2014 ;26 :681 –4\n.24667348 \n[12] Sabanis N Paschou E Gavriilaki E \nHypofibrinogenemia induced by tigecycline: a potentially life-threatening coagulation disorder\n. Infect Dis (Lond) \n2015 ;47 :743 –6\n.25951751 \n[13] Wu X Zhao P Dong L \nA case report of patient with severe acute cholangitis with tigecycline treatment causing coagulopathy and hypofibrinogenemia\n. Medicine (Baltimore) \n2017 ;96 :1 –3\n.\n[14] Wu PC Wu CC \nTigecycline-associated hypofibrinogenemia: a case report and review of the literature\n. ID Cases \n2018 ;11 :56 –7\n.29560313 \n[15] Yilmaz Duran F Yildirim H Şen EM \nA lesser known side effect of tigecycline: hypofibrinogenemia\n. Turk J Haematol \n2018 ;35 :83 –4\n.29212626 \n[16] Gagnier JJ Kienle G Altman DG \nThe CARE guidelines: consensus-based clinical case reporting guideline development\n. Glob Adv Heal Med \n2013 ;2 :38 –43\n.\n[17] Giamarellou H Poulakou G \nPharmacokinetic and pharmacodynamic evaluation of tigecycline\n. Expert Opin Drug Metab Toxicol \n2011 ;7 :1459 –70\n.21958044 \n[18] Cunha BA Baron J Cunha CB \nOnce daily high dose tigecycline- pharmacokinetic/pharmacodynamic based dosing for optimal clinical effectiveness: dosing matters, revisited\n. Expert Rev Anti Infect Ther \n2017 ;15 :257 –67\n.27917692 \n[19] Cunha BA Baron J Cunha CB \nMonotherapy with high-dose once-daily tigecycline is highly effective against Acinetobacter baumanii and other multidrug-resistant (MDR) gram-negative bacilli (GNB)\n. Int J Antimicrob Agents \n2018 ;52 :119 –20\n.29501604 \n[20] Garnacho-Montero J Ferrándiz-Millón C \nHigh dose of tigecycline for extremely resistant Gram-negative pneumonia: yes, we can\n. Critical Care \n2014 ;18 :157 –8\n.25043402 \n[21] De Pascale G Montini L Pennisi M \nHigh dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria\n. Critical Care \n2014 ;18 :2 –9\n.\n[22] Karaiskos I Ioannidis K Galani L \nHypofibrinogenaemia associated with the administration of tigecycline\n. Conference Paper ; 2014 .\n[23] Routsi C Kokkoris S Karaiskos I \nHigh-dose tigecycline-associated alterations in coagulation parameters in critically ill patients with severe infections\n. Int J Antimicrob Agents \n2015 ;45 :90 –3\n.\n[24] Zhang Q Zhou S Zhou J \nTigecycline treatment causes a decrease in fibrinogen levels\n. Antimicrob Agents Chemother \n2015 ;59 :1650 –5\n.25547356 \n[25] Leng B Xue YC Zhang W \nA retrospective analysis of the effect of tigecycline on coagulation function\n. Chem Pharm Bull \n2019 ;67 :258 –64\n.\n[26] Semeraro N Ammollo CT Semeraro F \nCoagulopathy of acute sepsis\n. Semin Thromb Hemost \n2015 ;41 :650 –8\n.26305237 \n[27] Naranjo CA Busto U Sellers EM \nA method for estimating the probability of adverse drug reactions\n. Clin Pharmacol Ther \n1981 ;30 :239 –45\n.7249508 \n[28] Collen D Tytgat GN Claeys H \nMetabolism and Distribution of Fibrinogen. I. Fibrinogen turnover in physiological conditions in humans\n. Br J Haematol \n1972 ;22 :681 –700\n.5064500 \n[29] Medved L Weisel JW \nRecommendations for nomenclature on fibrinogen and fibrin\n. J ThrombHaemost \n2009 ;7 :355 –9\n.\n[30] Tennent GA Brennan SO Stangou AJ \nHuman plasma fibrinogen is synthesized in the liver\n. Blood \n2007 ;109 :1971 –4\n.17082318 \n[31] Levy JH Goodnough LT \nHow I use fibrinogen replacement therapy in acquired bleeding\n. Blood \n2015 ;125 :1387 –93\n.25519751 \n[32] Gralnick HR Henderson E \nHypofibrinogenemia and coagulation factor deficiencies with L-asparaginase treatment\n. Cancer \n1971 ;27 :1313 –20\n.5282618 \n[33] Whitecar JP JrBodey GP Harris JE \nL-asparaginase\n. N Engl J Med \n1970 ;282 :732 –4\n.4906449 \n[34] Hauser E Seidl R Freilinger M \nHematologic manifestations and impaired liver synthetic function during valproate monotherapy\n. Brain Dev \n1996 ;18 :105 –9\n.8733899 \n[35] Yin ZQ Xu JL Li YQ \nTransient hypofibrinogenemia due to allopurinol\n. Drug Des DevelTher \n2014 ;8 :1231 –3\n.\n[36] Green F Humphries S \nControl of plasma fibrinogen levels\n. Baillieres Clin Haematol \n1989 ;2 :945 –59\n.2688760 \n[37] Woods A Brull DJ Humphries SE \nGenetics of inflammation and risk of coronary arterydisease: the central role of interleukin-6\n. Eur Heart J \n2000 ;21 :1574 –83\n.10988009 \n[38] Saliba R Paasch L El Solh A \nTigecycline attenuates staphylococcal superantigen-induced T-cell proliferation and production of cytokines and chemokines\n. Immunopharmacol Immunotoxicol \n2009 ;31 :583 –8\n.19874226\n\n",
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"mesh_terms": "D000328:Adult; D000347:Afibrinogenemia; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D005260:Female; D005340:Fibrinogen; D006801:Humans; D008297:Male; D008875:Middle Aged; D056687:Off-Label Use; D000078304:Tigecycline",
"nlm_unique_id": "2985248R",
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"pages": "e22638",
"pmc": null,
"pmid": "33120753",
"pubdate": "2020-10-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hypofibrinogenemia induced by high-dose tigecycline-case report and review of literature.",
"title_normalized": "hypofibrinogenemia induced by high dose tigecycline case report and review of literature"
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"abstract": "Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system and is characterized by severe optic neuritis and transverse myelitis.\nThe patient was a 74-year-old man with pneumonia. On admission, he exhibited lower limb weakness and rapid respiratory deterioration in the form of tachypnea. Subsequently, he was transported to the Emergency Center of our hospital. High-signal lesions were observed from the cervical spinal cord to the thoracic spinal cord on T2-weighted spinal magnetic resonance images. Neuromyelitis optica was suspected, and the patient received steroid pulse therapy and immunoadsorption plasmapheresis. Serum samples obtained upon transfer were positive for anti-aquaporin-4 antibodies, which confirmed the diagnosis of neuromyelitis optica. Thereafter, the patient was transferred to a rehabilitation hospital.\nRapid respiratory failure in neuromyelitis optica is rare, and care is needed while treating these cases.",
"affiliations": "Department of Emergency and Critical Care Center Nippon Medical School Musashi-Kosugi Hospital Kanagawa Japan.;Department of Emergency and Critical Care Center Nippon Medical School Musashi-Kosugi Hospital Kanagawa Japan.;Department of Emergency and Critical Care Center Nippon Medical School Musashi-Kosugi Hospital Kanagawa Japan.;Department of Emergency and Critical Care Center Nippon Medical School Musashi-Kosugi Hospital Kanagawa Japan.;Department of Neurology Nippon Medical School Musashi-Kosugi Hospital Kanagawa Japan.;Department of Emergency and Critical Care Center Nippon Medical School Musashi-Kosugi Hospital Kanagawa Japan.;Department of Emergency and Critical Care Center Nippon Medical School Musashi-Kosugi Hospital Kanagawa Japan.",
"authors": "Otake|Kosuke|K|https://orcid.org/0000-0003-0130-1078;Tagami|Takashi|T|;Kido|Norihiro|N|;Watanabe|Akihiro|A|;Sakamaki|Masanori|M|https://orcid.org/0000-0001-6953-1932;Mochizuki|Toru|T|;Matsuda|Kiyoshi|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ams2.655",
"fulltext": "\n==== Front\nAcute Med Surg\nAcute Med Surg\n10.1002/(ISSN)2052-8817\nAMS2\nAcute Medicine & Surgery\n2052-8817\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ams2.655\nAMS2655\nCase Report\nCase Reports\nNeuromyelitis optica with rapid respiratory failure: a case report\nNeuromyelitis optica with severe dyspnea\nK. Otake et al.\nOtake Kosuke https://orcid.org/0000-0003-0130-1078\n1 2 kosuk-4ht@hotmail.co.jp\n\nTagami Takashi 1 2\nKido Norihiro 1 2\nWatanabe Akihiro 1 2\nSakamaki Masanori https://orcid.org/0000-0001-6953-1932\n3\nMochizuki Toru 1 2\nMatsuda Kiyoshi 1 2\n1 Department of Emergency and Critical Care Center Nippon Medical School Musashi‐Kosugi Hospital Kanagawa Japan\n2 Department of Emergency and Critical Care Medicine Nippon Medical School Tokyo Japan\n3 Department of Neurology Nippon Medical School Musashi‐Kosugi Hospital Kanagawa Japan\n* Corresponding: Kosuke Otake, MD, PhD, Nippon Medical School Musashi‐Kosugi Hospital, Address: 1‐396 Kosugi‐cho, Nakahara‐ku, Kawasaki, Kanagawa 211‐8533, Japan. E‐mail: kosuk-4ht@hotmail.co.jp.\n\n24 6 2021\nJan-Dec 2021\n8 1 10.1002/ams2.v8.1 e65518 3 2021\n05 1 2021\n03 4 2021\n© 2021 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nBackground\n\nNeuromyelitis optica is an inflammatory demyelinating disease of the central nervous system and is characterized by severe optic neuritis and transverse myelitis.\n\nCase Presentation\n\nThe patient was a 74‐year‐old man with pneumonia. On admission, he exhibited lower limb weakness and rapid respiratory deterioration in the form of tachypnea. Subsequently, he was transported to the Emergency Center of our hospital. High‐signal lesions were observed from the cervical spinal cord to the thoracic spinal cord on T2‐weighted spinal magnetic resonance images. Neuromyelitis optica was suspected, and the patient received steroid pulse therapy and immunoadsorption plasmapheresis. Serum samples obtained upon transfer were positive for anti‐aquaporin‐4 antibodies, which confirmed the diagnosis of neuromyelitis optica. Thereafter, the patient was transferred to a rehabilitation hospital.\n\nConclusion\n\nRapid respiratory failure in neuromyelitis optica is rare, and care is needed while treating these cases.\n\nNeuromyelitis optica is an inflammatory central nervous system disorder characterized by severe optic neuritis and transverse myelitis. We present a case with acute respiratory failure.\n\nCentral nervous system\nrespiration\nsource-schema-version-number2.0\ncover-dateJanuary/December 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:24.06.2021\nFunding information\n\nNo funding information provided.\n==== Body\nIntroduction\n\nNeuromyelitis optica (NMO) is an inflammatory central nervous system disorder characterized by severe optic neuritis and transverse myelitis. NMO was classified as a separate condition in 2004 following the discovery of an immunoglobulin G antibody specific to it 1 with aquaporin‐4 (AQP4), a water channel protein densely expressed in the astrocyte foot process, as its target. 2 The main symptoms of this condition include impaired vision due to optic nerve damage and neuropathy due to spinal cord lesions. Although this disease exhibits a variety of symptoms depending on the localization of nerve lesions in the spinal cord, it rarely involves rapid deterioration of the patient’s respiratory conditions to a level where the patient would require a ventilator. Here, we report the case of a patient with NMO who experienced acute respiratory failure.\n\nCase report\n\nThe patient was a 74‐year‐old man with chronic obstructive pulmonary disease who had a 1‐month history of coughing. During this month, he visited a local clinic after developing a fever of 38°C, and was subsequently admitted at another hospital for detailed medical examination. His chest radiograph and computed tomography scan taken upon admission at the other hospital are shown in Figure 1A,B. Despite treatment with antibiotics (sulbactam/ampicillin), he experienced weakness in both lower limbs (manual muscle test [MMT] grade 1–2), pain, and hypoesthesia on day 6 of admission. An emergency magnetic resonance imaging was performed, which revealed high‐signal lesions in the center of the spinal cord from C1 to T12 (Fig. 2). Subsequently, the patient was transferred to our hospital for intensive care management due to respiratory deterioration and suspicions of a spinal cord infarction. On examination, we noted weakness in both lower limbs (MMT grade 1 or 2) and pain in the T3 dermatome. In addition, T2‐weighted magnetic resonance images taken at our hospital revealed high‐signal lesions from the cervical spinal cord to the thoracic spinal cord. NMO was suspected based on the patient’s clinical symptoms and the presence of lesions at more than three spinal levels. The patient received steroid pulse therapy between days 2 and 5 of admission, and immunoadsorption plasmapheresis was initiated on day 3 of admission. His respiratory condition gradually deteriorated, and he had CO2 retention. On day 5 of admission, the patient’s respiratory distress worsened despite the initiation of nasal high‐flow therapy, and he was intubated. He underwent the second and third rounds of immunoadsorption plasmapheresis on days 7 and 10 of admission, respectively. Thereafter, his respiratory condition gradually improved, and he was extubated on day 13 of admission. The fourth and fifth rounds of immunoadsorption plasmapheresis were performed on days 15 and 18 of admission, respectively. Steroid pulse therapy was administered again from day 16 to day 18 of admission (Fig. 3). The serum sample taken upon transfer to our hospital was positive for anti‐AQP4 antibodies, which confirmed the diagnosis of NMO. On day 20 of admission, the patient was transferred to the Department of Neurology at our hospital. Because he was capable of oral feeding without any issues, oral administration of steroids was started to prevent recurrence. Thereafter, his condition stabilized, and he was transferred to a rehabilitation hospital. His MMT grades 4 months after the onset of NMO were 5 in both upper limbs, 2 to 3 in the right leg, and 3 to 4 in the left leg. The patient continues to follow up at the Department of Neurology of our hospital.\n\nFig. 1 (A) Chest radiograph taken at another hospital showing infiltrative shadows in both lungs. (B) Chest computed tomography scan taken at another hospital showing scattered mottled nodular shadows in both lungs.\n\nFig. 2 T2‐weighted spinal magnetic resonance image (sagittal) taken at another hospital showing continuous (over 3 or vertebral segments) high‐signal areas (arrows) from the cervical spinal cord to the thoracic spinal cord. High signal areas spread from the C7 to Th10 levels with a focus on the medulla.\n\nFig. 3 The clinical course of the case on admission. MMT, manual muscle testing; NPPV, noninvasive positive pressure ventilation.\n\nDiscussion\n\nDevic reported the first case of NMO in France in 1984, describing a patient who presented with severe optic neuritis and transverse myelitis. 3 In general, NMO has a female predominance, a tendency to recur, and is prone to co‐occur with various autoimmune diseases. NMO tends to be associated with severe optic neuritis and myelitis; it is not rare for optic neuritis to lead to blindness, and in many cases, spinal lesions tend to be continuous and span more than three levels. The patients with NMO usually have pain unlike that of spinal infarction. The Wingerchuk criteria published in 2006 are widely used for the diagnosis of NMO. 4 It mentions optic neuritis and myelitis as essential items; however, in 2007, the term “NMO spectrum disorders” began to be used to describe a category of similar diseases, even in patients with optic neuritis or myelitis alone. 5 Cases of NMO, such as this case, with acute respiratory failure are very rare. However, depending on the site of the spinal lesions, there may be cases in which ventilator use is required. In our patient, it was important that we were able to distinguish NMO from spinal cord infarction from the beginning.\n\nMoreover, treatment during the acute exacerbation phase is very important for patients with NMO. Because optic neuritis can cause blindness and myelitis can significantly reduce a patient’s ability to perform activities of daily living, treatment must be initiated quickly. The first‐line treatment for NMO is steroid pulse therapy. If steroid pulse therapy proves ineffective, at times, clinical improvements can be achieved through immunoadsorption plasmapheresis. Studies have reported that immunoadsorption plasmapheresis may be effective as an acute‐phase treatment of NMO. 6 Our patient underwent a total of five rounds of immunoadsorption plasmapheresis (one round ended prematurely), which led to him becoming ventilator independent and eventually being extubated. Furthermore, his ability to perform activities of daily living had improved to the level of wheelchair use by the time he was transferred. Although cases exhibiting prolonged respiratory failure with advancement of nerve lesions are not rare, those with acute respiratory failure are very rare. There are some reports of patients with transient interstitial changes in the lungs due to NMO spectrum disorders. 7 At the time of transfer to our hospital, our patient was receiving antibiotic treatment for pneumonia. NMO was suspected due to the rapid emergence of symptoms in the extremities, but there is a great deal of urgency associated with this condition given the fact that it is not well known in the field of critical care and that it progresses rapidly. Because of the necessity of quickly administering immunoadsorption plasmapheresis, this condition should be considered during the differential diagnosis of patients presenting with respiratory failure and weakness of the extremities without any history of trauma. It is possible that removal of the anti‐AQP4 antibody improved the nerves, which affected the respiratory muscles.\n\nConclusion\n\nHere, we reported the case of a patient with NMO who required short‐term use of a ventilator after rapid development of respiratory failure.\n\nDisclosures\n\nApproval of the research protocol: N/A.\n\nInformed consent: We obtained written informed consent from the patient.\n\nRegistry and the registration no. of the study/trial: N/A.\n\nAnimal study: N/A.\n\nConflict of interest: None.\n\nAcknowledgements\n\nWe would like to thank Editage (www.editage.com) for English language editing.\n==== Refs\nReferences\n\n1 Lennon VA , Wingerchuk DM , Kryzer TJ et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004; 364 : 2106–12.15589308\n2 Lennon VA , Kryzer TJ , Pittock SJ , Verkman AS , Hinson SR . IgG marker of optic‐spinal multiple sclerosis binds to the aquaporin‐4 water channel. J. Exp. Med. 2005; 202 : 473–7.16087714\n3 Devic E . Myélite subaiguë compliquée de névrite optique. Bull Med 1894; 8 : 1033–4.\n4 Wingerchuk DM , Lennon VA , Pittock SJ , Lucchinetti CF , Weinshenker BG . Revised diagnostic criteria for neuromyelitis optica. Neurology 2006; 66 : 1485–9.16717206\n5 Wingerchuk DM , Lennon VA , Lucchinetti CF , Pittock SJ , Weinshenker BG . The spectrum of neuromyelitis optica. Lancet. Neurol. 2007; 6 : 805–15.17706564\n6 Watanabe S , Nakashima I , Misu T , et al. Therapeutic efficacy of plasma exchange in NMO‐IgG‐positive patients with neuromyelitis optica. Mult. Sclr. 2007; 13 : 128–32.\n7 Asato U , Kamitani T , Ootsuka K , et al. Transient pulmonary interstitial lesions in aquqporin‐4‐positive Neuromyelitis Optica Spectrum Disorder. Intern. Med. 2018; 57 : 2981–6.29780127\n\n",
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"keywords": "Central nervous system; respiration",
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"title": "Neuromyelitis optica with rapid respiratory failure: a case report.",
"title_normalized": "neuromyelitis optica with rapid respiratory failure a case report"
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"abstract": "To retrospectively evaluate the safety and efficacy of percutaneous image-guided mediastinal mass core-needle biopsy.\nRetrospective review of an institutionally maintained biopsy registry identified 337 computed tomography- or ultrasound-guided percutaneous mediastinal mass core needle biopsies between October 2002 and August 2017 in a single quaternary referral center. Mean patient age was 51 (range, 18 to 93) years. Procedural techniques, anticoagulation/antiplatelet therapy, and tumor anatomical characteristics were reviewed. Classification and gradation of complications was based on the Clavien-Dindo system. Diagnostic yield was defined as the ratio of diagnostic biopsy to all biopsies performed.\nMean tumor size was 59.2 (range, 10 to 180) mm with 89.9% (n=303) of lesions located in the prevascular (anterior) mediastinum. There was a single major complication (0.3%) of a symptomatic pneumothorax requiring intervention. There were seven (2.1%) minor complications, including three bleeding complications. A transpleural approach was the only variable associated with an increased complication rate (P<.01). Forty-one (12.2%) patients had a biopsy performed while taking an antiplatelet/anticoagulant agent within the therapeutic window, with a single case (0.3%) associated with a minor bleeding complication. Of 18 (5.3%) procedures performed without cessation of anticoagulant/antiplatelet therapy, there were no bleeding complications. Of all 337 biopsies, 322 (95.5%) were diagnostic. None of the analyzed variables were significantly associated with a nondiagnostic biopsy.\nImage-guided percutaneous core-needle biopsy of mediastinal masses is a safe procedure with high diagnostic yield. Further prospective studies are required to assess the complication profile in higher risk patients.",
"affiliations": "Department of Radiology, Mayo Clinic, Rochester, MN.;Department of Radiology, Mayo Clinic, Rochester, MN.;Department of Radiology, Mayo Clinic, Rochester, MN.;Department of Radiology, Mayo Clinic, Rochester, MN.;Department of Radiology, Mayo Clinic, Rochester, MN.;Department of Radiology, Mayo Clinic, Rochester, MN.;Department of Radiology, Mayo Clinic, Rochester, MN.;Department of Radiology, Mayo Clinic, Rochester, MN.;Department of Health Sciences Research, Mayo Clinic, Rochester, MN.;Department of Radiology, Mayo Clinic, Rochester, MN.",
"authors": "Navin|Patrick J|PJ|;Eickstaedt|Nathan L|NL|;Atwell|Thomas D|TD|;Young|Jason R|JR|;Eiken|Patrick W|PW|;Welch|Brian T|BT|;Schmitz|John J|JJ|;Schmit|Grant D|GD|;Johnson|Matthew P|MP|;Moynagh|Michael R|MR|",
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"doi": "10.1016/j.mayocpiqo.2021.09.006",
"fulltext": "\n==== Front\nMayo Clin Proc Innov Qual Outcomes\nMayo Clin Proc Innov Qual Outcomes\nMayo Clinic Proceedings: Innovations, Quality & Outcomes\n2542-4548\nElsevier\n\nS2542-4548(21)00140-5\n10.1016/j.mayocpiqo.2021.09.006\nOriginal Article\nSafety and Efficacy of Percutaneous Image-Guided Mediastinal Mass Core-Needle Biopsy\nNavin Patrick J. MB, BCh, BAO navin.patrick@mayo.edu\na∗\nEickstaedt Nathan L. MD a\nAtwell Thomas D. MD a\nYoung Jason R. MD a\nEiken Patrick W. MD a\nWelch Brian T. MD a\nSchmitz John J. MD a\nSchmit Grant D. MD a\nJohnson Matthew P. MS b\nMoynagh Michael R. MB, BCh a\na Department of Radiology, Mayo Clinic, Rochester, MN\nb Department of Health Sciences Research, Mayo Clinic, Rochester, MN\n∗ Correspondence: Address to Patrick J. Navin, MB, BCh, BAO, Department of Radiology, Mayo Clinic, 200 First Street, NW, Rochester, MN 55901. navin.patrick@mayo.edu\n25 11 2021\n12 2021\n25 11 2021\n5 6 11001108\n© 2021 THE Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nObjective\n\nTo retrospectively evaluate the safety and efficacy of percutaneous image-guided mediastinal mass core-needle biopsy.\n\nPatients and Methods\n\nRetrospective review of an institutionally maintained biopsy registry identified 337 computed tomography– or ultrasound-guided percutaneous mediastinal mass core needle biopsies between October 2002 and August 2017 in a single quaternary referral center. Mean patient age was 51 (range, 18 to 93) years. Procedural techniques, anticoagulation/antiplatelet therapy, and tumor anatomical characteristics were reviewed. Classification and gradation of complications was based on the Clavien-Dindo system. Diagnostic yield was defined as the ratio of diagnostic biopsy to all biopsies performed.\n\nResults\n\nMean tumor size was 59.2 (range, 10 to 180) mm with 89.9% (n=303) of lesions located in the prevascular (anterior) mediastinum. There was a single major complication (0.3%) of a symptomatic pneumothorax requiring intervention. There were seven (2.1%) minor complications, including three bleeding complications. A transpleural approach was the only variable associated with an increased complication rate (P<.01). Forty-one (12.2%) patients had a biopsy performed while taking an antiplatelet/anticoagulant agent within the therapeutic window, with a single case (0.3%) associated with a minor bleeding complication. Of 18 (5.3%) procedures performed without cessation of anticoagulant/antiplatelet therapy, there were no bleeding complications. Of all 337 biopsies, 322 (95.5%) were diagnostic. None of the analyzed variables were significantly associated with a nondiagnostic biopsy.\n\nConclusion\n\nImage-guided percutaneous core-needle biopsy of mediastinal masses is a safe procedure with high diagnostic yield. Further prospective studies are required to assess the complication profile in higher risk patients.\n\nAbbreviations and Acronyms\n\nCT, computed tomography\nINR, international normalized ratio\nSIR, Society of Interventional Radiology\nUS, ultrasound\n==== Body\npmcThe mediastinum is a soft tissue division between the two pleural sacs, densely populated with many vascular and neurological structures. Masses, when they arise within this space, may relate to malignant conditions such as lymphoma, invading lung cancer, thymic neoplasm, metastatic disease, or nonmalignant conditions such as infectious or granulomatous disease and benign neoplastic lesions.1 Image-guided percutaneous mediastinal biopsy allows three-dimensional appreciation of the biopsy field and real-time or near real-time confirmation of biopsy tract. Computed tomography (CT)– and ultrasound (US)–guided approaches have both demonstrated excellent efficacy and safety profiles in attaining adequate tissue volume.1, 2, 3, 4, 5\n\nPercutaneous image-guided biopsy of mediastinal masses shows high diagnostic accuracy combined with minimal patient sedation and low cost when compared to other more invasive approaches.6,7 Reported complications include pneumomediastinum, pneumothorax, and bleeding complications such as hemoptysis, hemothorax, and hematoma formation.1,6,8 Complication rates in CT-guided procedures range from 4% to 17% with a diagnostic yield ranging from 74% to 96%.1,4,9, 10, 11, 12 In studies assessing the US-guided approach, there were no reported complications with a diagnostic yield of 80% to 89%.3,13,14\n\nThe management of anticoagulant and antiplatelet medications, in particular aspirin, when considering percutaneous biopsy is widely debated. It is claimed that cessation may be unnecessary for many percutaneous organ biopsies15,16; however, there are conflicting studies demonstrating an increase in bleeding complications related to periprocedural use.17 The Society of Interventional Radiology (SIR) offers guidance for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions with varying recommendations depending on the type of anticoagulant or antiplatelet agent and the procedure involved.18 However, this bleeding risk must be balanced with the possible implications of medication withdrawal — in particular, the risk of cardiovascular events and peripheral ischemia.19\n\nOur aim was to evaluate US- and CT-guided mediastinal biopsies performed in a single center over a 15-year period and to assess the factors which may alter the complication rate and diagnostic yield.\n\nPatients and Methods\n\nEthical approval was attained from the Institutional Review Board with consent waived. This single-center study was compliant with the Health Insurance Portability and Accountability Act.\n\nPatients\n\nThis was a retrospective study, assessing percutaneous image-guided mediastinal core-needle biopsies (CNBs) performed between October 2002 and August 2017 in a single academic quaternary referral center, reviewing data from an institutional biopsy database and review of patient medical records. Adult patients (≥18 years old) were included who had undergone a percutaneous US-guided or CT-guided biopsy of a mediastinal mass or lymph node. Only patients who had consented to the retrospective use of medical records for research purposes were included. Exclusion criteria also included patients who only underwent lesion fine-needle aspiration without CNB or biopsy performed in pediatric patients (<18 years old).\n\nData were entered into the radiology department biopsy database at the time of biopsy and included information on patient demographics, biopsy technique, periprocedural medications, standard laboratory values, and presence of postprocedure complications. In particular, antiplatelet and anticoagulant medications such as aspirin (81 mg and 325 mg, respectively), warfarin, clopidogrel, intravenous heparin, and subcutaneous heparin were included in the database. The novel anticoagulants were not included during data accrual. The anatomical location of the lesion was based on the three-compartment CT model developed by the International Thymic Malignancy Interest Group which divides the mediastinum into prevascular (anterior), visceral (middle), and paravertebral (posterior) compartments.20 The final study cohort comprised 318 patients who underwent 337 biopsy procedures during the study period. Demographic information is included in Table 1. Mean age of the cohort was 50.6 (range, 18 to 93) years with almost identical female-to-male ratio of 166:171 (49.3%:50.7%).Table 1 Subject Demographics, Tumor Characteristics, and Procedural Informationa,b\n\nMean age (range), years\t51±18.9 (18 to 93)\t\nSex\t\t\n Male\t171 (50.7)\t\n Female\t166 (49.3)\t\nSite of tumor\t\t\n Anterior\t303 (89.9)\t\n Middle\t9 (2.7)\t\n Posterior\t25 (7.4)\t\nMean tumor size (range), mm\t59.2±33.8 (10 to 180)\t\nTumor pathology\t\t\n Benign\t63 (18.7)\t\n Primary mediastinal malignancy\t26 (7.7)\t\n Lymphoma\t136 (40.4)\t\n Metastatic\t97 (28.8)\t\n Nondiagnostic\t15 (4.5)\t\nModality\t\t\n CT\t323 (95.5)\t\n US\t14 (4.5)\t\nRoute\t\t\n Parasternal\t267 (79.2)\t\n Trans-sternal\t22 (6.5)\t\n Transpleural\t19 (5.6)\t\n Paraspinal\t29 (8.6)\t\nMean (range) number of passes\t5±2.5 (1 - 14)\t\nIntroducer needle\t\t\n Yes\t325 (96.4)\t\n No\t12 (3.6)\t\nGauge\t\t\n 16G\t11 (3.3)\t\n 18G\t236 (70.0)\t\n 20G\t90 (26.7)\t\na CT, computed tomography; US, ultrasound.\n\nb Values shown are n (%) or mean (range) as appropriate.\n\nBiopsy Technique\n\nImage-guided biopsy was either performed or supervised by a fellowship-trained staff radiologist. The median experience of the performing radiologist was 10 years with a range of 3 to 30 years. Image guidance technique, biopsy route, and biopsy device were selected at the discretion of the performing radiologist.\n\nPreprocedural coagulation profile consisting of an international normalized ratio (INR) and platelet count was obtained based on patient screening criteria as per institutional protocol. Standard prebiopsy target parameters included an INR of less than or equal to 1.6 and platelet count greater than 50×109/L. Patients were advised to remain off antiplatelet and anticoagulation medication before biopsy for a defined length based on SIR guidelines.21,22 Deviation from protocol was not a contraindication to biopsy as the ultimate decision was made following discussion between the referring provider and the radiologist performing the procedure.\n\nSeventy-nine patients were on some form of anticoagulation or antiplatelet medication in the 30 days before biopsy (23.4%), with 16 (4.7%) patients on multiple medications. This comprised 29 (8.6%) patients on 81-mg aspirin dose, 20 on 325-mg aspirin dose (5.9%), 16 on warfarin (4.7%), two on clopidogrel (0.6%), 13 on intravenous Heparin (3.9%), and 11 on subcutaneous heparin (3.3%). All medications were stopped within the recommended therapeutic efficacy time frame before biopsy except for 41 patients (12.2%). Of these 41 patients, 23 (56.1%) were taking aspirin 81 mg, 16 (39.0%) were taking aspirin 325 mg, and two (4.9%) were taking a prophylactic dose of subcutaneous heparin. Of this subgroup, 18 procedures were performed in patients who had not stopped taking their medication with 6 (33.3%) taking 81 mg aspirin, 10 (55.6%) taking 325 mg aspirin, and 2 (11.1%) taking subcutaneous heparin at the time of biopsy procedure.\n\nBiopsies were performed using sterile technique either under fluoroscopic CT guidance (GE LightSpeed 16-slice scanner GE Healthcare, Waukesha, Wisconsin) or ultrasound guidance (GE Logiq E9 system, GE Healthcare, Waukesha, WI). Local anesthesia in the form of 1% lidocaine was invariably used, with or without monitored moderate sedation with fentanyl and midazolam. A coaxial technique was used to perform all CT-guided biopsies. An introducer needle was not typically used for US-guided biopsies as the introduction of air can possibly lead to decreased target lesion visibility. A spring-loaded, side-cutting biopsy device was used, offered in a variety of gauges (Bard Monopty, Bard Medical, Covington, GA). Biopsy route was classified as either parasternal, paraspinal, trans-sternal, or transpleural if a portion of lung parenchyma was transgressed. The use of tract embolization was not standard practice in the department. A cytopathologist was not routinely present for the biopsy, with samples submitted for both cytology and pathology analysis as per institution protocol. Postbiopsy, patients were observed for a minimum of 2 hours postprocedure in the outpatient radiology recovery area. As per departmental protocol, a chest radiograph was requested for 1-hour postbiopsy to assess for potential complications. Additional imaging or investigations were performed depending on postprocedure symptoms.\n\nComplication Rate\n\nComplications were identified and classified as minor or major based on the definitions of the Clavien-Dindo system.23 This scale consists of seven grades with minor complications classified as grade I (any deviation from the normal postoperative course not requiring surgical, endoscopic, or radiological intervention), grade II (complications requiring drug treatments other than those allowed for grade I complications), and grade IIIa/b (major complications requiring surgical, endoscopic, or radiological intervention), grade IVa/b (life-threatening complications), or grade V (death).\n\nInformation on postprocedure complications was accrued via telephone conversations from a dedicated radiology registered nurse in the 24 to 72 hours following biopsy using a standardized format. Further information to identify any delayed complication was obtained by review of the patient’s electronic medical record by one of two investigators. If a discrepancy arose as to the presence of a postbiopsy complication, consensus was achieved by review of the patient’s electronic medical record by an additional investigator.\n\nDiagnostic Yield\n\nBased on the findings of a fellowship-trained pathologist, each biopsy was classified as either diagnostic for malignancy, benign, or nondiagnostic. Patients were followed for 1 year to ensure a benign biopsy result was correct. Nondiagnostic studies were classified as such based on the absence of adequate tissue for a diagnosis or if a prior benign result was deemed inaccurate on follow-up imaging or biopsy. Diagnostic yield was defined as the ratio of a diagnostic biopsy to all biopsies performed.\n\nStatistical Analysis\n\nDescriptive statistics are reported for subject demographics, diagnostic yield, and complication rate as numbers and percentages with means and standard deviations. All continuous variables were compared between the bleeding and nonbleeding groups by the Kruskal-Wallis test. Categorical variables were compared using the χ2 test and Fisher exact test for any n less than 5 variables. A P less than .05 was considered statistically significant. A P less than .05 was considered statistically significant. All statistical analyses were completed using Jmp software (JMP, version 13, SAS institute Inc, Cary, NC).\n\nResults\n\nOf the 337 mediastinal mass biopsies, the targeted mass was most commonly located in the prevascular (anterior) mediastinum (n=303 procedures; 89.9%), with CT imaging guidance most frequently used (n=322 procedures; 95.5%). Mean tumor axial diameter was 59.2 (range, 10 to 180) mm. A parasternal approach without crossing pleura was most used, occurring in 267 (79.2%) procedures. There were 106 patients classified as hypertensive during the periprocedural period (31.5%). Of the diagnostic biopsies (n=322), pathology revealed 63 patients (19.5%) with benign tissue, 26 patients (8.1%) with primary mediastinal malignancy, 136 patients (42.2%) with lymphoma, and 97 patients (30.1%) with metastatic disease (Table 1).\n\nComplication Rate\n\nThere were eight patients (2.4 %) who encountered a complication following biopsy, comprising seven (2.1%) minor complications and a single (0.3%) major complication (Tables 2 and 3). Of these, five patients (1.5%) had a pneumothorax and three patients (0.9%) had a minor bleeding complication. No subject encountered a pneumomediastinum. The single major complication occurred in a 79-year-old male subject who developed a symptomatic moderate-sized pneumothorax following biopsy of a prevascular (anterior) mediastinal mass using a transpleural approach (Figure). This required the insertion of a chest tube and a 2-day admission for observation and management. The other four pneumothoraces were small, requiring no further intervention, and patients were discharged on the same day as the procedure.Table 2 Complication Rates Depending on Subject and Procedure Variables (N=337)a,b,c\n\nVariable\tComplication (8)\tNo complication (329)\tP\t\nAge, years\t60.6±17.9\t50.6±18.8\t.13\t\nPlatelets, ×109/L\t337.3±163.1\t282.0±110.7\t.41\t\nINR\t1.1±0.1\t1.1±0.1\t.26\t\nNumber of passes\t4.0±1.5\t5.3±2.5\t.15\t\nDimensions, mm\t56.0±36.9\t59.3±33.8\t.71\t\nHypertension, 105 (31.2)\t4 (1.2)\t101 (29.9)\t.22\t\nModality\t\t\t\t\t\n US\t14 (4.2)\t0\t14\t.71\t\n CT\t323 (95.8)\t8\t315\t\t\nRoute\t\t\t\t\t\n Parasternal\t267 (79.2)\t4\t263\t<.01\t\n Trans-sternal\t22 (6.5)\t0\t22\t\t\n Transpleural\t19 (5.6)\t4\t15\t\t\n Paraspinal\t29 (8.6)\t0\t29\t\t\nIntroducer needle, 325 (96)\t8\t317\t.75\t\nCutting needle size, G\t\t\t\t.85\t\n 16\t11 (3.3)\t0\t11\t\n 18\t236 (70.0)\t6\t230\t\n 20\t90 (26.7)\t2\t88\t\nAnticoagulation in 1 month prior, 79 (23.4)\t\t1\t78\t.89\t\n Discontinued as per protocol, 38 (11.3)\t\t0\t38\t1.00\t\n Discontinued in therapeutic window, 23 (6.8)\t\t1\t22\t.44\t\n Not discontinued, 18 (5.3)\t\t0\t18\t1.00\t\na CT, computed tomography; INR, international normalized ratio; US, ultrasound.\n\nb Seven minor and one major complication.\n\nc Values presented are mean ± SD or n (%) as appropriate.\n\nTable 3 Characteristics of Subjects With Complicationsa\n\nComplication\tSubject\tAge\tSex\tPathology\tLocation\tGreatest mass dimension, mm\tBiopsy route\tComplication type\tAnticoagulant\tINR\tPlatelets, ×109/L\tNeedle size, G\tNo. of passes\t\nMajor\t1\t79\tM\tMalignant thymoma\tPrevascular\t24\tTranspleural\tPneumothorax\tNone\t1.2\t241\t20\t4\t\nMinor\t1\t80\tM\tBenign tissue\tPrevascular\t19\tParasternal\tBleeding\tAspirin 81mg, warfarin\t1.2\t139\t18\t5\t\n\t2\t41\tM\tLymphoma\tPrevascular\t99\tParasternal\tBleeding\tNone\t1\t608\t18\t2\t\n\t3\t41\tM\tNondiagnostic\tPrevascular\t99\tParasternal\tBleeding\tNone\t1\t512\t18\t3\t\n\t4\t78\tF\tBenign\tPrevascular\t30\tParasternal\tPneumothorax\tNone\t1\t199\t18\t5\t\n\t5\t49\tF\tBenign\tPrevascular\t17\tTranspleural\tPneumothorax\tNone\t1.1\t273\t20\t2\t\n\t6\t71\tM\tLymphoma\tPrevascular\t88\tTranspleural\tPneumothorax\tNone\t1.2\t295\t18\t6\t\n\t7\t46\tF\tLymphoma\tPrevascular\t72\tTranspleural\tPneumothorax\tNone\t1\t431\t18\t5\t\na F, female; INR, international normalized ratio; M, male.\n\nFigure Major complication of a large pneumothorax following biopsy of a prevascular mass (arrow) in a 78-year-old male patient with subsequent diagnosis of thymoma. A,B Contrast enhanced computed tomography (CT) showing infiltrative prevascular mediastinal mass in both lung and soft tissue windows in patient status post median sternotomy. C, CT image showing transpleural pathway of biopsy needle. D, CT shows postbiopsy symptomatic moderate-sized pneumothorax requiring chest tube insertion.\n\nThe only variable associated with increased risk of a complication was transpleural approach (P<.01). Of the five pneumothoraces, four were using transpleural approach, with the other using the parasternal approach.\n\nThree patients developed minor bleeding complications, none of whom required radiologic or surgical intervention. A single 80-year-old patient required overnight admission for observation and analgesia after developing a hematoma subsequent to biopsy of a 19-mm pericardiophrenic lymph node. The patient was discharged the following day with a stable hemoglobin level. This patient had discontinued aspirin (325 mg) therapy 4 days before biopsy. The patient had also been receiving warfarin therapy, which was also discontinued 4 days before biopsy with an INR of 1.2 at the time of biopsy.\n\nAll patients who had a history of antiplatelet/anticoagulation use did not show a significantly higher complication rate (n=79, P=.89) (Table 2). Of the 41 (12.2%) patients who were taking an anticoagulant/antiplatelet agent within the therapeutic window, there was only a single minor bleeding complication. Of 18 (5%) patients for whom a biopsy was performed without cessation of this agent, there were no bleeding complications.\n\nMean INR of the patients with bleeding complications was 1.07 (SD, 0.09) versus 1.05 (SD, 0.13) in patients without. There were only two patients with a supratherapeutic INR at the time of procedure (both with values of 1.7); neither of these patients encountered a complication. Only two patients required an intervention to improve coagulation profile; with the administration of platelets and vitamin K before the procedure, neither of these patients encountered a complication.\n\nDiagnostic Yield\n\nThere were 322 patients (95.5%) with an adequate diagnostic biopsy. Of the 15 nondiagnostic biopsies, 10 were ultimately found to have a malignant etiology on repeat biopsy, surgical removal, or clinical progression. Subject age, lesion size, pathology of the lesion, modality used, route of biopsy, use of an introducer needle, needle gauge, and number of passes were all not statistically significant in attaining a nondiagnostic biopsy (Table 4).Table 4 Effect of Subject and Procedure Variables on Diagnostic Yielda\n\n\tDiagnostic (322)\tNondiagnostic (15)\tP\t\nAge, years\t51±19.1\t44±12.4\t.12\t\nDimensions, mm\t59.5±34.2\t52.1±25.9\t.41\t\nModality\t\t\t\t\n US\t14\t0\t.41\t\n CT\t308\t15\t\t\nRoute\t\t\t\t\n Parasternal\t253\t14\t.42\t\n Trans-sternal\t22\t0\t\t\n Transpleural\t18\t1\t\t\n Paraspinal\t29\t0\t\t\nIntroducer needle\t\t\t\t\n Yes\t310\t15\t.45\t\n No\t12\t0\t\t\nCutting needle size, G\t\t\t\t\n 16\t11\t0\t.18\t\n 18\t228\t8\t\t\n 20\t83\t7\t\t\nNumber of passes\t5.3±2.5\t4.7±1.8\t.36\t\na CT, computed tomography; US, ultrasound.\n\nDiscussion\n\nImage-guided biopsy is often used to obtain tissue for oncologic, genetic, and immunologic testing of cancer mutations, with the intention to improve diagnosis and treatment of patients undergoing targeted therapy. The current study shows that image-guided percutaneous biopsy of mediastinal lesions is an efficacious and safe technique. Such a technique provides a favorable alternative to surgical or endoscopic techniques.\n\nThe diagnostic yield of the current study compares favorably with similar studies. In a recent meta-analysis, pooled diagnostic yield of CT-guided percutaneous biopsy measured 92%, compared to 96% in this current study.6 The range of reported diagnostic yield in each study included in the meta-analysis ranged from 74% to 96%.1,4,9, 10, 11, 12 Possible reasons for this variability may reflect technical advances in pathology, imaging, and biopsy equipment along with the volume of procedures performed in each institution. The experience represented in the current study is based in a large quaternary referral center including radiologists with subspecialty training with image-guided biopsy.\n\nSimilar to prior studies, there was no statistically significant variable which affected the diagnostic yield of the biopsy technique.1,4,9, 10, 11, 12 However, biopsy needle gauge has shown significance in one study assessing CT fluoroscopy–guided biopsy of anterior mediastinal masses.24 In that study it was found that using a 20-gauge needle was a significant risk factor for diagnostic failure. In the current study, although 7 of 15 diagnostic failures were performed using a 20-gauge biopsy needle (46.7%), this finding was not statistically significant (P=.18).\n\nThe overall and major complication rate in the current study was lower compared to other similar studies at 2% and 0.3%, respectively. In the same meta-analysis,6 the pooled complication rate was 13% with a major complication rate of 2%. However, the definition of a major complication in this meta-analysis may not be identical to the definition used in the current study. The complication rate in the current study is also lower compared to the prior largest sample, where they encountered an overall complication rate of 7%.1 However, they did not differentiate between major and minor complications. In the current study, the majority of complications were minor (n=7 of 8) and consisted of pneumothorax (n=5 of 8) and bleeding (n=3 of 8) complications.\n\nThe only variable associated with an increased rate of a complication was the transpleural approach. The rate of pneumothorax in transpleural mediastinal mass biopsy in this study (n=4 of 19, 21.1%) is slightly higher than the rate of pneumothorax in percutaneous lung mass biopsy,25,26 likely related to the crossing of two separate pleural interfaces. The choice of approach is often tailored to each individual mediastinal mass. Certain techniques may decrease the likelihood of pleural involvement such as hydrodisplacement or trans-sternal approach. These techniques may not be appropriate in certain scenarios; however, the transpleural approach is the safest option likely to lead to a diagnostic result.\n\nThe most appropriate management of patients on anticoagulant or antiplatelet medications before percutaneous biopsy is cause for much discussion. The rate of major complications in this current study of 0.3% is low and the clinical significance of the complication was relatively minimal. Guidance on performing biopsies varies between departments. Local protocols dictate that anticoagulation medication should be held for a predetermined time frame based on SIR guidelines,21,22 that INR should be less than 1.6, and that platelets should be greater than 50×109/L. In this study, 12.2% (n=41 patients) were on anticoagulant/antiplatelet therapy within the therapeutic period before biopsy, all of them taking aspirin therapy. There was only a single minor bleeding complication in this group. No bleeding complications occurred in the 5.3% (n=18) of patients who had not stopped aspirin therapy at time of biopsy. This observation supports that seen in prior studies.15,27 Application of these protocols varies depending on the clinical situation and institution. However, the balance of benefit to risk in this decision is sometimes biased towards the bleeding risk from the anticoagulant medication and neglects the risk of cessation of this medication. For instance, a figure of approximately 1% absolute risk of an embolic event when warfarin is discontinued for 4 to 7 days is quoted in the literature.28, 29, 30, 31 When compared to the 0.3% major complication risk encountered in the current study, it may lead more to question the validity of unmitigated anticoagulation medication discontinuation.\n\nThere are a number of limitations to the current study. There is inherent selection bias given the retrospective nature. Only patients who were deemed suitable for biopsy underwent the procedure, and the technique (including approach and biopsy gauge) was chosen by an experienced proceduralist on a case-by-case basis. As a result, there is a dearth of patients with elevated INR (>1.6) or on continued anticoagulation. Also, some parameters such as liver function or thromboplastin time were not available. Given that these biopsies were performed in a quaternary referral center with specialized staff encountering a high volume of mediastinal biopsies, this study may not be representative of other procedural practices.\n\nConclusion\n\nIn conclusion, the current study shows that image-guided percutaneous CNB of mediastinal masses is a safe procedure with high diagnostic yield, and that biopsy in these cases can be achieved with patients on recent anticoagulant/antiplatelet therapy. Further prospective studies are required to assess the complication profile in higher risk patients.\n\nPotential Competing Interests: The authors report no potential competing interests.\n==== Refs\nReferences\n\n1 de Margerie-Mellon C. de Bazelaire C. Amorim S. Diagnostic yield and safety of computed tomography-guided mediastinal core needle biopsies J Thorac Imaging 30 5 2015 319 327 25978277\n2 Westcott J.L. Transthoracic needle biopsy of the hilum and mediastinum J Thorac Imaging 2 2 1987 41 48 3599147\n3 Yang P.C. Chang D.B. Lee Y.C. Yu C.J. Kuo S.H. Luh K.T. Mediastinal malignancy: ultrasound guided biopsy through the supraclavicular approach Thorax 47 5 1992 377 380 1609382\n4 Bressler E.L. Kirkham J.A. Mediastinal masses: alternative approaches to CT-guided needle biopsy Radiology 191 2 1994 391 396 8153311\n5 Protopapas Z. Westcott J.L. Transthoracic hilar and mediastinal biopsy Radiol Clin North Am 38 2 2000 281 291 10765390\n6 Lee H.N. Yun S.J. Kim J.I. Ryu C.-W. Diagnostic outcome and safety of CT-guided core needle biopsy for mediastinal masses: a systematic review and meta-analysis Eur Radiol 30 1 2020 588 599 31418086\n7 Date H. Diagnostic strategies for mediastinal tumors and cysts Thorac Surg Clin 19 1 2009 29 35 vi 19288818\n8 Gupta S. Seaberg K. Wallace M.J. Imaging-guided percutaneous biopsy of mediastinal lesions: different approaches and anatomic considerations Radiographics 25 3 2005 763 786 discussion 86-88 15888624\n9 Kulkarni S. Kulkarni A. Roy D. Thakur M.H. Percutaneous computed tomography-guided core biopsy for the diagnosis of mediastinal masses Ann Thorac Med 3 1 2008 13 17 19561877\n10 Petranovic M. Gilman M.D. Muniappan A. Diagnostic yield of CT-guided percutaneous transthoracic needle biopsy for diagnosis of anterior mediastinal masses AJR Am J Roentgenol 205 4 2015 774 779 26397325\n11 Neyaz Z. Lal H. Thakral A. Nath A. Rao R.N. Verma R. Percutaneous computed tomography-guided aspiration and biopsy of intrathoracic lesions: results of 265 procedures Lung India 33 6 2016 620 625 27890990\n12 Rabbani M. Sarrami A.H. Computed tomography-guided percutaneous core needle biopsy for diagnosis of mediastinal mass lesions: experience with 110 cases in two university hospitals in Isfahan, Iran Adv Biomed Res 5 2016 152 27713873\n13 Yi D. Feng M. Wen Ping W. Zheng Biao J. Fan P.L. Contrast-enhanced US-guided percutaneous biopsy of anterior mediastinal lesions Diagn Interv Radiol 23 1 2017 43 48 27911263\n14 Otani Y. Yoshida I. Ishikawa S. Use of ultrasound-guided percutaneous needle biopsy in the diagnosis of mediastinal tumors Surg Today 26 12 1996 990 992 9017961\n15 Potretzke T.A. Harvey J.A. Gunderson T.M. Frequency of bleeding complications after percutaneous core needle biopsy and the association with aspirin usage and length of aspirin discontinuation AJR Ame J Roentgenol 213 2019 1 5\n16 Monahan H. Gunderson T. Greene E. Schmit G. Atwell T. Schmitz J. Risk factors associated with significant bleeding events after ultrasound-guided percutaneous native renal biopsies: a review of 2204 cases Abdom Radiol (NY) 44 6 2019 2316 2322 30830293\n17 Burger W. Chemnitius J.M. Kneissl G.D. Rucker G. Low-dose aspirin for secondary cardiovascular prevention — cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation — review and meta-analysis J Intern Med 257 5 2005 399 414 15836656\n18 Davidson J.C. Rahim S. Hanks S.E. Society of Interventional Radiology consensus guidelines for the periprocedural management of thrombotic and bleeding risk in patients undergoing percutaneous image-guided interventions — Part I: review of anticoagulation agents and clinical considerations: endorsed by the Canadian Association for Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe J Vasc Interv Radiol 30 8 2019 1155 1167 31229332\n19 Ferrari E. Benhamou M. Cerboni P. Marcel B. Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis J Am Coll Cardiol 45 3 2005 456 459 15680728\n20 Carter B.W. Benveniste M.F. Madan R. ITMIG classification of mediastinal compartments and multidisciplinary approach to mediastinal masses Radiographics 37 2 2017 413 436 28129068\n21 Patel I.J. Davidson J.C. Nikolic B. Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions J Vasc Interv Radiol 23 6 2012 727 736 22513394\n22 Patel I.J. Davidson J.C. Nikolic B. Addendum of newer anticoagulants to the SIR consensus guideline J Vasc Interv Radiol 24 5 2013 641 645 23622037\n23 Dindo D. Demartines N. Clavien P.A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey Ann Surg 240 2 2004 205 213 15273542\n24 Iguchi T. Hiraki T. Matsui Y. CT fluoroscopy-guided core needle biopsy of anterior mediastinal masses Diagn Interv Imaging 99 2 2018 91 97 29146413\n25 Lorenz J. Blum M. Complications of percutaneous chest biopsy Semin Intervent Radiol 23 2 2006 188 193 21326762\n26 Boskovic T. Stanic J. Pena-Karan S. Pneumothorax after transthoracic needle biopsy of lung lesions under CT guidance J Thorac Dis 6 suppl 1 2014 S99 S107 24672704\n27 Atwell T.D. Spanbauer J.C. McMenomy B.P. The timing and presentation of major hemorrhage after 18,947 image-guided percutaneous biopsies AJR Am J Roentgenol 205 1 2015 190 195 26102398\n28 Garcia D.A. Regan S. Henault L.E. Risk of thromboembolism with short-term interruption of warfarin therapy Arch Intern Med 168 1 2008 63 69 18195197\n29 Wahl M.J. Pinto A. Kilham J. Lalla R.V. Dental surgery in anticoagulated patients — stop the interruption Oral Surg Oral Med Oral Pathol Oral Radiol 119 2 2015 136 157 25577414\n30 Blacker D.J. Wijdicks E.F. McClelland R.L. Stroke risk in anticoagulated patients with atrial fibrillation undergoing endoscopy Neurology 61 7 2003 964 968 14557569\n31 Wysokinski W.E. McBane R.D. Daniels P.R. Periprocedural anticoagulation management of patients with nonvalvular atrial fibrillation Mayo Clinic Proc 83 6 2008 639 645\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2542-4548",
"issue": "5(6)",
"journal": "Mayo Clinic proceedings. Innovations, quality & outcomes",
"keywords": "CT, computed tomography; INR, international normalized ratio; SIR, Society of Interventional Radiology; US, ultrasound",
"medline_ta": "Mayo Clin Proc Innov Qual Outcomes",
"mesh_terms": null,
"nlm_unique_id": "101728275",
"other_id": null,
"pages": "1100-1108",
"pmc": null,
"pmid": "34877475",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": "27890990;29146413;15680728;18533080;10765390;15273542;25978277;22513394;3599147;19288818;9017961;21326762;28129068;27713873;24672704;19561877;14557569;26397325;15888624;18195197;30830293;25577414;15836656;26102398;23622037;27911263;8153311;31418086;30995091;1609382;31229332",
"title": "Safety and Efficacy of Percutaneous Image-Guided Mediastinal Mass Core-Needle Biopsy.",
"title_normalized": "safety and efficacy of percutaneous image guided mediastinal mass core needle biopsy"
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"companynumb": "US-BAYER-2022A043553",
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"abstract": "We describe a case of nevirapine-induced Stevens-Johnson Syndrome (SJS) and fulminant hepatic failure (FHF) requiring liver transplantation. Five weeks prior to admission, a 57-year-old female with HIV infection had been switched to a nevirapine-based regimen of highly active antiretroviral therapy (HAART) with a CD4 cell count of 695/mm(3). Examination of the explanted native liver at initial transplantation revealed massive hepatic necrosis consistent with drug-induced liver injury. Primary graft nonfunction complicated the early postoperative course and liver retransplantation was required. On follow-up 2 years later, she remains in good health with an undetectable viral load on an efavirenz-based regimen of HAART. To our knowledge, this is the first report of successful liver transplantation following SJS and FHF.",
"affiliations": "Department of Medicine, Mount Sinai Hospital and School of Medicine, New York, NY, USA. jennifer.jao@mssm.edu",
"authors": "Jao|J|J|;Sturdevant|M|M|;del Rio Martin|J|J|;Schiano|T|T|;Fiel|M I|MI|;Huprikar|S|S|",
"chemical_list": "D019380:Anti-HIV Agents; D019829:Nevirapine",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1600-6143.2010.03153.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "10(7)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": null,
"medline_ta": "Am J Transplant",
"mesh_terms": "D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D005260:Female; D015658:HIV Infections; D006440:Hemofiltration; D006801:Humans; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008875:Middle Aged; D019829:Nevirapine; D013262:Stevens-Johnson Syndrome; D016896:Treatment Outcome",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "1713-6",
"pmc": null,
"pmid": "20642694",
"pubdate": "2010-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nevirapine-induced stevens johnson-syndrome and fulminant hepatic failure requiring liver transplantation.",
"title_normalized": "nevirapine induced stevens johnson syndrome and fulminant hepatic failure requiring liver transplantation"
} | [
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP018547",
"fulfillexpeditecriteria": "2",
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"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
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{
"abstract": "Cerebral venous sinus thrombosis (CVST) and posterior reversible encephalopathy syndrome (PRES) are two rare diseases which may present with similar symptoms and signs. We report a case with coexisting PRES and CVST in a preeclamptic woman. A 24-year-old woman, G2 P1, at 33 wk and 5 d of pregnancy presented with headache. Her blood pressure was 180/120 mmHg and urinary test revealed +3proteinuria. Cesarean section was performed with indications of severe preeclampsia, intrauterine growth retardation and fetal distress. Cranial MR venography of the patient revealed thrombiin superior sagittal sinus, confluenssinuum, right transverse and right sigmoid sinus and diffusion MRI showed increased signal intensity (vasogenicoedema) in cortical and subcortical areas of parietooccipital and posterior frontal lobes.The patient was treated with magnesium sulfate and heparin successfully. After treatment period, control cranial MRI and diffusion MRI were normal. Thrombi within the sinuses were totally regressed. Albeit rare, these two diseases should be kept in mind especially in preeclamptic/eclamptic patients that present with neurological symptom and/or sign.",
"affiliations": "Specialist, Department of Obstetrics and Gynaecology, Bezmialem Vakif University , Istanbul, Turkey .;Specialist, Department of Obstetrics and Gynaecology, Bezmialem Vakif University , Istanbul, Turkey .;Senior Resident, Department of Obstetrics and Gynaecology, Bezmialem Vakif University , Istanbul, Turkey .;Professor, Department of Radiology, Bezmialem Vakif University , Istanbul, Turkey .;Professor, Department of Obstetrics and Gynaecology, Bezmialem Vakif University , Istanbul, Turkey .",
"authors": "KöRoglu|Nadiye|N|;Sudolmus|Sinem|S|;Sarioglu|Elif Asli|EA|;Alkan|Alpay|A|;Dansuk|Ramazan|R|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2015/9420.5408",
"fulltext": null,
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"issn_linking": "0973-709X",
"issue": "9(1)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Cranial MRI; Neurological symptoms; Pregnancy; Sinus thrombosis",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "QD09-11",
"pmc": null,
"pmid": "25738044",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports",
"references": "17403403;24959491;20435835;14976332;21551107;19383052;10622773;19478226;23395926;15858188",
"title": "Cerebral venous sinus thrombosis and posterior reversible encephalopathy syndrome in a preeclamptic woman.",
"title_normalized": "cerebral venous sinus thrombosis and posterior reversible encephalopathy syndrome in a preeclamptic woman"
} | [
{
"companynumb": "TR-BAYER-2015-396122",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "NIFEDIPINE"
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"drugadditional": null,
... |
{
"abstract": "Recent reclassification of the Klebsiella genus to include Klebsiella variicola, and its association with bacteremia and mortality, has raised concerns. We examined Klebsiella spp. infections among battlefield trauma patients, including occurrence of invasive K. variicola disease. Klebsiella isolates collected from 51 wounded military personnel (2009-2014) through the Trauma Infectious Disease Outcomes Study were examined using polymerase chain reaction (PCR) and pulsed-field gel electrophoresis. K. variicola isolates were evaluated for hypermucoviscosity phenotype by the string test. Patients were severely injured, largely from blast injuries, and all received antibiotics prior to Klebsiella isolation. Multidrug-resistant Klebsiella isolates were identified in 23 (45%) patients; however, there were no significant differences when patients with and without multidrug-resistant Klebsiella were compared. A total of 237 isolates initially identified as K. pneumoniae were analyzed, with 141 clinical isolates associated with infections (remaining were colonizing isolates collected through surveillance groin swabs). Using PCR sequencing, 221 (93%) isolates were confirmed as K. pneumoniae, 10 (4%) were K. variicola, and 6 (3%) were K. quasipneumoniae. Five K. variicola isolates were associated with infections. Compared to K. pneumoniae, infecting K. variicola isolates were more likely to be from blood (4/5 versus 24/134, p = 0.04), and less likely to be multidrug-resistant (0/5 versus 99/134, p<0.01). No K. variicola isolates demonstrated the hypermucoviscosity phenotype. Although K. variicola isolates were frequently isolated from bloodstream infections, they were less likely to be multidrug-resistant. Further work is needed to facilitate diagnosis of K. variicola and clarify its clinical significance in larger prospective studies.",
"affiliations": "Brooke Army Medical Center, JBSA Fort Sam Houston, San Antonio, Texas, United States of America.;Brooke Army Medical Center, JBSA Fort Sam Houston, San Antonio, Texas, United States of America.;Brooke Army Medical Center, JBSA Fort Sam Houston, San Antonio, Texas, United States of America.;Brooke Army Medical Center, JBSA Fort Sam Houston, San Antonio, Texas, United States of America.;Department of Preventive Medicine and Biostatistics, Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.;Department of Preventive Medicine and Biostatistics, Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.;Walter Reed National Military Medical Center, Bethesda, Maryland, United States of America.;Landstuhl Regional Medical Center, Landstuhl, Germany.;Department of Preventive Medicine and Biostatistics, Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.;Brooke Army Medical Center, JBSA Fort Sam Houston, San Antonio, Texas, United States of America.",
"authors": "Kiley|John L|JL|0000-0003-1726-1699;Mende|Katrin|K|;Beckius|Miriam L|ML|;Kaiser|Susan J|SJ|;Carson|M Leigh|ML|;Lu|Dan|D|;Whitman|Timothy J|TJ|;Petfield|Joseph L|JL|0000-0002-4488-1247;Tribble|David R|DR|;Blyth|Dana M|DM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0255636",
"fulltext": "\n==== Front\nPLoS One\nPLoS One\nplos\nPLoS ONE\n1932-6203\nPublic Library of Science San Francisco, CA USA\n\n10.1371/journal.pone.0255636\nPONE-D-21-10025\nResearch Article\nMedicine and Health Sciences\nMedical Conditions\nInfectious Diseases\nBacterial Diseases\nKlebsiella Infections\nBiology and Life Sciences\nOrganisms\nBacteria\nKlebsiella\nKlebsiella Pneumoniae\nBiology and Life Sciences\nMicrobiology\nMedical Microbiology\nMicrobial Pathogens\nBacterial Pathogens\nKlebsiella\nKlebsiella Pneumoniae\nMedicine and Health Sciences\nPathology and Laboratory Medicine\nPathogens\nMicrobial Pathogens\nBacterial Pathogens\nKlebsiella\nKlebsiella Pneumoniae\nMedicine and Health Sciences\nMedical Conditions\nInfectious Diseases\nRespiratory Infections\nMedicine and Health Sciences\nMedical Conditions\nRespiratory Disorders\nRespiratory Infections\nMedicine and Health Sciences\nPulmonology\nRespiratory Disorders\nRespiratory Infections\nBiology and Life Sciences\nAnatomy\nBody Fluids\nBlood\nMedicine and Health Sciences\nAnatomy\nBody Fluids\nBlood\nBiology and Life Sciences\nPhysiology\nBody Fluids\nBlood\nSocial Sciences\nPolitical Science\nGovernments\nArmed Forces\nMilitary Personnel\nBiology and Life Sciences\nMolecular Biology\nMolecular Biology Techniques\nArtificial Gene Amplification and Extension\nPolymerase Chain Reaction\nResearch and Analysis Methods\nMolecular Biology Techniques\nArtificial Gene Amplification and Extension\nPolymerase Chain Reaction\nMedicine and Health Sciences\nHematology\nBloodstream Infections\nMedicine and Health Sciences\nMedical Conditions\nInfectious Diseases\nNosocomial Infections\nResistance patterns and clinical outcomes of Klebsiella pneumoniae and invasive Klebsiella variicola in trauma patients\nKlebsiella infections in trauma patients\nhttps://orcid.org/0000-0003-1726-1699\nKiley John L. Conceptualization Formal analysis Investigation Writing – original draft 1*\nMende Katrin Conceptualization Data curation Formal analysis Investigation Writing – review & editing 123\nBeckius Miriam L. Data curation Formal analysis Writing – review & editing 1\nKaiser Susan J. Data curation Formal analysis Writing – review & editing 123\nCarson M. Leigh Investigation Writing – review & editing 23\nLu Dan Data curation Investigation Writing – review & editing 23\nWhitman Timothy J. Conceptualization Investigation Writing – review & editing 4¤a\nhttps://orcid.org/0000-0002-4488-1247\nPetfield Joseph L. Conceptualization Investigation Writing – review & editing 5¤b\nTribble David R. Conceptualization Investigation Writing – review & editing 2\nBlyth Dana M. Conceptualization Investigation Writing – review & editing 1¤c\n1 Brooke Army Medical Center, JBSA Fort Sam Houston, San Antonio, Texas, United States of America\n2 Department of Preventive Medicine and Biostatistics, Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America\n3 Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, United States of America\n4 Walter Reed National Military Medical Center, Bethesda, Maryland, United States of America\n5 Landstuhl Regional Medical Center, Landstuhl, Germany\nKarunasagar Iddya Editor\nNitte University, INDIA\nCompeting Interests: KM, SJK, MLC, and DL are employees of the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF), a not-for-profit Foundation authorized by Congress to support research at the Uniformed Services University of the Health Sciences (USU) and throughout military medicine. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Please see Data Availability Statement.\n\n¤a Current address: University of Vermont Medical Center, Burlington, Vermont, United States of America\n\n¤b Current address: Nemours Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America\n\n¤c Current address: Walter Reed National Military Medical Center, Bethesda, Maryland, United States of America\n\n* E-mail: john.l.kiley.mil@mail.mil\n2 8 2021\n2021\n16 8 e025563629 3 2021\n20 7 2021\nhttps://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.\n\nRecent reclassification of the Klebsiella genus to include Klebsiella variicola, and its association with bacteremia and mortality, has raised concerns. We examined Klebsiella spp. infections among battlefield trauma patients, including occurrence of invasive K. variicola disease. Klebsiella isolates collected from 51 wounded military personnel (2009–2014) through the Trauma Infectious Disease Outcomes Study were examined using polymerase chain reaction (PCR) and pulsed-field gel electrophoresis. K. variicola isolates were evaluated for hypermucoviscosity phenotype by the string test. Patients were severely injured, largely from blast injuries, and all received antibiotics prior to Klebsiella isolation. Multidrug-resistant Klebsiella isolates were identified in 23 (45%) patients; however, there were no significant differences when patients with and without multidrug-resistant Klebsiella were compared. A total of 237 isolates initially identified as K. pneumoniae were analyzed, with 141 clinical isolates associated with infections (remaining were colonizing isolates collected through surveillance groin swabs). Using PCR sequencing, 221 (93%) isolates were confirmed as K. pneumoniae, 10 (4%) were K. variicola, and 6 (3%) were K. quasipneumoniae. Five K. variicola isolates were associated with infections. Compared to K. pneumoniae, infecting K. variicola isolates were more likely to be from blood (4/5 versus 24/134, p = 0.04), and less likely to be multidrug-resistant (0/5 versus 99/134, p<0.01). No K. variicola isolates demonstrated the hypermucoviscosity phenotype. Although K. variicola isolates were frequently isolated from bloodstream infections, they were less likely to be multidrug-resistant. Further work is needed to facilitate diagnosis of K. variicola and clarify its clinical significance in larger prospective studies.\n\ninfectious disease clinical research program (idcrp) IDCRP-024 https://orcid.org/0000-0003-1726-1699\nKiley John L. http://dx.doi.org/10.13039/100006492 Division of Intramural Research, National Institute of Allergy and Infectious Diseases Y1-AI-5072 Tribble David R. Military Infectious Disease Research Program HU0001-15-2-0045 Mende Katrin Defense Health Program HU0001190002 Tribble David R. Department of Navy, Wounded, Ill, and Injured Program HU0001-10-1-0014 Tribble David R. Support for this work (IDCRP-024) was provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense program executed through the Uniformed Services University of the Health Sciences, Department of Preventive Medicine and Biostatistics through a cooperative agreement with The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF). This project has been funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, https://www.niaid.nih.gov/, under Inter-Agency Agreement Y1-AI-5072 to DRT, the Defense Health Program, U.S. DoD, under award HU0001190002 to DRT, the Department of the Navy under the Wounded, Ill, and Injured Program (HU0001-10-1-0014) to DRT, and the Military Infectious Diseases Research Program, https://midrp.amedd.army.mil/ (HU0001-15-2-0045) to KM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Support in the form of salaries was provided by HJF for authors KM, SJK, MLC, and DL; HJF did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. Data AvailabilityAll relevant data are within the manuscript and its Supporting Information files.\nData Availability\n\nAll relevant data are within the manuscript and its Supporting Information files.\n==== Body\nIntroduction\n\nKlebsiella pneumoniae is recognized as a frequent cause of healthcare-associated infections, including bloodstream infections (BSI), urinary tract infections, ventilator-associated pneumonia, and surgical site infections [1]. Among military personnel with battlefield injuries sustained in Iraq and Afghanistan, K. pneumoniae was one of the most common colonizing Gram-negative bacilli identified from groin surveillance cultures collected at hospital admission, with approximately 22% of isolates being classified as multidrug-resistant (MDR) [2,3]. Furthermore, K. pneumoniae was the third most frequently identified isolate from wounded warriors with MDR Gram-negative bacilli infections [4].\n\nRe-classification of the Klebsiella genus and description of new Klebsiella species has raised questions regarding species specific virulence [5–9]. Certain themes have emerged from early research done after this re-classification. Most notably, there is an association between Klebsiella variicola and healthcare-associated infections with potential for worsened outcomes and greater invasive disease (e.g., bacteremia) when compared to K. pneumoniae [5–10]. However, most modern clinical laboratories misidentify K. variicola as K. pneumoniae and only recently has polymerase chain reaction (PCR) and mass spectrometry techniques for identification been described [11–13]. Thus, epidemiology, clinical manifestations, and virulence patterns of K. variicola remain controversial.\n\nWith the importance of K. variicola as an emerging pathogen, we evaluated Klebsiella infections in patients who suffered battlefield-related trauma [8]. Specifically, we examined the epidemiology and resistance patterns of Klebsiella spp. infections, identified prior misclassifications of Klebsiella species, and assessed the prevalence and incidence of invasive K. variicola disease in this population.\n\nMaterials and methods\n\nStudy population and definitions\n\nData were collected through the Trauma Infectious Disease Outcomes Study (TIDOS), which is a retrospective observational study of infectious complications among military personnel wounded in Iraq or Afghanistan (2009–2014) [14,15]. All patients in the TIDOS population were ≥18 years of age active-duty personnel or Department of Defense (DoD) beneficiaries who initially received care in the combat theater, followed by medical evacuation to Landstuhl Regional Medical Center (LRMC) in Germany with ultimate transfer to participating military hospitals in the United States. The participating U.S. military hospitals were Brooke Army Medical Center in San Antonio, TX, and Walter Reed National Military Medical Center in the National Capital Region (National Naval Medical Center and Walter Reed Army Medical Center prior to September 2011) [14].\n\nThe Institutional Review Board (IRB) of the Uniformed Services University (Bethesda, MD) approved this study. Data were collected from subjects that provided authorization for the collection and analysis of their data through informed consent and HIPAA authorization processes, or through an IRB-approved waiver of consent for use of de-identified data not obtained through interaction or intervention with human subjects.\n\nInclusion in this analysis required isolation of a Klebsiella spp. isolate associated with clinical diagnosis of infection. Demographics, trauma characteristics, and information on casualty care were collected from the DoD Trauma Registry (DoDTR) [16] and infection-related information (e.g., infection syndromes, microbiology, and antibiotic treatment) was obtained from the TIDOS Infectious Disease module of the DoDTR. Infectious disease events were identified using a combination of clinical and laboratory findings and classified using National Healthcare Safety Network definitions as previously described [14,17]. Colonization was defined as recovery of isolates from groin swabs obtained as part of targeted infection control surveillance at hospital admission for their deployment-related injury. All other isolates were defined as infecting isolates as they were recovered during workups for clinical infection. Multidrug resistance was defined using Centers for Disease Control and Prevention criteria as either resistance to ≥3 classes of aminoglycosides, β-lactams, carbapenems, and/or fluoroquinolones or production of an extended spectrum beta-lactamase (ESBL) or carbapenamase [18].\n\nKlebsiella spp. isolate analysis\n\nInitial identification of organisms was performed by participating hospitals’ clinical microbiology laboratories. All hospital labs used either BD Automated Microbiology System (BD Diagnostics, Sparks, MD) or Vitek 2 (bioMérieux Inc., Hazelwood, MO). These two platforms are only able to identify K. pneumoniae and not differentiate this identification from K. variicola, or other members of the Klebsiella complex [9]. Isolates were stored at -80⁰C in a central TIDOS specimen repository.\n\nAll initial and serial infecting isolates identified as K. pneumoniae and stored in the TIDOS specimen repository were included for analysis. Serial isolation was defined as an isolate collected ≥7 days from a prior isolate. All colonizing isolates linked with infecting isolates (defined as isolation from groin admission swab prior to infection) were included. A convenience sample of the remaining colonizing isolates (50 MDR and 50 non-MDR colonizing K. pneumoniae archived isolates) were chosen randomly from the repository.\n\nAll isolates underwent passage on 5% sheep blood agar twice prior to confirmatory identification and antimicrobial susceptibility testing utilizing BD Phoenix Gram-negative panel (NMIC/ID-304) and BD Automated Microbiology System (BD Diagnostics, Sparks, MD)–this technique replicates typical clinical laboratory procedures and is only able to identify K. pneumoniae. Breakpoints were determined using Clinical Laboratory Standards Instituted guidelines (M100, 28th edition, 2018). Antimicrobials tested included cefazolin, ceftriaxone, cefepime, levofloxacin, amoxicillin-clavulanate, piperacillin-tazobactam, aztreonam, meropenem, ertapenem, amikacin, and trimethoprim/sulfamethoxazole.\n\nAll isolates underwent DNA extraction using QIAamp DNA Mini Kit (QIAGEN, Hilden, Germany) and subsequently pulsed-field gel electrophoresis (PFGE) analysis to assess for clonality. Any uninterpretable gel patterns on PFGE were repeated. In order to identify K. pneumoniae, K. quasipneumoniae, and K. variicola, all extracted DNA samples underwent PCR using the method and oligonucleotide primer sequences described by Garza-Ramos and colleagues [12,19]. Of note, this work was completed prior to the extensive molecular epidemiologic work resulting in the further expansion of the Klebsiella pneumoniae complex [8,9]. Due to early case reports of K. variicola being linked with hypermucoviscosity phenotypes, string tests were performed on all K. variicola isolates. String test length for positivity was defined as stranding from one colony >5 millimeters from the agar surface. We did not perform the string test on K. pneumoniae or K. quasipneumoniae isolates as our focus was describing any association between the hypermucoviscous phenotype and K. variicola.\n\nStatistical analysis\n\nAll patients with isolation of Klebsiella spp. were initially analyzed as a group. Patients who were subsequently identified to have K. variicola isolation by PCR assay were evaluated in a secondary analysis to examine clinical predictors of isolation and phenotypic behaviors. Univariate analysis by Χ2 and Fisher’s Exact Test was performed for categorical variables where appropriate. Continuous variables were analyzed using Mann-Whitney U. Statistical analysis was performed using IBM SPSS Statistics 22 (Version 22 IBM, NY, 2013). A p value of <0.05 was considered significant. Data availability: All relevant data are provided within the paper and its supporting documentation.\n\nResults\n\nStudy population\n\nAmong 2,699 TIDOS patients, 51 patients with infecting Klebsiella isolates met inclusion criteria for the analysis. All patients were young men with a median age of 23 years who were severely injured with 82% sustaining blast trauma, largely from improvised explosive devices (Table 1). All 51 patients received antibiotics prior to recovery of infecting Klebsiella spp. isolates. The most common antibiotics administered prior to recovery of an infecting isolate were tetracyclines (N = 46, 90%), first generation cephalosporins (N = 45, 88%), and vancomycin (N = 39, 76%). Duration of hospitalization was a median of 49 days. Overall, four (8%) patients died.\n\n10.1371/journal.pone.0255636.t001 Table 1 Characteristics of patients with Klebsiella species infections.\n\nCharacteristic or outcome, No. (%)\tPatients with Klebsiella spp. isolates N = 51\t\nAge, years, median (IQR)\t23 (21–28)\t\nMale sex\t51 (100)\t\nInjury severity score, median (IQR)\t38 (15–45)\t\nInjury Mechanism\t\t\n Blast injury\t42 (82)\t\n Improvised explosive device\t37 (72)\t\n Gunshot wound\t6 (12)\t\nInitial facility geographic locationa\t\t\n Southern Afghanistan:\t34 (67)\t\n Bastion\t13 (25)\t\n Role 2a\t1 (2)\t\n Kandahar\t18 (35)\t\n Role 2b\t1 (2)\t\n Role 2c\t1 (2)\t\n Eastern/Northeastern Afghanistan:\t10 (20)\t\n Role 2d\t1 (2)\t\n Role 2e\t1 (2)\t\n Role 2f\t3 (6)\t\n Role 2g\t1 (2)\t\n Role 2h\t1 (2)\t\n Role 2i\t2 (4)\t\n Role 2j\t1 (2)\t\n Central Afghanistan:\t2 (4)\t\n Bagram\t1 (2)\t\n Role 2k\t1 (2)\t\n Iraq\t1 (2)\t\n Landstuhl Regional Medical Center (Germany)\t2 (4)\t\n Other\t2 (4)\t\nU.S. military hospital\t\t\n Brooke Army Medical Center\t24 (47)\t\n National Capital Region\t26 (51)\t\nUse of Mechanical ventilation\t42 (82)\t\nAntibiotic exposure prior to isolation of Klebsiella spp.\t51 (100)\t\nDays between injury and 1st infecting isolate, median (IQR)\t15 (8–33)\t\nTotal length of hospital stay, median days (IQR)\t49 (28–70)\t\nDeath\t4 (8)\t\nIQR–interquartile range.\n\na Role 2 facilities are within the operational theater with a tent or structure-based operating room and limited personnel (mobile forward surgical teams for initial and resuscitative care are included). Bastion, Kandahar, and Bagram are Role 3 facilities, which are combat support hospitals within the operational theater.\n\nSources of the initial 51 infecting Klebsiella isolates were respiratory (N = 16, 31%), wound (N = 13, 26%), blood (N = 10, 20%), urine (N = 5, 10%), intra-abdominal (N = 4, 8%), and other (N = 3, 6%). There were a median of 23 (interquartile range [IQR]: 22–55) days between isolation of initial infecting isolate and death for the four patients who died.\n\nTwenty-three patients (45%) had initial Klebsiella spp. infections that were MDR. When compared to patients with initial non-MDR Klebsiella spp. infections (N = 28, 55%), there was no significant difference in age (median of 22 years [IQR: 21–29] with MDR infections versus 22 years [IQR: 21–26] for non-MDR infections, p = 0.42), or duration between injury and isolation of first infecting isolate (median of 10 [IQR: 7–27] days versus 19 [IQR: 9–37] days, p = 0.25). In addition, injury severity was similar between the two groups with patients who had MDR Klebsiella infections having a median injury severity score (ISS) of 38 (IQR: 32–46) compared to a median of 35 (IQR: 28–45; p = 0.65) for patients with non-MDR Klebsiella infections.\n\nSixteen (31% of 51) patients had serial isolation of Klebsiella spp. with sources being respiratory (N = 7, 43%), wound (N = 4, 25%), blood (N = 3, 19%), and urine (N = 2, 13%). Age, ISS, and days between injury and first infecting isolate of patients who had serial isolation of any Klebsiella spp. and those without (N = 35, 69%) were not statistically significant; however, patients with serial Klebsiella isolation trended towards higher mortality (19%) compared with patients who only had initial isolation (3%, p = 0.07; Table 2).\n\n10.1371/journal.pone.0255636.t002 Table 2 Patients with serial isolation of Klebsiella spp. versus those with initial isolation only.\n\nCharacteristic, median (IQR)\tPatients with single isolates (N = 35)\tPatients with serial isolation (N = 16)\tP-value\t\nAge, years\t22 (21–28)\t22 (21–28)\t0.23\t\nInjury Severity Score\t37 (30–45)\t28 (30–45\t0.42\t\nDays between injury and first infecting isolate\t16 (8–34)\t15 (8–33)\t0.81\t\nLength of hospital stay, days\t41 (29–59)\t62 (26–80)\t0.41\t\nDeath, No (%)\t1 (3)\t3 (19)\t0.07\t\nIQR–interquartile range.\n\nPulsed-field gel electrophoresis patterns\n\nThere were 12 unique PFGE patterns/types (PFTs) that were each identified in >1 patients with PFT 78 recovered from ten unique patients and PFT 80 from three unique patients. The remaining 10 PFTs were identified in two patients each. Seven (58% of 12) PFTs were associated with infections; however, none of the strains were isolated from patients who were treated at the same initial facilities. There were five (42%) unique PFTs identified among colonizing isolates recovered from patients who were evacuated from the same initial facility (Bastion, Afghanistan). Only one of these PFTs (PFT 78; identified from five colonized-patients) was identical to the PFT of an infecting isolate from a single patient (Table 3). The infecting isolate was recovered from a wound infection eight days after the first colonizing isolate was collected from the other patients. Isolation of this strain with PFT 78 from patients evacuated from Bastion ended four months after the first isolate was recovered. All infecting and colonizing isolates corresponding to PFT 78 were MDR.\n\n10.1371/journal.pone.0255636.t003 Table 3 Outbreak analysis of the single pulsed-field gel electrophoresis type (PFT) 78.\n\nPatient\tPFT\tInitial Location\tDate of isolation\tSource of initial clonal isolates\t\n\t\t\t\tWound (infecting)\tGroin (colonizing)\t\nI\t78\tBastion\t16 August 2010\t0\t1\t\nJ\t78\tBastion\t16 August 2010\t0\t1\t\nK\t78\tBastion\t21 August 2010\t0\t1\t\nL\t78\tBastion\t23 August 2010\t0\t1\t\nM\t78\tBastion\t24 August 2010\t1\t0\t\nN\t78\tBastion\t3 December 2010\t0\t1\t\n\nIsolate analysis\n\nTwo hundred and thirty-seven isolates from 121 patients included in the study were initially identified as K. pneumoniae, of which 141 were infecting isolates and 96 were colonizing isolates (four colonizing isolates initially chosen were excluded after discovering they were identified incorrectly as Klebsiella species). After undergoing PCR, 221 (93% [95% confidence interval [CI]: 90–96]) isolates were verified as K. pneumoniae (from 108 patients; 134 infecting isolates, 87 colonizing isolates from groin swabs), 10 (4% [95% CI: 1.5–6.5]) were identified as K. variicola (from 8 patients; 5 infecting isolates, 5 colonizing isolates), and 6 (3% [95% CI: 0.8–5.2]) as K. quasipneumoniae (from 5 patients; 2 infecting isolates, 4 colonizing isolates). The years of K. pneumoniae collection were 28 (13% of 221) isolates in 2009, 95 (43%) in 2010, 30 (14%) in 2011, 51 (23%) in 2012, 13 (6%) in 2013, and 4 (2%) in 2014. There were no K. variicola isolates collected in 2009, while three were collected in 2010, four were collected in 2011, and one isolate was collected per year from 2012–2014. Four of the K. quasipneumoniae isolates were collected in 2011, one isolate in 2013, and one isolate in 2014.\n\nSources of the 134 K. pneumoniae infecting isolates were wound (N = 57, 42%), respiratory (N = 29, 22%), blood (N = 24, 18%), intraabdominal (N = 4, 3%), and other (N = 20, 15%). Of the 68 initial infecting Klebsiella spp. isolates, 43 were MDR (63%). Similarly, 11 (65%) of 17 colonizing isolates obtained prior to infecting isolates were MDR. Antimicrobial susceptibility patterns demonstrated substantial resistance to cephalosporins, fluoroquinolones, and piperacillin/tazobactam (Table 4). Five infecting isolates recovered after non-MDR colonizing isolates from the same patient demonstrated resistance to new antimicrobials: two developed resistance to cefazolin at 10 and 17 days after colonization, one to piperacillin/tazobactam at 19 days, one to ertapenem at 7 days, and one to gentamicin at 200 days after colonization.\n\n10.1371/journal.pone.0255636.t004 Table 4 Antimicrobial susceptibilities of Klebsiella variicola compared with Klebsiella pneumoniae isolates, No. (%).\n\nAntimicrobial\tK. pneumoniae susceptibility (N = 221)\tK. variicola susceptibility (N = 10)\tP-value\t\nCefazolin\t50 (22)\t8 (80)\t<0.01\t\nCeftriaxone\t73 (33)\t10 (100)\t<0.01\t\nCefepime\t81 (37)\t10 (100)\t<0.01\t\nLevofloxacin\t135 (61)\t9 (90)\t0.09\t\nPiperacillin-tazobactam\t99 (44)\t10 (100)\t<0.01\t\nMeropenem\t213 (96)\t10 (100)\t1.00\t\nAmikacin\t200 (90)\t10 (100)\t0.31\t\n\nKlebsiella variicola\n\nThere were 10 (4% of 237 Klebsiella isolates) isolates of K. variicola identified from eight patients (7%). Five isolates were colonizers from groin swabs, while the five isolates associated with infections were from blood (N = 4), and intraabdominal specimens (N = 1). Among 51 patients with infections, 48 (94%) had infections attributed to K. pneumoniae and 3 (6%) had K. variicola infections. The three patients with K. variicola infections had a median age of 25 years (IQR: 21–46), median ISS of 38 (IQR: 30–45), and all were injured by improvised explosive devices. There were no statistically significant differences between these characteristics and those of patients with K. pneumoniae infections.\n\nFour of the five K. variicola isolates were collected from blood specimens. In comparison, 24 (18%) of 134 K. pneumoniae infecting isolates were from blood specimens (p = 0.04). No infecting K. variicola isolates were MDR compared to 99 (74%) of infecting K. pneumoniae (p<0.01). All K. variicola isolates were string test negative.\n\nThe PFGE analysis demonstrated eight genetically unique K. variicola isolates (Fig 1). The three infecting K. variicola isolates identical by PFGE were isolated from one patient’s blood cultures on days 28 and 29 post-injury. Three patients with unrelated K. variicola isolates were treated in the same Kandahar facility (Afghanistan) over a 12-month period. The remaining two patients with K. variicola were treated in the same facility in Bastion province (Southern Afghanistan) 15 months apart, but were unique strains by PFGE.\n\n10.1371/journal.pone.0255636.g001 Fig 1 Pulsed-field gel electrophoresis analysis of 10 K. variicola isolates collected from wounded military personnel.\n\nDiscussion\n\nThis study emphasizes the challenging resistance patterns of K. pneumoniae infections complicating battlefield trauma, even on initial isolation. It is also the first analysis of a broad archive of K. pneumoniae samples to systematically evaluate for K. variicola misidentification. Notably, while K. variicola infections were more likely to be associated with bacteremia, they were less likely to be MDR.\n\nGram-negative resistance is thought to develop in response to antimicrobial pressures and our patients are no exception as all had prolonged hospital stays and antimicrobial exposure prior to isolation of MDR Klebsiella infections. While there were no statistically significant differences between those with initial MDR compared with non-MDR infections, this is likely due to small numbers of patients. Similar to evidence in this study, evaluation of trauma patients either in developing countries or countries experiencing conflicts have demonstrated high rates of MDR Gram-negative infections [20–22]. For example, civilian trauma patients from the ongoing conflict in Syria were noted to have rates of MDR K. pneumoniae infections >80% [23]. Furthermore, nearly 74% of infecting K. pneumoniae isolates from a group of South African trauma patients were MDR [20]. These studies, along with others, have not only demonstrated high rates of MDR Gram-negative trauma-associated infections, but also confirmed risk factors for MDR infections to include older age, higher ISS, and prolonged intensive care unit length of stay [24–26]. Our data, which revealed a median of 15 days between injury and Klebsiella spp. isolation among these severely injured patients, also emphasizes the nosocomial nature of this pathogen. Adherence to infection control practices and antimicrobial stewardship practices are vital to mitigating the challenge presented by MDR organisms [27–29].\n\nThree important points can be highlighted regarding K. variicola. One, this is the first study to systematically evaluate and comprehensively assess rates of misidentification of K. variicola in a unique trauma patient population. The overall incidence of K. variicola isolates in our battlefield wounded group (4%) is on the lower end of the range that has been described in the literature. In one study, Maatallah and colleagues [7] reported on K. variicola BSIs where they noted that 24% of K. pneumoniae isolates over a three-year period (2007–2009) were misidentified initially and later correctly identified as K. variicola. An outbreak of BSI in neonates in a Bangladesh neonatal intensive care unit also described a high rate of K. variicola (38% among 36 bacteremia patients) [6]. Our data identified a relatively small incidence of K. variicola (4% [95% CI: 1.5–6.5]), which is likely related to our use of a broader trauma population, rather than focusing on a specific source of infection, like bloodstream isolates. The findings of our study are similar to those described by Rodriguez-Medina and colleagues [8] who examined 1,060 K. pneumoniae clinical isolates from a group of hospitals in Mexico and reported a K. variicola prevalence of 2.1%. Furthermore, Long and colleagues [30] while examining misidentification in ESBL-producing K. pneumoniae, identified nearly 2% as K. variicola. The overall proportion of misidentified K. variicola bloodstream isolates (4 isolates misidentified; 14% of 28) in our study is comparable to these prior published reports. This could suggest that beyond BSIs, misidentification of K. variicola is uncommon; however, further analysis is warranted.\n\nThe second notable point is that four of the five infecting K. variicola isolates were identified from blood. Even though these are small numbers, coupled with what has been published previously, it does raises important questions. Is there some characteristic of K. variicola that leads to an increased propensity to invade the bloodstream? And does this, or some other characteristic portend worse patient outcomes? When Maatallah and colleagues published their work on K. variicola BSIs in 2014, the association with K. variicola BSI and mortality was alarming (30-day mortality approached 30% compared to 13.5% with K. pneumoniae) [7]. Concerns continued to be raised by a study reporting 54% mortality amongst patients who were infected with K. variicola in a Bangladesh neonatal intensive care unit [6]. Description of the first hypermucoviscous K. variicola organism in 2015 raised further questions that hypermucosviscosity might be an underlying mechanism to explain its invasive behavior [11]. While our findings did show an association between K. variicola and BSIs, there was no increase in mortality in these patients and none showed the hypermucoviscosity phenotype. Specifically, no patients with K. variicola infections in our analysis died, in contrast to worrisome mortality rates reported previously. It is important to note that the lack of the hypermucoviscous phenotype does not necessarily exclude a particular isolate from the hypervirulent phenotype [31].\n\nThe third point is that K. variicola isolates in this group were significantly more susceptible to first-line antimicrobials than K. pneumoniae isolates (Table 4). Data on susceptibility patterns for K. variicola are sparse due to the limited number of studies published; however, greater susceptibility does seem to be a common emerging theme. In particular, Maatalah and colleagues reported no MDR patterns in 34 K. variicola isolates from their repository analysis [7]. Moreover, assessment of K. pneumoniae (6 isolates) and K. variicola (2 isolates) isolated from a single patient demonstrated that while K. pneumoniae was imipenem-resistant, K. variicola was susceptible [32]. Our findings provide further evidence that while K. variicola may be more likely to be invasive, it is less likely to be MDR.\n\nOur analysis is limited by the small numbers of Klebsiella infections and isolates, which may have impacted the ability to detect statistical differences between patients with MDR and non-MDR infection. As suggested by the variation in number of isolates over the years of the study, some of this limitation is likely related to the slowing rate of combat evacuations as the conflicts de-escalated and with the end of combat operations in Afghanistan by the end of 2014. Nevertheless, the findings provide useful information to help with rank ordering likelihood of this specific infection in trauma patients with these characteristics. Our second limitation lies in the PFGE analysis, which necessarily provides a broader view of relatedness among isolated organisms. However in this case, PFGE provides an important first pass analysis for clonality among isolates and argues that similarities between isolates that were associated with the Bastion group of patients, the overlapping location, temporal association of their isolation, and historical challenges with infection control in the deployed environment argues in favor of an outbreak [27,33]. Lastly, the analysis is limited by the lack of granularity in the MDR analysis–for example, further work would be helpful to include mechanisms of resistance such as de-repressed AmpC. The role K. variicola plays in healthcare-associated infections and outbreaks has been previously suggested [6,7] and further study of the Klebsiella genus over the last four years [8,30] has rapidly expanded the understanding of how the species variicola fits within the broader complex.\n\nOverall, our data support findings from previous studies from infections complicating combat-trauma: these patients were severely injured, had prolonged hospital stays with exposure to antibiotics, and K. pneumoniae infections were marked by a high rate of multidrug resistance, even early in their hospitalizations [2,4,14,15]. K. variicola was more likely to be identified from BSIs and invasive disease. Further work is needed to help clinicians in interpreting the clinical significance of K. variicola. Larger Klebsiella isolate repositories that could be analyzed for resistance patterns, clinical characteristics, and for misidentification of K. variicola would be helpful in this regard. More phylogenetic work expanding our understanding of the genus Klebsiella is vital to further characterizing the role of specific species and their relevant pathogenic characteristics.\n\nSupporting information\n\nS1 Fig Raw images for pulsed-field gel electrophoresis analysis of 10 K. variicola isolates collected from wounded military personnel.\n\n(PDF)\n\nClick here for additional data file.\n\nWe are indebted to the Infectious Disease Clinical Research Program Trauma Infectious Disease Outcomes Study team of clinical coordinators, microbiology technicians, data managers, clinical site managers, and administrative support personnel for their tireless hours to ensure the success of this project.\n\nDisclaimer\n\nThe views expressed are those of the authors and do not reflect the official views of the Uniformed Services University of the Health Sciences, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the National Institute of Health or the Department of Health and Human Services, Brooke Army Medical Center, Walter Reed National Military Medical Center, Landstuhl Regional Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of Defense, or the Departments of the Army, Navy or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.\n\n10.1371/journal.pone.0255636.r001\nDecision Letter 0\nKarunasagar Iddya Academic Editor\n© 2021 Iddya Karunasagar\n2021\nIddya Karunasagar\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nSubmission Version0\n13 May 2021\n\nPONE-D-21-10025\n\nResistance patterns and clinical outcomes of Klebsiella pneumoniae and invasive Klebsiella variicola in trauma patients\n\nPLOS ONE\n\nDear Dr. Kiley,\n\nThank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. 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Thank you for stating the following in the Financial Disclosure section:\n\n[Support for this work (IDCRP-024) was provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense program executed through the Uniformed Services University of the Health Sciences, Department of Preventive Medicine and Biostatistics through a cooperative agreement with The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF). This project has been funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, https://www.niaid.nih.gov/, under Inter-Agency Agreement Y1-AI-5072 to DRT, the Defense Health Program, U.S. DoD, under award HU0001190002 to DRT, the Department of the Navy under the Wounded, Ill, and Injured Program (HU0001-10-1-0014) to DRT, and the Military Infectious Diseases Research Program, https://midrp.amedd.army.mil/ (HU0001-15-2-0045) to KM. 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You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)\n\nReviewer #1: The comments are attached. The comments for the paper \" Resistance patterns and clinical outcomes of Klebsiella pneumoniae and invasive K. variicola in trauma patients\". There are comments and observations made which the authors are requested to address before publication\n\nReviewer #2: Dear Authors\n\nThe paper describes the speciation of Klebsiella variicola spp among previously isolated from trauma patients and identified as Klebsiella pneumoniae along with the resistance patters and clinical outcomes. While epidemiological studies like this throws so much light on speciation and outcomes of infections in patients with trauma especially in army veterans returning from Afghanistan, the authors may consider the following to improve the manuscript.\n\n1. The authors have included isolates that were colonizers and those from infections. However, the time line of the colonization and if they had any clinical significance to go on and cause infection does not seem clear. How long ago from the posting in Afghanistan did they colonize with the isolates? Were these isolates fond before the posting or after the posting? Did the colonizers have any relevance to the isolates in the wound swabs of the patients?\n\n2. Why did the authors stick to identifying only 3 species when Klebsiella pneumoniae , Klebsiella quasipneumoniae subsp. quasipneumoniae , Klebsiella quasipneumoniae subsp. similipneumoniae , Klebsiella variicola subsp. variicola , Klebsiella variicola subsp. tropica , Klebsiella quasivariicola , Klebsiella africana have been described?\n\n3. Would the authors opine that these infections and colonizations were health care associated/ health care acquired infections?\n\n4. Why was PCR not used to differentiated the hipervirulent isolates? String test seems to be a very crude method. Further, data on hypermucoviscosity vs hypervirulence may be a great add on.\n\n5. What were the number of ESBL's detected in this population of isolates studied? What was the method employed to classify them as ESBL's? Which CLSI guideline was used ( Version)\n\n6. Isolates from clinical samples need to be detailed if they were associated with healthcare associated infection. Were wound swabs the main source. If so were the wound sites in the groin region? If so were the same isolates found as colonizers and then went on to cause infections? The percentages of isolates and their distribution may also be shown in a figure. However, the percentage of K. variicola seems too small to draw any conclusions especially when isolated from the blood culture\n\n7. Since the study period is between 2009-2014, in 5 years were there changes in the isolation rates? Maybe a timeline of the distribution of isolates in a figure would be useful?\n\n**********\n\n6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.\n\nIf you choose “no”, your identity will remain anonymous but your review may still be made public.\n\nDo you want your identity to be public for this peer review? 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Please note that Supporting Information files do not need this step.\n\nAttachment Submitted filename: D-21-10025 MAY 2021 RESISTANCE PATTERNS OF K. PNEUMONIAE AND VARIICOLA IN TRAUMA PATIENTS.docx\n\nClick here for additional data file.\n\n10.1371/journal.pone.0255636.r002\nAuthor response to Decision Letter 0\nSubmission Version1\n14 Jun 2021\n\nAdditional Editor Comments:\n\nTwo reviewers have commented on the manuscript and raised important questions about the methodology used for antimicrobial sensitivity testing, to characterise hypervirulent strains, differentiation of colonisers from those causing infection, species of Klebsiella considered and other aspects of the manuscript. Please address all points raised by the reviewers and revise the manuscript.\n\nAuthor Response: Thank you for the opportunity to revise. We have reviewed and comments from the reviewers and made changes to the manuscript accordingly.\n\nJournal Requirements:\n\nWhen submitting your revision, we need you to address these additional requirements.\n\n1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at\n\nhttps://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf\n\nAuthor Response: The manuscript has been formatted according to the style requirements and named according to the file naming guidelines.\n\n2. PLOS ONE now requires that authors provide the original uncropped and unadjusted images underlying all blot or gel results reported in a submission’s figures or Supporting Information files. This policy and the journal’s other requirements for blot/gel reporting and figure preparation are described in detail at https://journals.plos.org/plosone/s/figures#loc-blot-and-gel-reporting-requirements and https://journals.plos.org/plosone/s/figures#loc-preparing-figures-from-image-files. When you submit your revised manuscript, please ensure that your figures adhere fully to these guidelines and provide the original underlying images for all blot or gel data reported in your submission. See the following link for instructions on providing the original image data: https://journals.plos.org/plosone/s/figures#loc-original-images-for-blots-and-gels.\n\nIn your cover letter, please note whether your blot/gel image data are in Supporting Information or posted at a public data repository, provide the repository URL if relevant, and provide specific details as to which raw blot/gel images, if any, are not available. 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This project has been funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, https://www.niaid.nih.gov/, under Inter-Agency Agreement Y1-AI-5072 to DRT, the Defense Health Program, U.S. DoD, under award HU0001190002 to DRT, the Department of the Navy under the Wounded, Ill, and Injured Program (HU0001-10-1-0014) to DRT, and the Military Infectious Diseases Research Program, https://midrp.amedd.army.mil/ (HU0001-15-2-0045) to KM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.].\n\nWe note that one or more of the authors are employed by a commercial company: Advancement of Military Medicine, Inc.\n\n1. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form.\n\nAuthor Response: The company you are referencing is the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., which is a non-profit authorized by Congress to support research at the Uniformed Services University. The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., is directly referenced in the submitted Funding Statement that was supplied during the initial submission “Support for this work (IDCRP-024) was provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense program executed through the Uniformed Services University of the Health Sciences, Department of Preventive Medicine and Biostatistics through a cooperative agreement with The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF).” The text has been revised to reference authors who received salaries from HJF. “Support in the form of salaries was provided by HJF for authors KM, SJK, MLC, and DL; HJF did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.”\n\nWe reviewed the author contribution section and no changes are needed.\n\nPlease also include the following statement within your amended Funding Statement.\n\n“The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.”\n\nIf your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement.\n\nAuthor Response: Please see response above\n\n2. 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Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests\n\n \n\nReviewers' comments:\n\nReviewer's Responses to Questions\n\nComments to the Author\n\n1. Is the manuscript technically sound, and do the data support the conclusions?\n\nThe manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.\n\nReviewer #1: Partly\n\nReviewer #2: Yes\n\n________________________________________\n\n2. Has the statistical analysis been performed appropriately and rigorously?\n\nReviewer #1: Yes\n\nReviewer #2: N/A\n\n________________________________________\n\n3. Have the authors made all data underlying the findings in their manuscript fully available?\n\nThe PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n________________________________________\n\n4. Is the manuscript presented in an intelligible fashion and written in standard English?\n\nPLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n________________________________________\n\n5. Review Comments to the Author\n\nPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)\n\nReviewer #1: The comments are attached. The comments for the paper \" Resistance patterns and clinical outcomes of Klebsiella pneumoniae and invasive K. variicola in trauma patients\". There are comments and observations made which the authors are requested to address before publication\n\nAn unique article detailing the incidence of infections and colonization by Klebsiella species, particularly K. variicola which may be misidentified as K. pneumoniae. The authors have selected trauma patients among the army veterans who participated in the battle in Afghanistan and were supposedly hospitalized and underwent procedures for various indications\n\nThe article is well presented and thoughts have been collated to bring out the said manuscript. The following observations are in order:\n\n1. Colonisation was defined through the study to reflect those isolates obtained from groin surveillance swabs. Any particular reason for doing so, as Klebsiella spp are known to colonise a number of body sites including the respiratory and urinary tract without causing clinical infections. Can the authors substantiate this criteria for selection site for surveillance of colonization\n\nAuthor Response: Thank you for the comment. As you rightly point out, Klebsiella spp. are known to colonize many organ systems. As part of infection control measures to identify patients with skin colonization of a wide variety of organisms and to limit transmission of multidrug-resistant organisms, surveillance cultures were collected at admission to the military hospitals (groin/axillary swabs at Landstuhl and groin/axillary/nares swabs at U.S.-based hospitals). The collection of the admission surveillance swabs was per policies at each of the sites and not based on instructions from TIDOS investigators. The sentence defining colonization in the Methods text (lines 93-95) was revised to clarify this point and now reads “Colonization was defined as recovery of isolate from groin swabs obtained as part of targeted infection control surveillance at hospital admission for their deployment-related injury.”\n\n2. Klebsiella isolate analysis: The authors have alluded to the fact that Vitek and BD systems are unable to differentiate between K. pneumoniae, variicola and quasipneumoniae. Why have the authors chosen just three species for ability or inability of the systems for species differentiation. What may be the reason for this specific focus on the said three species and not the others\n\nAuthor Response: Thank you for the comment. At the time of the study development, we had elected to utilize the PCR technique described by Garza-Ramos and colleagues (BMC Microbiol. 2015; 15:64; BMC Microbiol. 2016; 16:43) that would be able to distinguish these three species, primarily because of the ability to identify K. variicola. This decision hinged on our specific clinical question raised by the Sweden bacteraemia data (Maatallah et al. 2014. PLoS One. 9(11): e113539) and further discussed/elucidated by Garza-Ramos and colleagues. Since the laboratory bench work on our project was completed, there has continued to be literature published in the area of the phylogenetic and epidemiologic nature of the Klebsiella genus, leading ultimately to the elucidation of five different species (including here K. quasivariicola). Given this evolution in the landscape of the genus, we added a new reference as #9 (Barrios-Camacho H, et al. Sci Rep. 2019; 9(1): 10610) to the Introduction and clarifying language to the discussion of this manuscript on page 17 (lines 336-338) to give the reader a greater sense of the scope of this work and recent developments that have taken place in the scientific community.\n\nDoes literature suggest that there aren’t other species of Klebsiella that could prove pathogenic other than the ones tested for here in this article?\n\nAuthor Response: Thank you for the comment. There has been literature published (or is in pre-print) since we completed our study that indicates the occurrence of other species of Klebsiella that have specific pathogenicity associated with them, in particular the association with K. variicola as a uropathogen and hypervirulent strains of K. quasipneumoniae. The recently described K. africanensis and K. quasivariicola would also deserve attention for future work attempting to further fill in the details of the pathogenicity of the entire complex. As above, we have alluded to this evolving information with edits in lines 336-338.\n\n3. The same (? bias) is reflected in this subsequent section on PFGE of the isolates where the PCR method and the primers used were dictated by the choice of the species rather than a broad range of species. It may have been useful to carry out the PCR to be able to identify other unusual species of Klebsiella too. Can this be substantiated by the authors?\n\nAuthor Response: We agree that broad range PCR would have given additional data. Based off what we knew from the published literature at the time of the initiation of the analysis, we felt a more targeted approach, particularly of a clinical cohort of patients would be better suited to try to answer the specific question we had on K. variicola.\n\n4. Virulence factors for Hypervirulence in Klebsiella species is best done with a genetic analysis of the isolates where there is an attempt made to amplify the presence of genes such as mag A gene ( for instance) String test is a crude method and is not acceptable for drawing conclusion on the possible hypervirulence of Klebsiella species .\n\nAuthor Response: We completely agree that the string test is a crude test and clarified the text in the Methods (the choice of using this bench side test; page 6, lines 131-133), as well as in the Discussion on page 16 (lines 311-312) to emphasize the careful distinctions made between virulence and hyperviscosity made by Catalan-Najera and colleagues in Virulence (2017; 8[7]:1111-1123) regarding this important point.\n\n5. Of the 51 infecting Klebsiella isolates, 16 were from the respiratory tract. Can the authors furnish information/ data on whether these respiratory infections were Lower respiratory tract infections, VAP, HAP etc. This is important as Klebsiella is known to colonise the respiratory tract of hospital and facility in- patients. The same holds good for the 5 isolates from the urinary tract.\n\nAuthor Response: Thank you for the question. These were lower respiratory tract infections – the way the initial data collection was done, the isolates were definitional not colonizers. Timing of infections was also part of the data collection, but not explicitly identified as VAP. Urinary isolates were considered associated with infection as defined in the methods (lines 95-96). We have since clarified the text in the Methods (lines 93-96) to reflect that only isolates collected from groin swabs were considered colonizers, and all remaining clinical isolates included were considered infecting.\n\n6. Isolate analysis: The fourth line in the 2nd paragraph talks about substantial resistance to ESBL inhibitors. Can the authors qualify this please, as one only alludes to Beta lactam lactamase inhibitors in scientific literature. The only inhibitor visible in Table -4 was Piperacillin tazobactam and this is not classified scientifically as an ESBL inhibitor\n\nAuthor Response: Thank you for the comment and we agree. We have updated the language on page 12 (line 225) to specify piperacillin-tazobactam.\n\n7. There was a mention in the Materials and methods section of classifying isolates as MDR based on resistance / ESBL/ Carbapenamase etc. However the same is not reflected in the Results section as to how many of the isolates showed ESBL, derepressed Amp C or a Carbapenamase enzyme. This may be an useful information in a manuscript dealing with resistance patterns and related clinical outcomes\n\nAuthor Response: Thank you for your comment and we agree. Ultimately, we had very few CRE organisms, and we did not have the bench work to support genetic evidence for specific cases of suspected Amp C derepression, so we felt that for comparing groups, our analysis would be strongest by grouping the mechanisms into multidrug resistance. We have included text on page 17 (lines 334-335), fully acknowledging this limitation.\n\n8. Klebsiella variicola: in the Results section: The authors have stated that 80% of the K. variicola isolates were from blood cultures. 4 of the 5 isolates does not qualify for a percentage. The same concept is again represented in the discussion section.\n\nAuthor Response: Thank you for your comment. We have revised the sentence in the Results to remove the 80%, so it is a statement of numbers only. The statement in the Discussion was revised to be the following: “The second notable point is that four of the five infecting K. variicola isolates were identified from blood.”\n\nWe also adjusted a sentence in the abstract that referenced the data to now be “Compared to K. pneumoniae, infecting K. variicola isolates were more likely to be from blood (4/5 versus 24/134, p=0.04), and less likely to be multidrug-resistant (0/5 versus 99/134, p<0.01).”\n\n9. Discussion section Page 14: The last two lines taken about the “overall proportion of misidentified blood stream isolates 14% of 28 in our study”. this statement needs clarification as this does impact the discussion and the concluding paragraph.\n\nAuthor Response: Thank you for your question. There were 28 BSI isolates initially identified as K. pneumoniae, but 4 were later classified as K. variicola. The text has been revised for clarity to read “Nevertheless, the overall proportion of misidentified K. variicola bloodstream isolates (4 isolates misidentified; 14% of 28) in our study is comparable to these prior published reports.” The goal of this language was to compare our reported misidentification in bloodstream isolates to the other published reports.\n\nReviewer #2: Dear Authors\n\nThe paper describes the speciation of Klebsiella variicola spp among previously isolated from trauma patients and identified as Klebsiella pneumoniae along with the resistance patters and clinical outcomes. While epidemiological studies like this throws so much light on speciation and outcomes of infections in patients with trauma especially in army veterans returning from Afghanistan, the authors may consider the following to improve the manuscript.\n\nAuthor Response: Thank you for your comments\n\n1. The authors have included isolates that were colonizers and those from infections. However, the time line of the colonization and if they had any clinical significance to go on and cause infection does not seem clear. How long ago from the posting in Afghanistan did they colonize with the isolates? Were these isolates fond before the posting or after the posting? Did the colonizers have any relevance to the isolates in the wound swabs of the patients?\n\nAuthor Response: Thank you for your comments. The colonizing isolates were recovered as part of infection control procedures (groin surveillance swabs) at hospital admission for their deployment-related injury following medical evacuation from Afghanistan. The sentence defining colonization in the Methods text (lines 93-95) was revised to clarify this point and now reads “Colonization was defined as recovery of isolates from groin swabs obtained as part of targeted infection control surveillance at hospital admission for their deployment-related injury.” In addition, the sentence (lines 110-111) that described the linking of infecting isolates to colonizing isolates was revised to “All colonizing isolates linked with infecting isolates (defined as isolation from groin admission swab prior to infection) were included.”\n\n2. Why did the authors stick to identifying only 3 species when Klebsiella pneumoniae, Klebsiella quasipneumoniae subsp. quasipneumoniae, Klebsiella quasipneumoniae subsp. similipneumoniae, Klebsiella variicola subsp. variicola, Klebsiella variicola subsp. tropica, Klebsiella quasivariicola, Klebsiella africana have been described?\n\nAuthor Response: Thank you for the comment. Essentially, we felt that one of the questions we had pre-specified before doing this work was to focus on the role of K. variicola that had been published in the literature and that our N and subsequent design of the bench work didn’t allow us to broadly PCR for the rest of the species within the genus –as you rightly point out. Please also see the response to comment #2 from Reviewer #1.\n\n3. Would the authors opine that these infections and colonizations were health care associated/ health care acquired infections?\n\nAuthor Response: Thank you for the question—we have added a sentence that clarifies the nosocomial nature of these isolates within the Discussion (lines 274-276), prior to a sentence that discusses the essential role of infection prevention and control as well as antimicrobial stewardship in decreasing their impact.\n\n4. Why was PCR not used to differentiated the hipervirulent isolates? String test seems to be a very crude method. Further, data on hypermucoviscosity vs hypervirulence may be a great add on.\n\nAuthor Response: Thank you for your comment and we completely agree. We felt that this would be a question that many readers might have (the string test), but ultimately after this crude screening test, felt that beyond reporting the data, there were not any additional conclusions to be drawn. A statement was added to the Discussion on page 16 (lines 311-312), which states “It is important to note here that the lack of the hypermucoviscous phenotype does not necessarily exclude a particular isolate from the hypervirulent phenotype” and as above, added the reference by Catalan-Najera and colleagues in Virulence (2017; 8[7]:1111-1123) regarding this important point.\n\n5. What were the number of ESBL's detected in this population of isolates studied? What was the method employed to classify them as ESBL's? Which CLSI guideline was used ( Version)\n\nAuthor Response: ESBL’s were not explicitly re-identified outside of the automated breakpoint data that accompanies the BD Phoenix. The CLSI guideline used was M100, 28th edition published in 2018 and that information was added to line 119 on page 6 in the Methods section.\n\n6. Isolates from clinical samples need to be detailed if they were associated with healthcare associated infection. Were wound swabs the main source. If so were the wound sites in the groin region? If so were the same isolates found as colonizers and then went on to cause infections? The percentages of isolates and their distribution may also be shown in a figure. However, the percentage of K. variicola seems too small to draw any conclusions especially when isolated from the blood culture\n\nAuthor Response: Thank you for your comments. The text in the Results Isolate Analysis section was revised to clarify the number of K. pneumoniae infecting isolate sources. The revised sentence reads “Sources of the 134 K. pneumoniae infecting isolates were wound (N=57, 43%), respiratory (N=29, 22%), blood (N=24, 18%), intraabdominal (N=4, 3%), and other (N=20, 15%).” Text in the Klebsiella variicola section was also revised to clarify the sources of the infecting isolates and now reads “Five isolates were colonizers from groin swabs, while the five isolates associated with infections were from blood (N=4), and intraabdominal specimens (N=1).”\n\nYes, wound swabs were the main source for K. pneumoniae, but it was blood for K. variicola. Wound sites could derive from the abdomen, gluteal, hand, lower leg, pelvis, thigh, and upper arm. Additionally, we further clarified within the methods (as discussed in response to reviewer 1) the definitions of colonizing vs infecting isolates.\n\n7. Since the study period is between 2009-2014, in 5 years were there changes in the isolation rates? Maybe a timeline of the distribution of isolates in a figure would be useful?\n\nAuthor Response: Thank you for the comment. We did have similar questions about isolation rates, particularly when it comes out in outbreak analyses; however, outside of our outbreak analysis where there were important features of timing, we thought that battlefield kinetics and timing of injuries would be hard to control for. Text related to the number of isolates collected over the study years was added to the Results on page 11, lines 214-219. The new text states that ‘The years of K. pneumoniae collection were 28 (13% of 221) isolates in 2009, 95 (43%) in 2010, 30 (14%) in 2011, 51 (23%) in 2012, 13 (6%) in 2013, and 4 (2%) in 2014. There were no K. variicola isolates collected in 2009, while three were collected in 2010, four were collected in 2011, and one isolate was collected per year from 2012-2014. Four of the K. quasipneumoniae isolates were collected in 2011, one isolate in 2013, and one isolate in 2014.’\n\nWe have also added a sentence to the Discussion (lines 324-326) to discuss how the number of isolates tapering off likely reflects the decreasing numbers of evacuated casualties towards the end of the study period, coinciding with the end of combat operations in Afghanistan.\n\nAttachment Submitted filename: Response to Reviewers.docx\n\nClick here for additional data file.\n\n10.1371/journal.pone.0255636.r003\nDecision Letter 1\nKarunasagar Iddya Academic Editor\n© 2021 Iddya Karunasagar\n2021\nIddya Karunasagar\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nSubmission Version1\n21 Jul 2021\n\nResistance patterns and clinical outcomes of Klebsiella pneumoniae and invasive Klebsiella variicola in trauma patients\n\nPONE-D-21-10025R1\n\nDear Dr. Kiley,\n\nWe’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.\n\nWithin one week, you’ll receive an e-mail detailing the required amendments. 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Your manuscript is now with our production department.\n\nIf your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.\n\nIf we can help with anything else, please email us at plosone@plos.org.\n\nThank you for submitting your work to PLOS ONE and supporting open access.\n\nKind regards,\n\nPLOS ONE Editorial Office Staff\n\non behalf of\n\nDr. Iddya Karunasagar\n\nAcademic Editor\n\nPLOS ONE\n==== Refs\nReferences\n\n1 Calfee DP . Recent advances in the understanding and management of Klebsiella pneumoniae. F1000Res. 2017; 6 :1760. doi: 10.12688/f1000research.11532.1 29043069\n2 Gilbert LJ , Li P , Murray CK , Yun HC , Aggarwal D , Weintrob AC , et al . 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Multidrug-Resistant Organism and Clostridium difficile Infection (MDRO/CDI) Module. Available from: https://www.cdc.gov/nhsn/PDFs/pscManual/12pscMDRO_CDADcurrent.pdf.\n19 Garza-Ramos U , Silva-Sanchez J , Martinez-Romero E , Tinoco P , Pina-Gonzales M , Barrios H , et al . Development of a multiplex-PCR probe system for the proper identification of Klebsiella variicola. BMC Microbiol. 2015; 15 :64. doi: 10.1186/s12866-015-0396-6 25886267\n20 Pillai J , Yazicioglu C , Moeng S , Rangaka T , Monareng T , Jayakrishnan R , et al . Prevalence and patterns of infection in critically ill trauma patients admitted to the trauma ICU, South Africa. J Infect Dev Ctries. 2015; 9 (7 ):736–742. doi: 10.3855/jidc.5865 26230124\n21 Zorgani A , Abofayed A , Glia A , Albarbar A , Hanish S . Prevalence of device-associated nosocomial infections caused by Gram-negative bacteria in a trauma intensive care unit in Libya. Oman Med J. 2015; 30 (4 ):270–275. doi: 10.5001/omj.2015.54 26366261\n22 Teicher CL , Ronat J-B , Fakhri RM , Basel M , Labar AS , Herard P , et al . Antimicrobial drug-resistant bacteria isolated from Syrian war-injured patients, August 2011-March 2013. Emerg Infect Dis. 2014; 20 (11 ):1949–1951. doi: 10.3201/eid2011.140835 25340505\n23 Älgå A , Wong S , Shoaib M , Lundgren K , Giske CG , von Schreeb J , et al . Infection with high proportion of multidrug-resistant bacteria in conflict-related injuries is associated with poor outcomes and excess resource consumption: a cohort study of Syrian patients treated in Jordan. BMC Infect Dis. 2018; 18 (1 ):233. doi: 10.1186/s12879-018-3149-y 29788910\n24 Patterson SB , Mende K , Li P , Lu D , Carson ML , Murray CK , et al . Stenotrophomonas maltophilia infections: clinical characteristics in a military trauma population. Diagn Microbiol Infect Dis. 2020; 96 (2 ):114953. doi: 10.1016/j.diagmicrobio.2019.114953 31791809\n25 Murray CK , Yun HC , Griffith ME , Thompson B , Crouch HK , Monson LS , et al . Recovery of multidrug-resistant bacteria from combat personnel evacuated from Iraq and Afghanistan at a single military treatment facility. Mil Med. 2009; 174 (6 ):598–604. doi: 10.7205/milmed-d-03-8008 19585772\n26 Mende K , Stewart L , Shaikh F , Bradley W , Lu D , Krauss MR , et al . Microbiology of combat-related extremity wounds: Trauma Infectious Disease Outcomes Study. Diagn Microbiol Infect Dis. 2019; 94 (2 ):173–179. doi: 10.1016/j.diagmicrobio.2018.12.008 30691724\n27 Yun HC , Murray CK . Infection prevention in the deployed environment. US Army Med Dep J. 2016; (2–16 ):114–118. 27215877\n28 Barsoumian AE , Roth AL , Solberg SL , Hanhurst AS , Funari TS , Crouch H , et al . Antimicrobial stewardship challenges in the deployed setting. Mil Med. 2020; 185 (5–6 ):e818–e824. doi: 10.1093/milmed/usz412 31786601\n29 Ake J , Scott P , Wortmann G , Huang X-Z , Barber M , Wang Z , et al . Gram-negative multidrug-resistant organism colonization in a US military healthcare facility in Iraq. Infect Control Hosp Epidemiol. 2011; 32 (6 ):545–552. doi: 10.1086/660015 21558766\n30 Long SW , Linson SE , Saavedra MO , Cantu C , Davis JJ , Brettin T , et al . Whole-genome sequencing of human clinical Klebsiella pneumoniae isolates reveals misidentification and misunderstandings of Klebsiella pneumoniae, Klebsiella variicola, and Klebsiella quasipneumoniae. mSphere. 2017; 2 (4 ): e00290–17. doi: 10.1128/mSphereDirect.00290-17 28776045\n31 Catalan-Najera JC , Garza-Ramos U , Barrios-Camacho H . Hypervirulence and hypermucoviscosity: two different but complementary Klebsiella spp. phenotypes? Virulence. 2017; 8 (7 ): 1111–1123. doi: 10.1080/21505594.2017.1317412 28402698\n32 Garza-Ramos U , Moreno-Dominguez S , Hernández-Castro R , Silva-Sanchez J , Barrios H , Reyna-Flores F , et al . Identification and characterization of imipenem-resistant Klebsiella pneumoniae and susceptible Klebsiella variicola isolates obtained from the same patient. Microb Drug Resist. 2016; 22 (3 ):179–184. doi: 10.1089/mdr.2015.0181 26571390\n33 Hospenthal DR , Crouch HK , English JF , Leach F , Pool J , Conger NG , et al . Response to infection control challenges in the deployed setting: Operations Iraqi and Enduring Freedom. J Trauma. 2010; 69 (Suppl 1 ):S94–S101. doi: 10.1097/TA.0b013e3181e44b3f 20622627\n\n",
"fulltext_license": "CC0",
"issn_linking": "1932-6203",
"issue": "16(8)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
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"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0255636",
"pmc": null,
"pmid": "34339473",
"pubdate": "2021",
"publication_types": "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": "31259664;28776045;17159678;21558766;19585772;26867965;26571390;31778199;30691724;31786601;26984789;29173084;21795875;29788910;20622627;24011372;25886267;25340505;26230124;25858850;31791809;30581423;28402698;30204843;31337792;23449877;29043069;27215877;25426853;26063851;26366261",
"title": "Resistance patterns and clinical outcomes of Klebsiella pneumoniae and invasive Klebsiella variicola in trauma patients.",
"title_normalized": "resistance patterns and clinical outcomes of klebsiella pneumoniae and invasive klebsiella variicola in trauma patients"
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"abstract": "Manic episodes induced by antidepressant withdrawal are rarely reported. Mirtazapine is a tetracyclic, piperazinoazepine compound and is a noradrenergic, adrenergic, serotonergic, histaminergic, and muscarinic-antagonist antidepressant that is used for the treatment of major depression and other psychiatric illnesses. There are several reported cases of manic/hypomanic episodes induced by mirtazapine withdrawal based on suspected clinical symptoms that were not confirmed by autopsy and toxicology. We present the first reported case of mirtazapine withdrawal-induced mania/hypomania associated with sudden death and confirmed by autopsy and toxicology. Our patient was a 26-year-old male who had been diagnosed with schizophreniform disorder, borderline intellectual functioning, polysubstance abuse, mild mental retardation, and attention deficit hyperactive disorder. He took only mirtazapine in the final and terminal weeks of his life and stopped taking mirtazapine 4 days before his death. He exhibited a sudden manic/hypomanic episode and died during a physical altercation during this episode. A full autopsy with comprehensive toxicologic analysis of his body fluids and tissues was performed. Autopsy revealed that he died from blunt force trauma of the head, neck, and trunk with extremely low and markedly subtherapeutic levels of mirtazapine and desmethylmirtazapine in the blood (mirtazapine: 0.005 mg/L; desmethylmirtazapine 0.011 mg/L). Advanced selective radioligand and neurochemical assays for density and affinity-binding parameters of dopamine transporter and heat shock protein 70 did not reveal any evidence of excited delirium or autonomic hyperactivity state. We recommend that toxicologic analysis of blood for antidepressants should become routine parts of autopsy protocols for the investigation of sudden death following terminal manic/hypomanic episodes for further elucidation of mania/hypomania induced by antidepressant withdrawal.",
"affiliations": "San Joaquin County Coroner, CA, USA.;San Joaquin County Coroner, CA, USA.;San Joaquin County Coroner, CA, USA.;San Joaquin County Coroner, CA, USA.",
"authors": "Pombo|Rena|R|;Johnson|Etta|E|;Gamboa|Alejandra|A|;Omalu|Bennet|B|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/jpp.JPP_162_16",
"fulltext": "\n==== Front\nJ Pharmacol PharmacotherJ Pharmacol PharmacotherJPPJournal of Pharmacology & Pharmacotherapeutics0976-500X0976-5018Medknow Publications & Media Pvt Ltd India JPP-8-18510.4103/jpp.JPP_162_16Case ReportAutopsy-proven Mirtazapine Withdrawal-induced Mania/Hypomania Associated with Sudden Death Pombo Rena 1Johnson Etta 1Gamboa Alejandra 1Omalu Bennet 12San Joaquin County Coroner, CA, USA1 Department of Pathology and Laboratory Medicine, University of California, Davis, USAAddress for correspondence: Rena Pombo, San Joaquin County Coroner, CA, USA. E-mail: rmpombo8@gmail.comOct-Dec 2017 8 4 185 187 06 11 2016 29 12 2016 27 1 2017 Copyright: © 2018 Journal of Pharmacology and Pharmacotherapeutics2018This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Manic episodes induced by antidepressant withdrawal are rarely reported. Mirtazapine is a tetracyclic, piperazinoazepine compound and is a noradrenergic, adrenergic, serotonergic, histaminergic, and muscarinic-antagonist antidepressant that is used for the treatment of major depression and other psychiatric illnesses. There are several reported cases of manic/hypomanic episodes induced by mirtazapine withdrawal based on suspected clinical symptoms that were not confirmed by autopsy and toxicology. We present the first reported case of mirtazapine withdrawal-induced mania/hypomania associated with sudden death and confirmed by autopsy and toxicology. Our patient was a 26-year-old male who had been diagnosed with schizophreniform disorder, borderline intellectual functioning, polysubstance abuse, mild mental retardation, and attention deficit hyperactive disorder. He took only mirtazapine in the final and terminal weeks of his life and stopped taking mirtazapine 4 days before his death. He exhibited a sudden manic/hypomanic episode and died during a physical altercation during this episode. A full autopsy with comprehensive toxicologic analysis of his body fluids and tissues was performed. Autopsy revealed that he died from blunt force trauma of the head, neck, and trunk with extremely low and markedly subtherapeutic levels of mirtazapine and desmethylmirtazapine in the blood (mirtazapine: 0.005 mg/L; desmethylmirtazapine 0.011 mg/L). Advanced selective radioligand and neurochemical assays for density and affinity-binding parameters of dopamine transporter and heat shock protein 70 did not reveal any evidence of excited delirium or autonomic hyperactivity state. We recommend that toxicologic analysis of blood for antidepressants should become routine parts of autopsy protocols for the investigation of sudden death following terminal manic/hypomanic episodes for further elucidation of mania/hypomania induced by antidepressant withdrawal.\n\nKeywords\nAutopsymania/hypomaniamirtazapinesudden deathtoxicology\n==== Body\nINTRODUCTION\nMirtazapine is a tetracyclic piperazinoazepine compound, structurally related to mianserin, and is a noradrenergic, adrenergic, serotonergic, histaminergic, and muscarinic antagonist antidepressant that is used for the treatment of major depression and other psychiatric illnesses including anxiety disorders, panic disorder and social anxiety disorder, obsessive-compulsive disorder, undifferentiated somatoform disorder, and schizophrenia.[12] Manic and hypomanic episodes induced by mirtazapine withdrawal are not commonly reported. There have been several reported cases which have been based on suspected clinical symptoms that were not confirmed by autopsy and toxicology.[3456]\n\nOur case will be the first reported autopsy-confirmed terminal mania, associated with sudden and unexpected traumatic death, with autopsy confirmation by comprehensive postmortem toxicologic analyses of body fluids, which showed extremely low and markedly subtherapeutic levels of mirtazapine in the blood, vitreous humor, urine, and bile. The deceased stopped taking his prescribed mirtazapine about 4 days before his terminal manic episode and death.\n\nCASE DESCRIPTION\nOur patient was a 26-year-old Hispanic male who had been diagnosed with schizophreniform disorder, borderline intellectual functioning, cannabis abuse, polysubstance abuse, mild mental retardation, and attention deficit hyperactive disorder. He had been receiving treatment occasionally for 6 years before his death.\n\nHis medical records revealed that he was prescribed with and took mirtazapine, aripiprazole, and quetiapine in the final year of his life. The records indicate that he took only mirtazapine in the final and terminal weeks of his life and stopped taking mirtazapine 4 days before his death.\n\nIn the evening of the day of his death, the patient, who lived with his family, began spontaneously climbing the houses of neighbors, jumped on the roofs, and attempted entering their houses forcefully. He went to one house, began banging the windows and doors, eventually made a forced entry through a door, and began attacking and fighting with the inmates of the house. He then grabbed a young child, began to attack her and attempted to kill her. He was struck multiple times by a resident in the home with an object in an attempt to stop him from harming the child. The police was called, and upon arrival of the police, the patient began fighting with the police, a taser device was deployed, and as the police was attempting to take him into custody, he became unresponsive and died at the scene.\n\nA full autopsy was performed which revealed fatal blunt force trauma injuries of the head, face, neck, trunk, and extremities, with contusions and lacerations of the liver and hemoperitoneum. Comprehensive quantitative toxicologic analyses of femoral vein blood, intraperitoneal blood, vitreous humor, bile, and urine revealed the presence of only ibuprofen, cannabinoids, mirtazapine and its metabolite, desmethylmirtazapine. Alcohol, synthetic cannabinoids, bath salts, and other common acidic, neutral, or basic drugs were not detected in the blood, vitreous humor, bile, or urine. The levels of the detected drugs are shown in Table 1. Qualitative toxicologic analysis of the brain tissue revealed nondetectable levels of mirtazapine in the brain; however, desmethylmirtazapine was detected in the brain tissue. The plasma therapeutic level for mirtazapine is 0.03–0.08 mg/L.[7] The ratio of the levels of mirtazapine in postmortem blood to levels in plasma is 2.5,[8] therefore the expected therapeutic postmortem blood levels of mirtazapine would be 0.08–0.2 mg/L. The mirtazapine blood levels in our reported case are very much below the expected postmortem therapeutic blood levels for mirtazapine.\n\nTable 1 Levels of mirtazapine, desmethylmirtazapine, ibuprofen, and cannabinoids detected by toxicologic analyses of postmortem samples of blood, vitreous humor, bile, and urine\n\nAdvanced selective radioligand and validated neurochemical assays for density and affinity-binding parameters of striatal dopamine transporter and heat shock protein 70 did not reveal any evidence of excited delirium or autonomic hyperactivity state. The cause of death was determined to be blunt force trauma of the head, neck, and trunk associated with a terminal, premortem mirtazapine withdrawal/discontinuation-induced hypomania/mania.\n\nDISCUSSION\nAutopsy and toxicologic analysis of body fluids in our case exculpated excited delirium or autonomic hyperactivity state, acute drug intoxication by stimulants such as cocaine, phencyclidine, and amphetamine, and the presence of any other confounding drugs except cannabinoids. He was a habitual user of marijuana and was not known to exhibit any adverse reaction to cannabinoids.\n\nThe levels of mirtazapine in the blood of our patient were 16–40 times lower than the expected postmortem blood therapeutic levels of mirtazapine. The known half-life of mirtazapine is 20–40 h,[1] and the markedly low postmortem blood levels we have observed confirm the premortem forensic scenario that our patient stopped taking his prescribed mirtazapine several days prior to his terminal manic episode and death.\n\nDesmethylmirtazapine is the only metabolite of mirtazapine that contributes to its pharmacodynamic profile but is not believed to contribute significantly to the overall effects of the drug due to very low blood concentrations, like we have in our case.[29]\n\nOur case fulfills the diagnostic criteria for antidepressant discontinuation or withdrawal “manic state” as have been proposed by Narayan and Haddad.[10] Most reported cases of antidepressant withdrawal mania are due to sudden discontinuation and may be associated with a broad variety of symptoms that may include anxiety, restlessness, depression, insomnia, diarrhea, vomiting, and rarely hypomania or mania. Withdrawal-induced cholinergic overdrive and the actions of the cholinergic-noradrenergic system remain one of the most investigated hypotheses for explaining antidepressant withdrawal-induced mania. It has been postulated that upon cholinergic overdrive, the monoaminergic synthetic pathways are activated in an effort to maintain homeostasis. When the cholinergic overdrive abates, the monoaminergic system should downregulate in tandem. However, in some patients, for unknown reasons, the system fails to downregulate, which leads to relative monoaminergic (serotonergic and adrenergic) excess and resultant mania and hypomania.[4]\n\nWe do not know exactly what role cannabinoids may have played in our case. In the cases of mirtazapine withdrawal-induced mania reported by Verma and Mohapatra[4] and by Soutullo et al.,[6] there was a presence of other nonconfounding drugs that included lithium carbonate and sertraline, respectively. We do not have any explanation about the role, if any, that these drugs may have played in the induction of mania/hypomania by mirtazapine withdrawal in our case or in their cases.\n\nWe recommend that specific and targeted toxicologic analysis for mirtazapine and other antidepressants should become routine components of autopsy protocols of sudden traumatic and nontraumatic deaths that exhibit terminal psychotic, manic, and hypomanic episodes. We believe that such routine toxicologic analyses will identify more fatal cases of antidepressant withdrawal-induced mania/hypomania that may be associated with sudden and unexpected deaths.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Croom KF Perry CM Plosker GL Mirtazapine: A review of its use in major depression and other psychiatric disorders CNS Drugs 2009 23 427 52 19453203 \n2 Baselt RC Disposition of Toxic Drugs and Chemicals in Man 2014 10th ed Seal Beach, California Biomedical Publications 211 220 \n3 MacCall C Callender J Mirtazapine withdrawal causing hypomania Br J Psychiatry 1999 175 390 \n4 Verma JK Mohapatra S Mirtazapine withdrawal-induced mania J Pharmacol Pharmacother 2015 6 214 5 26816474 \n5 Basavraj V Nanjundappa GB Chandra PS Mirtazapine induced mania in a woman with major depression in the absence of features of bipolarity Aust N Z J Psychiatry 2011 45 901 21692606 \n6 Soutullo CA McElroy SL Keck PE Jr Hypomania associated with mirtazapine augmentation of sertraline J Clin Psychiatry 1998 59 320 9671349 \n7 Schulz M Iwersen-Bergmann S Andresen H Schmoldt A Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics Crit Care 2012 16 R136 22835221 \n8 Launiainen T Ojanperä I Drug concentrations in post-mortem femoral blood compared with therapeutic concentrations in plasma Drug Test Anal 2014 6 308 16 23881890 \n9 Meineke I Steinmetz H Kirchheiner J Brockmöller J Therapeutic drug monitoring of mirtazapine, desmethylmirtazapine, 8-hydroxymirtazapine, and mirtazapine-N-oxide by enantioselective HPLC with fluorescence detection Ther Drug Monit 2006 28 760 5 17164691 \n10 Narayan V Haddad PM Antidepressant discontinuation manic states: A critical review of the literature and suggested diagnostic criteria J Psychopharmacol 2011 25 306 13 20156925\n\n",
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"journal": "Journal of pharmacology & pharmacotherapeutics",
"keywords": "Autopsy; mania/hypomania; mirtazapine; sudden death; toxicology",
"medline_ta": "J Pharmacol Pharmacother",
"mesh_terms": null,
"nlm_unique_id": "101552113",
"other_id": null,
"pages": "185-187",
"pmc": null,
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"pubdate": "2017",
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"title": "Autopsy-proven Mirtazapine Withdrawal-induced Mania/Hypomania Associated with Sudden Death.",
"title_normalized": "autopsy proven mirtazapine withdrawal induced mania hypomania associated with sudden death"
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"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2018US-165335",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MIRTAZAPINE"
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{
"abstract": "The shortage of suitable organ donors for transplantation has stimulated the use of organs from donors with transmissible infections such as Chagas disease in noninfected recipients. A case is described of liver transplantation from an anti-Trypanosoma cruzi-positive donor to a noninfected recipient who showed favorable evolution despite not having undergone preemptive therapy.",
"affiliations": "Tropical Medicine Unit, Spain. Electronic address: azucenarodriguez@telecable.es.;Hepatology Unit, Spain.;Microbiology Unit, Hospital Universitario Central de Asturias, Oviedo, Spain.;Leishmaniasis and Chagas Disease Unit, National Microbiology Center, Instituto de Salud Carlos III, Madrid, Spain.;Microbiology Unit, Hospital Universitario Central de Asturias, Oviedo, Spain.;ISGlobal, Centre for International Health Research (CRESIB), Barcelona, Spain.",
"authors": "Rodriguez-Guardado|A|A|;González|M L|ML|;Rodriguez|M|M|;Flores-Chavez|M|M|;Boga|J A|JA|;Gascon|J|J|",
"chemical_list": null,
"country": "England",
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"journal": "Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases",
"keywords": "Benznidazole; Chagas disease; evolution; liver transplant; therapy",
"medline_ta": "Clin Microbiol Infect",
"mesh_terms": "D014355:Chagas Disease; D005260:Female; D006801:Humans; D016031:Liver Transplantation; D008875:Middle Aged; D013030:Spain; D066027:Transplant Recipients; D016896:Treatment Outcome; D014349:Trypanosoma cruzi",
"nlm_unique_id": "9516420",
"other_id": null,
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"pmid": "25882355",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Trypanosoma cruzi infection in a Spanish liver transplant recipient.",
"title_normalized": "trypanosoma cruzi infection in a spanish liver transplant recipient"
} | [
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"companynumb": "PHHY2015ES168800",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
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"activesubstancename": "TACROLIMUS"
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{
"abstract": "OBJECTIVE\nThere are limited data on the risk of nonmelanoma skin cancer (NMSC) among individuals with inflammatory bowel disease (IBD), including those with or without exposure to immunosuppressant medications.\n\n\nMETHODS\nIndividuals with IBD (n = 9618) were identified from the University of Manitoba IBD Epidemiology Database and matched with randomly selected controls (n = 91,378) based on age, sex, and postal area of residence on the date of IBD diagnosis (index date). Groups were followed up from the index date until a diagnosis of any invasive cancer (including NMSC), death, migration from the province, or the end of the study (December 31, 2009), whichever came first. Cox regression analysis was performed to calculate the relative risk of NMSC among the individuals with IBD, adjusting for frequency of ambulatory care visits and socioeconomic status.\n\n\nRESULTS\nOf the individuals followed, 1696 were diagnosed with basal cell skin cancer (BCC) and 341 were diagnosed with squamous cell skin cancer (SCC). Individuals with IBD had an increased risk for BCC, compared with controls (hazard ratio, 1.20; 95% confidence interval [CI], 1.03-1.40). Among patients with IBD, use of thiopurines increased the risk of SCC (hazard ratio, 5.40; 95% CI, 2.00-14.56), compared with controls. Use of thiopurines also was associated with SCC in a case-control, nested analysis of individuals with IBD (odds ratio, 20.52; 95% CI, 2.42-173.81).\n\n\nCONCLUSIONS\nThe risk of BCC could be increased among individuals with IBD. Use of thiopurines increases the risk of SCC among individuals with IBD.",
"affiliations": "Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. singh@cc.umanitoba.ca",
"authors": "Singh|Harminder|H|;Nugent|Zoann|Z|;Demers|Alain A|AA|;Bernstein|Charles N|CN|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D011687:Purines",
"country": "United States",
"delete": false,
"doi": "10.1053/j.gastro.2011.07.039",
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"issn_linking": "0016-5085",
"issue": "141(5)",
"journal": "Gastroenterology",
"keywords": null,
"medline_ta": "Gastroenterology",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D008297:Male; D008875:Middle Aged; D018295:Neoplasms, Basal Cell; D018307:Neoplasms, Squamous Cell; D015995:Prevalence; D011687:Purines; D012307:Risk Factors; D012878:Skin Neoplasms",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "1612-20",
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"pubdate": "2011-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Increased risk of nonmelanoma skin cancers among individuals with inflammatory bowel disease.",
"title_normalized": "increased risk of nonmelanoma skin cancers among individuals with inflammatory bowel disease"
} | [
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"companynumb": "CA-JNJFOC-20161012479",
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"activesubstancename": "INFLIXIMAB"
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{
"abstract": "New COVID-19 skin manifestations continue to be described. We present a patient with COVID-19 related anagen effluvium. The patient was treated with and responded to low dose systemic steroids to treat an accompanying extensive COVID-19-related urticaria and maculopapular rash.",
"affiliations": "Department of Dermatology and Venereology, Specialist Dermatologist at Baghdad Teaching Hospital, Baghdad, Iraq.",
"authors": "Shanshal|Mohammed|M|https://orcid.org/0000-0003-2877-5919",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09546634.2020.1792400",
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"issue": null,
"journal": "The Journal of dermatological treatment",
"keywords": "Anagen effluvium; COVID-19 cutaneous manifestations; COVID-19 hair manifestations",
"medline_ta": "J Dermatolog Treat",
"mesh_terms": null,
"nlm_unique_id": "8918133",
"other_id": null,
"pages": "1-2",
"pmc": null,
"pmid": "32628051",
"pubdate": "2020-07-16",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "COVID-19 related anagen effluvium.",
"title_normalized": "covid 19 related anagen effluvium"
} | [
{
"companynumb": "IQ-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-258060",
"fulfillexpeditecriteria": "1",
"occurcountry": "IQ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
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... |
{
"abstract": "OBJECTIVE\nCoexistence of mantle cell lymphoma and lung adenocarcinoma is extremely rare. The aim of this study is to present the first case of incidental discovery of primary lung adenocarcinoma associated to lymph node mantle cell lymphoma.\n\n\nMETHODS\nA 45 year-old man, admitted for inguinal mass appeared since three months. Physical examination showed a 1 cm axillary and 3 cm inguinal adenopathies which were hard and fixed. A biopsy of inguinal mass revealed mantle cell lymphoma. Assessment of disease extension found a right superior lobe tumor with mediastinal lymphadenopathies. Fibreoptic bronchoscopy was normal. A fine needle biopsy of lung tumor was performed to determinate the nature of the pulmonary lesion. Histopathological findings were consistent with primary poor differentiated pulmonary adenocarcinoma with TTF-1 expression. A first mediastinoscopy was realized to verify mediastinal lymphadenopathies; frozen section showed a mantle cell lymphoma. A right lobectomy was then performed confirming the diagnosis of lung adenocarcinoma. Then, the patient was treated for the mantle cell lymphoma by 6 cures of alternating RCHOP and RDHAP (dexamethasone, high-dose Ara-Cytarabine and cisplatin) regimens followed by autologous stem cell transplantation.\n\n\nRESULTS\nThe patient died because of treatment complications 3 years after diagnosis.\n\n\nCONCLUSIONS\nProgresses are necessary to understand the pathogenesis of of synchronous occurrence of both diseases.",
"affiliations": "Department of Pathology, Abderrahmen Mami Hospital, Ariana, Tunisia.;Department of Pneumology, Abderrahmen Mami Hospital, Ariana, Tunisia.;Department of Pathology, Abderrahmen Mami Hospital, Ariana, Tunisia.;Department of Thoracic Surgery, Abderrahmen Mami Hospital, Ariana, Tunisia.;Department of Pathology, Abderrahmen Mami Hospital, Ariana, Tunisia.",
"authors": "Braham|Emna|E|;Zarrouk|Mourad|M|;Mlika|Mouna|M|;Kilani|Tarek|T|;El Mezni|Faouzi|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/crj.12352",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1752-6981",
"issue": "11(4)",
"journal": "The clinical respiratory journal",
"keywords": "adenocarcinoma - mantle cell lymphoma - pathology",
"medline_ta": "Clin Respir J",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D004358:Drug Therapy; D017809:Fatal Outcome; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D033162:Incidental Findings; D008168:Lung; D008175:Lung Neoplasms; D008198:Lymph Nodes; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008481:Mediastinoscopy; D008875:Middle Aged",
"nlm_unique_id": "101315570",
"other_id": null,
"pages": "430-432",
"pmc": null,
"pmid": "26256690",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Synchronous mantle cell lymph node lymphoma and pulmonary adenocarcinoma: a case report with literature review.",
"title_normalized": "synchronous mantle cell lymph node lymphoma and pulmonary adenocarcinoma a case report with literature review"
} | [
{
"companynumb": "TN-HQ SPECIALTY-TN-2017INT000332",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null... |
{
"abstract": "The subacute cutaneous lupus erythematosus (SCLE) is a distinct subtype of lupus erythematosus (LE) representing specific clinical and serological features. Almost 20%-30% of the cases with SCLE are predicted to associated with medications. Thiazide diuretics, terbinafine, antiepileptic, and proton pump inhibitors are the best-known drugs to induce drug-related SCLE. Herein we want to present a 65-year-old female with alendronate induced SCLE, resistant to classical therapies, and respond well to intravenous immunoglobulin (IVIG), suggesting that IVIG could be an alternative treatment in patients resistant to classical treatment protocols.",
"affiliations": "Department of Dermatology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.;Department of Dermatology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.;Department of Dermatology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.;Department of Dermatology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.;Department of Rheumatology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.;Department of Pathology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.;Department of Dermatology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.",
"authors": "Uzuncakmak|Tugba Kevser|TK|0000-0001-8057-3463;Bayazit|Samet|S|;Askin|Ozge|O|0000-0003-1413-9436;Engin|Burhan|B|;Ugurlu|Serdal|S|;Sar|Mehmet|M|;Serdaroglu|Server|S|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D019386:Alendronate",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.14477",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "33(6)",
"journal": "Dermatologic therapy",
"keywords": "dapsone; dermatology; dermatopathology; discoid lupus; intravenous immunoglobulin; mycophenolate mofetil; subacute cutaneous lupus erythematosus",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000368:Aged; D019386:Alendronate; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008178:Lupus Erythematosus, Cutaneous; D008180:Lupus Erythematosus, Systemic",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e14477",
"pmc": null,
"pmid": "33125828",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Alendronate induced subacute cutaneous lupus erythematosus successfully treated with intravenous immunoglobulin.",
"title_normalized": "alendronate induced subacute cutaneous lupus erythematosus successfully treated with intravenous immunoglobulin"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-269784",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
... |
{
"abstract": "Wegener's granulomatosis (WG) is a granulomatous disorder associated with systemic necrotizing vasculitis. Wegener's granulomatosis predominantly involves the upper airways, lung and kidneys. The disease is often associated with cytoplasmic antineutrophil cytoplasmic antibodies (cANCA). B lymphocytes are potential cANCA producers and there is an evident correlation between cANCA titre, severity of the disease and response to treatment. Wegener's granulomatosis usually begins with symptoms limited mostly to the upper and/or lower respiratory tracts and may transform into the generalized phase, characterized by systemic necrotizing vasculitis. If left untreated, it can turn fulminant with poor prognosis. The severe form of the disease is usually treated with a combination of cyclophosphamide and corticosteroids. In refractory cases, rituximab that binds to CD20 expressed on B-cells should be considered. We presented a case of a 38-year-old woman with severe form of WG, refractory to standard therapy. Despite the standard treatment with cyclophosphamide and corticosteroids and the addition of infliximab with methotrexate, progression of the disease was observed. Exacerbation affected mainly the lungs and caused the gradual destruction of pulmonary tissue and development of respiratory insufficiency. Rituximab (500 mg) was given intravenously every week in four infusions, causing a partial remission of WG and the arrest of lung deterioration. The following administration of 500 mg was given every two weeks, which induced the remission of WG and enabled the patient to return to her normal activity and work. Such treatment appeared to be successful and prevented severe pulmonary involvement.",
"affiliations": "Department of Rheumatology and Internal Diseases of the University Clinical Hospital, Wrocław, Poland. bkhematol@wp.pl",
"authors": "Kowalewska|Bozena|B|;Szechiński|Jacek|J|;Roszkowska|Eliza|E|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "118(6)",
"journal": "Polskie Archiwum Medycyny Wewnetrznej",
"keywords": null,
"medline_ta": "Pol Arch Med Wewn",
"mesh_terms": "D000328:Adult; D019268:Antibodies, Antineutrophil Cytoplasmic; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D005260:Female; D014890:Granulomatosis with Polyangiitis; D006801:Humans; D011859:Radiography; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "0401225",
"other_id": null,
"pages": "381-5",
"pmc": null,
"pmid": "18619196",
"pubdate": "2008-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Wegener's granulomatosis effectively treated with rituximab: a case study.",
"title_normalized": "wegener s granulomatosis effectively treated with rituximab a case study"
} | [
{
"companynumb": "PL-JNJFOC-20200224507",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nDapsone hypersensitivity syndrome (DHS) is a rare, but potentially life-threatening reaction to dapsone.\n\n\nOBJECTIVE\nEvaluation of immunological factors involved in the sparing of borderline-lepromatous (BL) leprosy patches by the severe exanthema related to DHS.\n\n\nMETHODS\nThe authors describe a 19-year-old man with borderline-lepromatous leprosy with a recent diffuse rash, sparing only the hypochromic patches of leprosy, generalized lymphadenopathy, hepatomegaly, and jaundice 25 days after the start of multibacillary multidrug therapy.\n\n\nRESULTS\nLaboratory testing was remarkable for leukocytosis with eosinophilia, atypical lymphocytosis, and elevated liver and canalicular enzymes. Immunohistopathology of the rash showed stronger expression of Th1 cytokines (IL1β, TNFα, IFNγ, and iNOS), and limited expression of IL17, TGFb, IL4, and IL10. Whereas the hypochromic leprosy patches showed high expression of inflammatory cytokines IL1β, TNFα, IFNγ, iNOS, and TGFβ (Th1), and presented strong expression of IL17 and TGFβ with no IL4 and IL10 expression, by the inflammatory infiltrate, characterizing a participation of Th17 response.\n\n\nCONCLUSIONS\nTh17 response, coupled with the presence of subepidermal collagen band, seems to be directly related to the absence of DHS rash in these hypochromic leprosy patches.",
"affiliations": "Dermatology Division, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.;Dermatology Division, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.;Department of Medicine, State University of Ponta Grossa, Ponta Grossa, Paraná, Brazil.;Pathology Department, Ribeirao Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.;Dermatology Division, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.;Dermatology Division, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.",
"authors": "de Nardo Vanzela|Tamara|T|;Bernardes Filho|Fred|F|;Wambier|Carlos Gustavo|CG|;Faria|Francesca Maia|FM|;Foss|Norma Tiraboschi|NT|;Frade|Marco Andrey Cipriani|MAC|",
"chemical_list": "D007917:Leprostatic Agents; D003622:Dapsone",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000000839",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "40(3)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D003622:Dapsone; D063926:Drug Hypersensitivity Syndrome; D006801:Humans; D007917:Leprostatic Agents; D015439:Leprosy, Borderline; D008297:Male; D058504:Th17 Cells; D055815:Young Adult",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "205-208",
"pmc": null,
"pmid": "28937434",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Th17 Response of Borderline-Lepromatous Leprosy Inhibits Rash Manifestation of Dapsone Hypersensitivity Syndrome: Case Report.",
"title_normalized": "th17 response of borderline lepromatous leprosy inhibits rash manifestation of dapsone hypersensitivity syndrome case report"
} | [
{
"companynumb": "BR-VIRTUS PHARMACEUTICALS, LLC-2018VTS00111",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": "065",
... |
{
"abstract": "Subacute cutaneous lupus erythematosus (SCLE) is a subset of cutaneous lupus erythematosus with unique immunologic and clinical features. The first description dates back to 1985 when a series of five patients were found to have hydrochlorothiazide-induced SCLE. Since that time, at least 40 other drugs have been implicated in the induction of SCLE.",
"affiliations": "Division of Dermatology, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA. jefca@aol.com",
"authors": "Callen|J P|JP|",
"chemical_list": "D006852:Hydrochlorothiazide",
"country": "England",
"delete": false,
"doi": "10.1177/0961203310370349",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "19(9)",
"journal": "Lupus",
"keywords": null,
"medline_ta": "Lupus",
"mesh_terms": "D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D006852:Hydrochlorothiazide; D008178:Lupus Erythematosus, Cutaneous; D010787:Photosensitivity Disorders; D012867:Skin",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "1107-11",
"pmc": null,
"pmid": "20693204",
"pubdate": "2010-08",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Drug-induced subacute cutaneous lupus erythematosus.",
"title_normalized": "drug induced subacute cutaneous lupus erythematosus"
} | [
{
"companynumb": "CZ-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-298455",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OMEPRAZOLE"
},
"drug... |
{
"abstract": "To determine optimal dosage, Dihydroxyanthracenedione (DHAD) was given once daily for 3 days at dosage levels of 6, 7, 8, and 10 mg/m2 in combination with a 7-day continuous infusion of cytosine arabinoside (Ara-C). Nineteen of 20 children with leukemia who received these agents developed fever requiring hospitalization. There were 4 deaths-2 due to proven infection. One patient developed nonfatal cardiotoxicity. No other significant toxicity was noted. Responses were seen in 7 of 20 patients. The recommended DHAD dosage was 8 mg/m2/day when given in combination with Ara-C.",
"affiliations": "Baylor College of Medicine, Houston, TX.",
"authors": "Steuber|C P|CP|;Land|V J|VJ|;Civin|C I|CI|;Ragab|A H|AH|;Krischer|J|J|;Vietti|T J|TJ|",
"chemical_list": "D003561:Cytarabine; D008942:Mitoxantrone",
"country": "United States",
"delete": false,
"doi": "10.1007/BF00169979",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6997",
"issue": "5(4)",
"journal": "Investigational new drugs",
"keywords": null,
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine; D006331:Heart Diseases; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D007945:Leukemia, Lymphoid; D007951:Leukemia, Myeloid; D008942:Mitoxantrone; D009325:Nausea; D010198:Pancytopenia; D014839:Vomiting",
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "379-82",
"pmc": null,
"pmid": "3481363",
"pubdate": "1987-12",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "427798;7029296;3857968;7370989;628005;239155;6385264",
"title": "Toxicity evaluation of dihydroxyanthracenedione (DHAD) in combination with cytosine arabinoside (Ara-C).",
"title_normalized": "toxicity evaluation of dihydroxyanthracenedione dhad in combination with cytosine arabinoside ara c"
} | [
{
"companynumb": "US-PFIZER INC-202200840744",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAcute ischemic stroke in pregnancy is a cause of maternal and fetal morbidity. Optimal treatment strategies for stroke in this population are undefined. Thrombolysis is recommended by guidelines should the benefit outweigh uterine bleeding risk. Alternately, data regarding mechanical thrombectomy (MT) is extremely limited. We present a 37-year-old woman in the first trimester that developed recurrent proximal middle cerebral artery (MCA) occlusion after previous thrombolysis and underwent MT via transradial access. This report of transradial MT represents the first case performed through an extrafemoral route for large vessel occlusion in early pregnancy found in the literature.\n\n\nMETHODS\nA 37-year-old gravida 8 para 7 at 9 weeks' gestation presented with left-sided hemiplegia and right gaze preference and underwent successful thrombolysis for a right MCA occlusion. Two days later, she exhibited the same symptoms, and a reoccluded right MCA was identified. Because thrombolysis was unavailable given the recent stroke, the patient underwent emergent MT via radial access (to minimize fetal radiation exposure) and achieved thrombolysis in cerebral infarction 2b revascularization without complication to her or her child. At 2-month follow-up, the patient is on anticoagulation and has a healthy pregnancy with only minor left-sided facial weakness.\n\n\nCONCLUSIONS\nWhen thrombolysis is contraindicated, thrombectomy should be considered and weighed against risks of fetal radiation exposure and contrast load, especially in early pregnancy. Transradial MT is safe, feasible, and mitigates pelvic radiation. A multidisciplinary approach with obstetrics, stroke teams, and neurointerventionalists is vital for successful therapy.",
"affiliations": "Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA.;Marcus Neuroscience Institute, Boca Raton Regional Hospital, Boca Raton, Florida, USA.;Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA.;Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA.;Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA.;Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA.;Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA.;Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Radiology, University of Miami Miller School of Medicine, Miami, Florida, USA.;Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida, USA. Electronic address: ericpete@med.miami.edu.",
"authors": "Shah|Sumedh S|SS|;Snelling|Brian M|BM|;Brunet|Marie Christine|MC|;Sur|Samir|S|;McCarthy|David J|DJ|;Stein|Alan|A|;Khandelwal|Priyank|P|;Starke|Robert M|RM|;Peterson|Eric C|EC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2018.09.095",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "120()",
"journal": "World neurosurgery",
"keywords": "Mechanical thrombectomy; Pregnancy; Transradial access",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000328:Adult; D002533:Cerebral Angiography; D000072226:Computed Tomography Angiography; D057510:Endovascular Procedures; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D020244:Infarction, Middle Cerebral Artery; D008279:Magnetic Resonance Imaging; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011261:Pregnancy Trimester, First; D017534:Radial Artery; D012008:Recurrence; D017131:Thrombectomy; D015912:Thrombolytic Therapy; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "415-419",
"pmc": null,
"pmid": "30261390",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transradial Mechanical Thrombectomy for Proximal Middle Cerebral Artery Occlusion in a First Trimester Pregnancy: Case Report and Literature Review.",
"title_normalized": "transradial mechanical thrombectomy for proximal middle cerebral artery occlusion in a first trimester pregnancy case report and literature review"
} | [
{
"companynumb": "US-ROCHE-2212553",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MIDAZOLAM HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "To describe 4 cases of conjunctival squamous cell carcinoma (SCC) with corneal stromal invasion.\nRetrospective, clinicopathologic case series.\nAll patients had prior resections of presumed pterygia. The degree of corneal involvement dictated the extent of surgical management. One eye with localized invasion was treated with lamellar keratoplasty and plaque brachytherapy. Another case with widespread invasion warranted penetrating keratoplasty and eventual enucleation. Two cases were treated medically prior to surgical intervention: one with localized invasion was treated with topical interferon and retinoic acid; another with significant inflammation was treated with doxycycline and fluorometholone. The patient who underwent keratoplasty and brachytherapy had no recurrence after 7 years of follow-up. Those initially treated medically had resections of recurrence but ultimately required enucleation. Histologically, specimens demonstrated SCC invading the deep corneal stroma, with 2 tumors of the mucoepidermoid type.\nThis series demonstrates the importance of maintaining clinical suspicion of conjunctival squamous neoplasia in pterygia. We recommend that all excised pterygia be submitted for histopathologic evaluation and be carefully evaluated for dysplasia and variants of SCC associated with increased risk of intraocular invasion. Undetected ocular surface squamous neoplasia may give rise to potentially vision- and eye-threatening invasive corneal SCC.",
"affiliations": "Department of Pathology and Laboratory Medicine, Atlanta, GA, USA.;Department of Ophthalmology, Emory University, Atlanta, GA, USA.;Department of Department of Ophthalmology, University of New South Wales at Prince of Wales Hospital, Sydney, NSW, Australia.;Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, USA.;Department of Department of Ophthalmology, University of New South Wales at Prince of Wales Hospital, Sydney, NSW, Australia.;Department of Pathology and Laboratory Medicine, Atlanta, GA, USA.",
"authors": "Mendoza|Pia R|PR|;Craven|Caroline M|CM|;Ip|Matthew H|MH|;Wilson|Matthew W|MW|;Coroneo|Minas T|MT|;Grossniklaus|Hans E|HE|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000485425",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2296-4657",
"issue": "4(4)",
"journal": "Ocular oncology and pathology",
"keywords": "Conjunctiva; Cornea; Ocular surface squamous neoplasia; Pterygium; Squamous cell carcinoma",
"medline_ta": "Ocul Oncol Pathol",
"mesh_terms": null,
"nlm_unique_id": "101656139",
"other_id": null,
"pages": "240-249",
"pmc": null,
"pmid": "30643769",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": "10355832;10976567;1115670;12583781;1562262;16671897;16950250;17440284;17721310;18187195;18264653;18499017;19139334;19702707;20871462;21217137;21281814;21670690;21762990;22169876;22189448;22704832;22704834;23107578;23960894;23974890;24227983;24237784;24255045;24439046;24557333;25546258;26050538;26249131;28275607;3301209;3951824;7322472;8759259;9082277;9194740;9395829;991088",
"title": "Conjunctival Squamous Cell Carcinoma with Corneal Stromal Invasion in Presumed Pterygia: A Case Series.",
"title_normalized": "conjunctival squamous cell carcinoma with corneal stromal invasion in presumed pterygia a case series"
} | [
{
"companynumb": "US-IMPAX LABORATORIES, INC-2018-IPXL-00407",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROMETHOLONE"
},
"drugadd... |
{
"abstract": "High cortisol level in endogenous Cushing's syndrome suppresses the immune system and after treatment there may be an over activity of immune reaction leading to autoimmune diseases mostly thyroid and rheumatologic disorders. This is the second reported case of multiple sclerosis developing after treatment of Cushing's syndrome. A 42-year old man is reported who presented with bone fracture and osteoporosis and diagnosed with Cushing's disease. Six months after surgical treatment of his pituitary adenoma, he developed progressive multiple sclerosis. We conclude that after treatment of endogenous Cushing's syndrome, the patients should be watched for development of autoimmune disorders including those affecting the central nervous system.",
"affiliations": "Endocrine and Metabolism Research Center,Namazi Hospital, Shiraz, Iran, e-mail: msoveid@sums.ac.ir.",
"authors": "Soveid|Mahmood|M|;Petramfar|Peyman|P|",
"chemical_list": "D007074:Immunoglobulin G; D006854:Hydrocortisone",
"country": "Iran",
"delete": false,
"doi": "IJIv13i1A8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1735-1383",
"issue": "13(1)",
"journal": "Iranian journal of immunology : IJI",
"keywords": null,
"medline_ta": "Iran J Immunol",
"mesh_terms": "D000328:Adult; D001921:Brain; D003480:Cushing Syndrome; D006801:Humans; D006854:Hydrocortisone; D007074:Immunoglobulin G; D008279:Magnetic Resonance Imaging; D008297:Male; D009103:Multiple Sclerosis; D010911:Pituitary Neoplasms",
"nlm_unique_id": "101282932",
"other_id": null,
"pages": "64-8",
"pmc": null,
"pmid": "27026048",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Immune Rebound: Multiple Sclerosis after Treatment of Cushing's Disease.",
"title_normalized": "immune rebound multiple sclerosis after treatment of cushing s disease"
} | [
{
"companynumb": "IR-MYLANLABS-2017M1020268",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "The American Heart Association/American College of Cardiology Foundation recommends vitamin K1 for warfarin-related coagulopathy. In Japan, vitamin K2 is used more commonly for such purpose. The difference between vitamins K1 and K2 in reversing warfarin-related coagulopathy has not been discussed. Herein, we report a case that was reversed with vitamin K2; alterations in vitamins K1 and K2 levels and coagulation markers are also presented.",
"affiliations": "Kagawa University Hospital, Emergency Medical Center, Kita, Kagawa, 761-0793, Japan. Electronic address: hifumitoru@gmail.com.;Department of Critical Care Medicine and Trauma National Hospital Organization Disaster Medical Center, Tokyo, 190-0014, Japan. Electronic address: hiroaki_takada@msn.com.;Kagawa University Hospital, Emergency Medical Center, Kita, Kagawa, 761-0793, Japan. Electronic address: ohio@kms.ac.jp.;Kagawa University Hospital, Emergency Medical Center, Kita, Kagawa, 761-0793, Japan. Electronic address: flying1369@yahoo.co.jp.;Kagawa University Hospital, Emergency Medical Center, Kita, Kagawa, 761-0793, Japan. Electronic address: hidedoc@med.kagawa-u.ac.jp.;Kagawa University Hospital, Emergency Medical Center, Kita, Kagawa, 761-0793, Japan. Electronic address: natsuyot@med.kagawa-u.ac.jp.;Kagawa University Hospital, Emergency Medical Center, Kita, Kagawa, 761-0793, Japan. Electronic address: abekulo@med.kagawa-u.ac.jp.;Kagawa University Hospital, Emergency Medical Center, Kita, Kagawa, 761-0793, Japan. Electronic address: ktakano@med.kagawa-u.ac.jp.;Kagawa University Hospital, Emergency Medical Center, Kita, Kagawa, 761-0793, Japan. Electronic address: kenfact@med.kagawa-u.ac.jp.;Kagawa University Hospital, Emergency Medical Center, Kita, Kagawa, 761-0793, Japan. Electronic address: hagiike@med.kagawa-u.ac.jp.;Department of Critical Care Medicine and Trauma National Hospital Organization Disaster Medical Center, Tokyo, 190-0014, Japan. Electronic address: koido@outlook.jp.;Kagawa University Hospital, Emergency Medical Center, Kita, Kagawa, 761-0793, Japan. Electronic address: kuroday@kms.ac.jp.",
"authors": "Hifumi|Toru|T|;Takada|Hiroaki|H|;Ogawa|Daisuke|D|;Suzuki|Kenta|K|;Hamaya|Hideyuki|H|;Shinohara|Natsuyo|N|;Abe|Yuko|Y|;Takano|Koshiro|K|;Kawakita|Kenya|K|;Hagiike|Masanobu|M|;Koido|Yuichi|Y|;Kuroda|Yasuhiro|Y|",
"chemical_list": "D000925:Anticoagulants; D000933:Antifibrinolytic Agents; D024482:Vitamin K 2; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "33(8)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000369:Aged, 80 and over; D000925:Anticoagulants; D000933:Antifibrinolytic Agents; D001132:Arm; D001778:Blood Coagulation Disorders; D005260:Female; D006406:Hematoma; D006801:Humans; D011859:Radiography; D035441:Thoracic Wall; D024482:Vitamin K 2; D014859:Warfarin",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1108.e1-3",
"pmc": null,
"pmid": "25636520",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vitamin K2 for the reversal of warfarin-related coagulopathy.",
"title_normalized": "vitamin k2 for the reversal of warfarin related coagulopathy"
} | [
{
"companynumb": "JP-TEVA-584630ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARVEDILOL"
},
"drugadditional": null,
"dru... |
{
"abstract": "BACKGROUND\nAcetazolamide is contraindicated in patients undergoing dialysis and should be used with caution in patients with chronic kidney disease (CKD). Here, we evaluate the effect of the concomitant use of aspirin by patient with CKD using acetazolamide.\n\n\nMETHODS\nA 63-year-old man with CKD and multimorbidity presented at our Emergency Department (ED) with general weakness and dyspnea for 4 days. Work-up at the ED revealed severe metabolic acidosis and hyperammonemia, which were initially considered signs of sepsis due to an elevated C-reactive protein level and pyuria. However, subsequent blood work indicated hyperchloremic acidosis with low lactate levels. After reviewing his medical history, we suspected the concomitant use of acetazolamide and aspirin as the etiology. Weakness, acidosis, and hyperammonemia were resolved after the patient discontinued acetazolamide. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Severe acidosis can be life threatening. Acetazolamide is known for causing mild metabolic acidosis, except in patients with severely impaired renal function. Here, we present a patient with mildly impaired renal function and concomitant aspirin use who developed severe metabolic acidosis and hyperammonemia after being prescribed acetazolamide. Regardless of the severity of the disease, patients with CKD should avoid taking acetazolamide concomitantly with aspirin.",
"affiliations": "Department of Emergency Medicine, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.;Department of Emergency Medicine, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.",
"authors": "Chen|Tien-En|TE|;Liu|Shao-Ying|SY|",
"chemical_list": "D000086:Acetazolamide; D001241:Aspirin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2020.11.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "60(5)",
"journal": "The Journal of emergency medicine",
"keywords": "acetazolamide; hyperammonemia; polypharmacy; severe metabolic acidosis",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000086:Acetazolamide; D000138:Acidosis; D001241:Aspirin; D006801:Humans; D022124:Hyperammonemia; D007668:Kidney; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "e115-e117",
"pmc": null,
"pmid": "33608163",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe Metabolic Acidosis and Hyperammonemia Induced by the Concomitant Use of Acetazolamide and Aspirin in a Patient With Impaired Renal Function.",
"title_normalized": "severe metabolic acidosis and hyperammonemia induced by the concomitant use of acetazolamide and aspirin in a patient with impaired renal function"
} | [
{
"companynumb": "US-XGen Pharmaceuticals DJB, Inc.-2123202",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAZOLAMIDE"
},
"drugaddit... |
{
"abstract": "BACKGROUND\nBefore this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation.\n\n\nMETHODS\nFor this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m(2) at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 μg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m(2) given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants.\n\n\nRESULTS\nBetween Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8-79·8). 2 year event-free survival was 92·6% (95% CI 89·6-95·7) for treatment including doxorubicin and 88·2% (84·5-92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4-9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3-98·8) for treatment including doxorubicin and 95·8% (93·3-98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (<1%) of 291 receiving treatment including doxorubicin died of sepsis, three (1%) of 292 receiving treatment excluding doxorubicin died of varicella, metabolic seizure, and sepsis during treatment for relapse. 17 patients (3%) had hepatic veno-occlusive disease. Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin. 12 children receiving treatment including doxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence.\n\n\nCONCLUSIONS\nDoxorubicin does not need to be included in treatment of stage II-III intermediate risk Wilms' tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification.\n\n\nBACKGROUND\nSee Acknowledgments for funders.",
"affiliations": "Cancer Section, University College London Institute of Child Health, London, UK. Electronic address: k.pritchard-jones@ucl.ac.uk.;Department of Paediatric Haemato-Oncology, Centre Léon Bérard, Lyon, France.;Paediatric Haemato-Oncology Program, Research Center, Instituto Nacional do Cancer, Rio de Janeiro, Brazil.;Princess Màxima Center for Paediatric Oncology, Utrecht, Netherlands.;Unidad de Oncología Pediátrica, Hospital Materno-Infantil Carlos Haya, Malaga, Spain.;Department of Paediatric Surgery, Marciniak Hospital, Wroclaw, Poland.;Department of Radiotherapy, Academic Medical Centre, Amsterdam, Netherlands.;Department of Paediatric Pathology, University Hopital Armand Trousseau, Paris, France.;Kiel Paediatric Tumour Registry, Department of Paediatric Pathology, University Hospital of Schleswig-Holstein, Kiel, Germany.;Department of Paediatric Pathology, Institute of Cancer & Genetics, Cardiff University, Cardiff, UK.;Childhood Cancer Research Unit, Karolinska Institutet, Stockholm, Sweden.;Department of Pediatric Haemato-Oncology, Academic Medical Centre, Amsterdam, Netherlands.;Department of Biostatistics, Netherlands Cancer Institute, Amsterdam, Netherlands.;Department of Paediatric Haemato-Oncology, University of Saarland, Homburg, Germany.",
"authors": "Pritchard-Jones|Kathy|K|;Bergeron|Christophe|C|;de Camargo|Beatriz|B|;van den Heuvel-Eibrink|Marry M|MM|;Acha|Tomas|T|;Godzinski|Jan|J|;Oldenburger|Foppe|F|;Boccon-Gibod|Liliane|L|;Leuschner|Ivo|I|;Vujanic|Gordan|G|;Sandstedt|Bengt|B|;de Kraker|Jan|J|;van Tinteren|Harm|H|;Graf|Norbert|N|;|||",
"chemical_list": "D003609:Dactinomycin; D014750:Vincristine; D004317:Doxorubicin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "386(9999)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D003609:Dactinomycin; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms; D008297:Male; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009392:Nephrectomy; D016896:Treatment Outcome; D014750:Vincristine; D009396:Wilms Tumor",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "1156-64",
"pmc": null,
"pmid": "26164096",
"pubdate": "2015-09-19",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Omission of doxorubicin from the treatment of stage II-III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial.",
"title_normalized": "omission of doxorubicin from the treatment of stage ii iii intermediate risk wilms tumour siop wt 2001 an open label non inferiority randomised controlled trial"
} | [
{
"companynumb": "GB-PFIZER INC-2015245064",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": "3",... |
{
"abstract": "BACKGROUND\nCoagulase-negative Staphylococcus (CoNS) is the most common cause of bloodstream infections (BSI) in hospitalized infants. CoNS BSI is most reliably treated with vancomycin; however, concerns about side effects and promoting resistance often delay empirical vancomycin therapy until culture results become available.\n\n\nMETHODS\nAll infants with CoNS BSI discharged from 348 neonatal intensive care units managed by the Pediatrix Medical Group from 1997 to 2012 were identified. Empirical vancomycin therapy was defined as vancomycin exposure on the day of the first positive blood culture. Delayed vancomycin therapy was defined as vancomycin exposure 1-3 days after the first positive blood culture. We used multivariable logistic regression with random effects for site to evaluate the association between the use of empirical vancomycin therapy versus delayed vancomycin therapy and 30-day mortality, controlling for gestational age, small-for-gestational age status, postnatal age on the day of the first positive culture, oxygen requirement, ventilator support and inotropic support on the day the first positive culture was obtained.\n\n\nRESULTS\nA total of 4364 infants with CoNS BSI were identified; 2848 (65%) were treated with empirical vancomycin. The median postnatal age at first positive culture was 14 days (interquartile range: 9, 21). Unadjusted 30-day mortality was similar for infants treated with empirical vancomycin and infants treated with delayed vancomycin therapy [166/2848 (6%) vs. 69/1516 (4%); P = 0.08]. There was no significant difference in 30-day mortality on multivariable analysis [odds ratio: 1.14 (0.84, 1.56)]. The median duration of bacteremia was 1 day longer for infants with delayed vancomycin therapy [4 days (interquartile range: 2, 6) vs. 3 days (2, 5); P < 0.0001].\n\n\nCONCLUSIONS\nThe median duration of bacteremia was 1 day longer in infants with CoNS BSI who received delayed vancomycin therapy. Despite this finding, empirical vancomycin therapy for CoNS BSI was not associated with improved mortality.",
"affiliations": "From the *Department of Pediatrics, Duke University; †Duke Clinical Research Institute, Duke University; ‡Department of Medicine, Duke University, Durham, NC; and §Pediatrix-Obstetrix Center for Research and Education, Sunrise, FL.",
"authors": "Ericson|Jessica E|JE|;Thaden|Joshua|J|;Cross|Heather R|HR|;Clark|Reese H|RH|;Fowler|Vance G|VG|;Benjamin|Daniel K|DK|;Cohen-Wolkowiez|Michael|M|;Hornik|Christoph P|CP|;Smith|P Brian|PB|;|||",
"chemical_list": "D000900:Anti-Bacterial Agents; D003030:Coagulase; D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000000573",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "34(4)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000900:Anti-Bacterial Agents; D016470:Bacteremia; D003030:Coagulase; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D008297:Male; D055502:Secondary Prevention; D013203:Staphylococcal Infections; D013210:Staphylococcus; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D014640:Vancomycin",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "371-5",
"pmc": null,
"pmid": "25760564",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "2305739;7565541;15547163;16396862;16375769;21085051;21666399;21455009;21814760;22633525;22424952;23324523;23669299;23899966;24168984;16882828;10768436;11099593;12165580;12359815;14985775;15046276;15286215;15484797;16449030;16740839;19117861;19858773;20100760;20363447;20504376;20636126;20888013",
"title": "No survival benefit with empirical vancomycin therapy for coagulase-negative staphylococcal bloodstream infections in infants.",
"title_normalized": "no survival benefit with empirical vancomycin therapy for coagulase negative staphylococcal bloodstream infections in infants"
} | [
{
"companynumb": "US-BAXTER-2015BAX024322",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Methotrexate toxicity can be avoided following high-dose therapy if certain management procedures are adhered to. These include careful fluid balance management and therapeutic drug level monitoring. A case is reported of an episode of methotrexate toxicity resulting from a fluid balance problem.",
"affiliations": null,
"authors": "Remington|H S|HS|;Bailey|C C|CC|",
"chemical_list": "D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1177/106002808501900508",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-6578",
"issue": "19(5)",
"journal": "Drug intelligence & clinical pharmacy",
"keywords": null,
"medline_ta": "Drug Intell Clin Pharm",
"mesh_terms": "D002648:Child; D005260:Female; D006801:Humans; D008727:Methotrexate; D008991:Monitoring, Physiologic; D013997:Time Factors",
"nlm_unique_id": "0212457",
"other_id": null,
"pages": "372-3",
"pmc": null,
"pmid": "4006725",
"pubdate": "1985-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Methotrexate blood level monitoring.",
"title_normalized": "methotrexate blood level monitoring"
} | [
{
"companynumb": "GB-PFIZER INC-2021058768",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "1",... |
{
"abstract": "BACKGROUND\nAngiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers (AAs) are used for several indications, with cessation recommended in pregnancy due to toxic effects. AA fetopathy phenotype is similar to renal tubular dysgenesis including reduced proximal convoluted tubules (PCTs). Our study aimed to quantify the reduction of PCTs in fetuses and infants with prenatal exposure to AAs.\n\n\nMETHODS\nWe identified 5 fetal AA exposure cases that underwent autopsy at our institution between 2011 and 2018 and compared with 5 gestational age-matched controls. Immunohistochemistry with CD10 and epithelial membrane antigen (EMA) was utilized.\n\n\nRESULTS\nCD10 and EMA identified a median PCT density of 19.0% ± 12.3% in AA fetopathy patients, significantly less than controls (52.8% ± 4.4%; p < 0.0001). One case with in utero cessation had a PCT density of 34.2% ± 0.2%. Among other AA fetopathy findings, 1 case demonstrated unilateral renal vein thrombosis and 4 had hypocalvaria.\n\n\nCONCLUSIONS\nWe have quantified the reduction in AA fetopathy PCT density, and demonstrated in utero cessation may recover PCT differentiation. Future studies may benefit from calculating PCT percentage as a potential biomarker to correlate with post-natal renal function and maternal factors including medication type, dosage, duration, and time from medication cessation.",
"affiliations": "Division of Anatomical Pathology, British Columbia Children's Hospital and Women's Hospital and Health Center, Vancouver, Canada.;Hospital Escuela, Instituto Hondureño de Seguridad Social, Tegucigalpa, Honduras.;Section of Neonatology, British Columbia Children's Hospital and Women's Hospital and Health Center, Vancouver, Canada.;Department of Pediatrics, University of British Columbia, Vancouver, Canada.;Division of Anatomical Pathology, British Columbia Children's Hospital and Women's Hospital and Health Center, Vancouver, Canada.;Division of Anatomical Pathology, British Columbia Children's Hospital and Women's Hospital and Health Center, Vancouver, Canada.",
"authors": "Saunders|Jessica|J|;Callejas Salgado|Allison Marie|AM|;Ting|Joseph Y|JY|https://orcid.org/0000-0002-5246-8823;Mammen|Cherry|C|;Terry|Jefferson|J|https://orcid.org/0000-0001-5464-8679;Bush|Jonathan W|JW|https://orcid.org/0000-0001-9432-2390",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/10935266211018922",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1093-5266",
"issue": "24(5)",
"journal": "Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society",
"keywords": "ACE; ARB; Angiotensin; fetopathy",
"medline_ta": "Pediatr Dev Pathol",
"mesh_terms": null,
"nlm_unique_id": "9809673",
"other_id": null,
"pages": "438-444",
"pmc": null,
"pmid": "34082612",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Quantifying Proximal Collecting Tubule Deficiency in Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker Fetopathy.",
"title_normalized": "quantifying proximal collecting tubule deficiency in angiotensin converting enzyme inhibitor and angiotensin ii receptor blocker fetopathy"
} | [
{
"companynumb": "CA-AUROBINDO-AUR-APL-2022-007819",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VALSARTAN"
},
"drugadditional": "4",
... |
{
"abstract": "A 74-year-old woman was clinically diagnosed with possible amyotrophic lateral sclerosis (ALS) and was administered 100 mg/day of riluzole. After 2 months, she developed dyspnea and experienced gradual difficulty walking. Chest computed tomography revealed ground-glass opacity and consolidation in the lower lobes of both the lungs, thereby suggesting a diagnosis of interstitial pneumonia. Because the condition was suspected to be drug-induced, riluzole administration was discontinued and steroid (methylprednisolone) pulse therapy (1,000 mg/day, 3 days) was started. Her symptoms and radiological findings improved immediately. At 16 months later, she wanted to take riluzole again. She had the similar interstitial pneumonia on the 4(th) day of the re-administration. Drug (riluzole)-induced lymphocyte stimulation tests (DLST) were negative two times. The symptoms of interstitial pneumonia, a rare adverse effect of riluzole, are very similar to worsening symptoms of ALS; therefore, patients with ALS receiving riluzole therapy should be carefully monitored.",
"affiliations": "Department of Neurology, Brain Attack Center Ota Memorial Hospital.",
"authors": "Takeshima|Shinichi|S|;Neshige|Shuichiro|S|;Himeno|Takahiro|T|;Takamatsu|Kazuhiro|K|;Shimoe|Yutaka|Y|;Kuriyama|Masaru|M|",
"chemical_list": "D018696:Neuroprotective Agents; D019782:Riluzole",
"country": "Japan",
"delete": false,
"doi": "10.5692/clinicalneurol.cn-000763",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-918X",
"issue": "55(11)",
"journal": "Rinsho shinkeigaku = Clinical neurology",
"keywords": null,
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D000368:Aged; D000690:Amyotrophic Lateral Sclerosis; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D018696:Neuroprotective Agents; D019782:Riluzole",
"nlm_unique_id": "0417466",
"other_id": null,
"pages": "840-3",
"pmc": null,
"pmid": "26399668",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Riluzole-induced interstitial pneumonia in a case with amyotrophic lateral sclerosis.",
"title_normalized": "riluzole induced interstitial pneumonia in a case with amyotrophic lateral sclerosis"
} | [
{
"companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2020-01636",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RILUZOLE"
},
"drugadd... |
{
"abstract": "Restless legs syndrome (RLS) is a common condition that results in uncomfortable sensations and an urge to move the limbs. Two centers tested a new dopamine agonist, pramipexole, in 23 patients with RLS in a time-limited, open-label, clinical trial. After 4 weeks or more, 19 patients reported significant improvement as assessed by the short International Restless Legs Syndrome Study Group questionnaire (p < 0.0001). These encouraging preliminary results justify larger, controlled trials for pramipexole in patients with RLS.",
"affiliations": "Sleep Medicine Associates of Texas, University of Texas Southwestern Medical Center at Dallas, USA.",
"authors": "Becker|P M|PM|;Ondo|W|W|;Sharon|D|D|",
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"doi": "10.1212/wnl.51.4.1221",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D052160:Benzothiazoles; D018491:Dopamine Agonists; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077487:Pramipexole; D012148:Restless Legs Syndrome; D011795:Surveys and Questionnaires; D013844:Thiazoles",
"nlm_unique_id": "0401060",
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"pages": "1221-3",
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"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
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"title": "Encouraging initial response of restless legs syndrome to pramipexole.",
"title_normalized": "encouraging initial response of restless legs syndrome to pramipexole"
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"abstract": "Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease characterized by recurring abscesses, nodules, and fistulas predominantly in the groin and axillae. The association between HS and Crohn's disease (CD) has been well documented. Tumor necrosis factor (TNF) inhibitors have shown to be effective in treating both HS and CD. We report 2 patients who developed HS while on TNF inhibitor treatment for CD.",
"affiliations": "Department of Gastroenterology, Hepatology and Nutrition, Brody School of Medicine at East Carolina University, Greenville, N.C., USA.;Department of Gastroenterology, Hepatology and Nutrition, Brody School of Medicine at East Carolina University, Greenville, N.C., USA.",
"authors": "Harvin|Glenn|G|;Kasarala|George|G|",
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"fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000444442crg-0010-0088Case ReportTwo Cases of Paradoxical Hidradenitis Suppurativa while on Adalimumab Harvin Glenn *Kasarala George Department of Gastroenterology, Hepatology and Nutrition, Brody School of Medicine at East Carolina University, Greenville, N.C., USA*Dr. Glenn Harvin, Mail Stop 628, Internal Medicine - Gastroenterology, Hepatology, and Nutrition, Vidant Medical Center, TA 338, Greenville, NC 27834 (USA), E-Mail harving@ecu.eduJan-Apr 2016 19 5 2016 19 5 2016 10 1 88 94 12 1 2016 4 2 2016 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease characterized by recurring abscesses, nodules, and fistulas predominantly in the groin and axillae. The association between HS and Crohn's disease (CD) has been well documented. Tumor necrosis factor (TNF) inhibitors have shown to be effective in treating both HS and CD. We report 2 patients who developed HS while on TNF inhibitor treatment for CD.\n\nKeywords\nHidradenitis SuppurativaAdalimumabCrohn's disease\n==== Body\nIntroduction\nCrohn's disease (CD) is an idiopathic chronic inflammatory bowel disease that can affect any part of the gastrointestinal tract. Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent deep, painful nodules, often of the axilla, groin and gluteal areas, that can lead to abscesses and chronic draining sinus tracts [1]. The association between HS and CD is well documented [2]. Patients with inflammatory bowel disease were approximately nine times more likely to develop HS than the general population in a population-based cohort study [3]. Tumor necrosis factor (TNF) inhibitors have been shown to be effective in treating recalcitrant HS [4] and moderate to severe CD. [5] Paradoxical psoriatic skin lesions while on anti-TNF therapy have also been well described [6]. We present 2 patients who developed HS while receiving treatment with adalimumab for CD. We describe some of the immunologic similarities between HS and the psoriasiform rash that has been noted on anti-TNF therapy, and explain why HS should be considered as one of the rare skin rashes that can develop while a patient is on anti-TNF therapy.\n\nCase 1\nA 57-year-old African American female presented to our emergency department with a 6-month history of diarrhea, urgency and tenesmus. She was found to have a perirectal abscess. CT of the abdomen was significant for thickening of the rectum and sigmoid colon. On rectal examination, she was noted to have an anal fistula. The perirectal abscess was drained, and a seton was placed for the anal fistula. A colonoscopy was performed showing erythema and friability consistent with colitis extending to the transverse colon, although most pronounced in the sigmoid colon and rectum. The remainder of the colon and the terminal ileum were normal. Biopsies from the involved portion of the colon including the rectum showed acute cryptitis with crypt abscess formation and crypt distortion and were consistent with CD. The patient was started on adalimumab and mesalamine suppositories with significant clinical improvement. A follow-up sigmoidoscopy after 8 months showed resolution of the colitis with only mild proctitis remaining. The patient continues to smoke despite counseling.\n\nTwelve months into treatment, she developed recurrent boils and nodules in her groin. Her white blood cell count was normal (6,900/μl). She was started on amoxicillin 875 mg and clavulanic acid 125 mg orally twice a day for 10 days. With the suspicion of HS, she was referred to the dermatology clinic, and the diagnosis was confirmed. Her skin lesions improved only transiently on the antibiotics. Her disease progressed with multiple boils and draining sinus tracts in her groin bilaterally with involvement of her right posterior thigh (fig. 1, HS of the right posterior thigh; fig. 2, HS of the left groin) but no axillary involvement. She had no prior history of HS or psoriasis. She was started on doxycycline 100 mg orally twice a day for 10 days and subsequently also with 10-day courses of cephalexin followed by clindamycin with minimal improvement. She was started on suppressive therapy with doxycycline 100 mg orally twice a day for 2 months with some improvement. She was transitioned off the antibiotics but the disease recurred. She was treated with several additional 10-day courses of amoxicillin/clavulanic acid followed by clindamycin. She was placed back on suppressive therapy with doxycycline 100 mg orally twice a day for the next 3 months followed by minocycline for one month. Over the past 2 years, she received intralesional triamcinolone injections on five occasions with little improvement. Currently, she is being evaluated by plastic surgery for surgical excision.\n\nThirty months into treatment, the patient developed erythematous scaly plaques on her back (fig. 3) and at the site of adalimumab injections (fig. 4) and was diagnosed with psoriasis. Meanwhile, her CD was well controlled on adalimumab with mild disease confined to the rectum with no new fistula formation. It was believed that the adalimumab was causing the HS, and the drug was discontinued despite good control of her CD. The patient was switched to azathioprine.\n\nCase 2\nA 24 year-old African American male non-smoker presented to the emergency room with a 1-year history of intermittent bright red blood per rectum with no associated abdominal pain or tenesmus. A colonoscopy was performed showing erythema and friability from the rectum to the descending colon. The biopsies showed chronic colitis with granulomas consistent with Crohn's colitis. He was started on oral Lialda 2.4 g daily, but the disease progressed with worsening abdominal pain, diarrhea and the development of an anal fistula. Therapy was changed to adalimumab for moderate-severe CD. Nine months into adalimumab therapy, he developed a right groin abscess with spontaneous drainage. Initially, it was thought that this was folliculitis, and he was treated with Bactrim for 2 weeks. He went on to develop multiple nodules in his groin bilaterally with the development of draining sinuses but no axillary lesions. He was diagnosed with HS; he had no personal or family history of HS. He was treated by dermatology with several 10- to 14-day courses of Bactrim and amoxicillin 875 mg/clavulanic acid 125 mg separately with transient improvement. He also had surgical excision of these areas and was started on chronic suppressive therapy with doxycycline 100 mg orally twice a day. On follow-up, his CD was not well controlled with worsening anal fistula, and azathioprine was added to adalimumab. HS also progressed to involve his axillary region.\n\nDiscussion\nThe association of CD with HS has been determined [2], and TNF antagonists to include infliximab have been shown to be helpful in treating patients with CD and HS [2, 7]. TNF plays an important role in both CD and HS [7]. CD is characterized by the predominance of increased T helper 1 (Th1) lymphocytes with Th17 cytokine expression [8]. TNF antagonists such as infliximab and adalimumab have been used to treat diseases such as CD, ulcerative colitis and psoriasis.\n\nRecent studies have implicated anti-TNF antibodies as a cause of psoriasiform skin lesions in a small subset of patients with inflammatory bowel disease treated with these agents. Historically, this risk has been believed to be very small. However, several studies have indicated a higher risk than previously thought. In a recent study of 434 anti-TNF treated patients with inflammatory bowel disease, 4.8% developed psoriasiform skin lesions [9]. Smoking has been shown to be a risk factor for anti-TNF-induced skin lesions [9]. In the study by Tillack et al., 76% of the patients that developed psoriasiform skin lesions on anti-TNF were smokers or ex-smokers [9]. The skin lesions developed on average 13 months after initiation of the drug in multiple studies [6, 10], and most of the cases were confined to the palmoplantar and scalp areas [10]. In many cases, the drug had to be withdrawn due to the rash (43% in the study by Cullen et al. [11]). The psoriasiform rash is believed to be likely a class effect. Of the patients switched to an alternative anti-TNF in the review by Cullen et al. [11], 52% were unable to continue the drug due to recurrence of the rash, and only 15% were successful in controlling the rash by switching to an alternative anti-TNF.\n\nIn normal skin, TNF-α acts to inhibit the overproduction of interferon-γ [10]. It has been theorized that anti-TNF drugs allow unopposed interferon -γ production leading to activation of T helper cells producing IL-17 [10]. Increased concentrations of IL-17A and IL-23 have been shown in CD patients who developed skin lesions while on anti-TNF-α therapy [12]. It has also been shown that anti-TNF-induced psoriasiform skin lesions have infiltrates of Th17 and Th1 cells, which are similar to the cytokine profile of psoriasis [9], and as noted below are similar to the profiles seen in HS. It is believed that the TNF blockade may cause the disruption of the cytokine balance in patients with psoriasiform skin lesions leading to unopposed interferon-α production by plasmacytoid dendritic cells in these genetically predisposed patients [13].\n\nStudies have highlighted skin lesions such as psoriasiform lesions and eczema that can develop on ant-TNF therapy, but there is no mention of HS [6, 10, 12]. There was a recent case series of several patients that developed HS during treatment with adalimumab [14]. This is interesting, as adalimumab has been shown to be effective in treating HS in some small studies [4], though not all [15]. There was a range of several weeks to 24 months to the onset or exacerbation of HS after starting adalimumab in this series [14]. Two of the 4 patients in this series did have CD. The development of HS has also been described on etanercept [16]. Also, in a study looking at adalimumab for treatment of HS, 40% of the patients withdrew due to worsening of HS [15]. Due to very few reported cases of HS developing while on anti-TNF therapy, a conclusion as to whether this is a class effect of TNF antagonists cannot be determined. However, the occurrence of anti-TNF-induced psoriasiform lesions is believed to be a class effect [9], and this opens up the possibility that anti-TNF-induced HS might also be a class effect.\n\nIn the case series by Delobeau et al., 3 of the 4 patients were able to continue on the anti-TNF, while 1 patient required a switch to ustekinumab [14]. One of the 2 patients in our series had to be switched to another agent due to poorly controlled HS despite multiple therapeutic agents. This is only the second case in which we are aware of the development of HS associated with psoriasis [14]. Our series and the series by Delobeau et al. are unique in that the patients developed HS while already on adalimumab rather than being started as a potential treatment for HS.\n\nIncreased concentrations of TNF-α has been seen in the serum of patients with HS [17] and in HS skin [18]. Adalimumab treatment has been shown to cause a large reduction in the number of CD11c+ dendritic cells which are involved in HS pathophysiology [18]. Abundant expression of IL-12 and IL-23 was seen in the lesional skin of patients with HS [19]. IL-23 has an important role in Th17 development, and Th17 cells were seen to infiltrate the lesional skin in a study of HS patients [19].\n\nThe cytokine profiles of HS, psoriasis and anti-TNF induced psoriasiform lesions as noted above are very similar. This opens the possibility that like psoriasis, HS is a rare skin lesion that can develop while on anti-TNF therapy and is perhaps due to a cytokine dysregulation as has been seen with TNF antagonists and psoriasiform skin lesions. Ustekinumab is an anti-IL-12/IL-23 antibody, which has been used for anti-TNF-induced psoriasiform skin lesions [9] and has shown some benefit in CD [20]. This opens the way for a possible use of Ustekinumab to treat both CD and HS.\n\nIn conclusion, HS should be considered as a potential rare paradoxical side effect of anti-TNF therapy.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThere are no conflicts of interest for either author.\n\nFig. 1 HS of the posterior thigh.\n\nFig. 2 HS of the left groin.\n\nFig. 3 Psoriasiform rash that developed on her back.\n\nFig. 4 Psoriasiform skin lesion at the adalimumab injection site.\n==== Refs\nReferences\n1 Danby FW Margesson LJ Hidradenitis suppurativa Dermatol Clin 2010 28 779 793 20883920 \n2 Kamal N Cohen BL Buche S Delaporte E Colombel JF Features of patients with Crohn's disease and hidradenitis suppurativa Clin Gastroenterol Hepatol 2016 14 71 79 25956836 \n3 Yadav S Singh S Edakkanambeth Varayil J Hidradenitis suppurativa in patients with inflammatory bowel disease: a population-based cohort study in Olmsted County, Minnesota Clin Gastroenterol Hepatol 2016 14 65 70 25952308 \n4 Kimball AB Kerdel F Adams D Adalimumab for the treatment of moderate to severe Hidradenitis suppurativa: a parallel randomized trial Ann Intern Med 2012 157 846 855 23247938 \n5 Hanauer SB Sandborn WJ Rutgeerts P Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial Gastroenterology 2006 130 323 333 quiz 591 16472588 \n6 Denadai R Teixeira FV Steinwurz F Romiti R Saad-Hossne R Induction or exacerbation of psoriatic lesions during anti-TNF-α therapy for inflammatory bowel disease: a systematic literature review based on 222 cases J Crohns Colitis 2013 7 517 524 22960136 \n7 Blazquez I Gonzalez-Lama Y Roustan G Crohn's disease and hidradenitis suppurativa. An uncommon association that responds to infliximab J Crohns Colitis 2013 7 e717 e718 24080248 \n8 Caprioli F Pallone F Monteleone G Th17 immune response in IBD: a new pathogenic mechanism J Crohns Colitis 2008 2 291 295 21172226 \n9 Tillack C Ehmann LM Friedrich M Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-gamma-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment Gut 2014 63 567 577 23468464 \n10 George LA Gadani A Cross RK Jambaulikar G Ghazi LJ Psoriasiform Skin lesions are caused by anti-TNF agents used for the treatment of inflammatory bowel disease Dig Dis Sci 2015 60 3424 3430 26115749 \n11 Cullen G Kroshinsky D Cheifetz AS Korzenik JR Psoriasis associated with anti-tumour necrosis factor therapy in inflammatory bowel disease: a new series and a review of 120 cases from the literature Aliment Pharmacol Ther 2011 34 1318 1327 21957906 \n12 Wlodarczyk M Sobolewska A Wojcik B Loga K Fichna J Wisniewska-Jarosinska M Correlations between skin lesions induced by anti-tumor necrosis factor-alpha and selected cytokines in Crohn's disease patients World J Gastroenterol 2014 20 7019 7026 24944497 \n13 Collamer AN Battafarano DF Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: clinical features and possible immunopathogenesis Semin Arthritis Rheum 2010 40 233 240 20580412 \n14 Delobeau M Abdou A Puzenat E Observational case series on adalimumab-induced paradoxical hidradenitis suppurativa J Dermatolog Treat 2015 Epub ahead of print \n15 Amano M Grant A Kerdel FA A prospective open-label clinical trial of adalimumab for the treatment of hidradenitis suppurativa Int J Dermatol 2010 49 950 955 21128923 \n16 Pellegrino M Taddeucci P Peccianti C Mei S Fioravanti A Fimiani M Etanercept induced hidradenitis suppurativa G Ital Dermatol Venereol 2011 146 503 504 22095184 \n17 Matusiak L Bieniek A Szepietowski JC Increased serum tumour necrosis factor-alpha in hidradenitis suppurativa patients: is there a basis for treatment with anti-tumour necrosis factor-alpha agents? Acta Derm Venereol 2009 89 601 603 19997690 \n18 van der Zee HH Laman JD de Ruiter L Dik WA Prens EP Adalimumab (antitumour necrosis factor-alpha) treatment of hidradenitis suppurativa ameliorates skin inflammation: an in situ and ex vivo study Br J Dermatol 2012 166 298 305 22013960 \n19 Schlapbach C Hanni T Yawalkar N Hunger RE Expression of the IL-23/Th17 pathway in lesions of hidradenitis suppurativa J Am Acad Dermatol 2011 65 790 798 21641076 \n20 Wils P Bouhnik Y Michetti P Subcutaneous ustekinumab provides clinical benefit for two-thirds of patients with Crohn's disease refractory to anti-tumor necrosis factor agents Clin Gastroenterol Hepatol 2016 14 242 250.e2 26432476\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "10(1)",
"journal": "Case reports in gastroenterology",
"keywords": "Adalimumab; Crohn's disease; Hidradenitis Suppurativa",
"medline_ta": "Case Rep Gastroenterol",
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"nlm_unique_id": "101474819",
"other_id": null,
"pages": "88-94",
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"title": "Two Cases of Paradoxical Hidradenitis Suppurativa while on Adalimumab.",
"title_normalized": "two cases of paradoxical hidradenitis suppurativa while on adalimumab"
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"abstract": "One disadvantage of direct anticoagulant drug is the lack of an antidote, which may become relevant in patients with traumatic brain injury. A 77-years old man with atrial fibrillation and syncope received dabigatran despite recurrent falls. Due to a ground-level-fall, he suffered from subarachnoidal and intraparenchymal hemorrhages, subdural hematoma and brain edema with a midline shift. Despite osteoclastic trepanation and hematoma-evacuation he remained comatose and died seven days later without regaining consciousness. Most probably, decreased dabigatran clearance due to increased age might have contributed to the fatal course. We suggest withholding anticoagulant therapy in patients with unexplained falls. If anticoagulant therapy is deemed necessary, vitamin-K-antagonists with their potential for laboratory monitoring and reversal of anticoagulant activity should be preferred.",
"affiliations": "Hospital Rudolfstiftung, Juchgasse 25, A-1030 Vienna, Austria.;Hospital Rudolfstiftung, Juchgasse 25, A-1030 Vienna, Austria.;Hospital Rudolfstiftung, Juchgasse 25, A-1030 Vienna, Austria.;Hospital Rudolfstiftung, Juchgasse 25, A-1030 Vienna, Austria.",
"authors": "Stöllberger|Claudia|C|;Ulram|Andreas|A|;Bastovansky|Adam|A|;Finsterer|Josef|J|",
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"fulltext": "\n==== Front\nJ Geriatr CardiolJ Geriatr CardiolJGCJournal of Geriatric Cardiology : JGC1671-5411Science Press jgc-12-01-08310.11909/j.issn.1671-5411.2015.01.010Case ReportTraumatic fatal cerebral hemorrhage in an old patient with a history of multiple sclerosis under dabigatran: a case report and review of the literature Stöllberger Claudia Ulram Andreas Bastovansky Adam Finsterer Josef Hospital Rudolfstiftung, Juchgasse 25, A-1030 Vienna, AustriaCorrespondence to: Claudia Stöllberger, MD, Hospital Rudolfstiftung, Juchgasse 25, A-1030 Vienna, Austria. E-mail: claudia.stoellberger@chello.atTelephone:+43-676-40311 87Fax:+43-1-71165 22091 2015 12 1 83 87 8 10 2014 6 11 2014 12 11 2014 Institute of Geriatric Cardiology2015This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License, which allows readers to alter, transform, or build upon the article and then distribute the resulting work under the same or similar license to this one. The work must be attributed back to the original author and commercial use is not permitted without specific permission.One disadvantage of direct anticoagulant drug is the lack of an antidote, which may become relevant in patients with traumatic brain injury. A 77-years old man with atrial fibrillation and syncope received dabigatran despite recurrent falls. Due to a ground-level-fall, he suffered from subarachnoidal and intraparenchymal hemorrhages, subdural hematoma and brain edema with a midline shift. Despite osteoclastic trepanation and hematoma-evacuation he remained comatose and died seven days later without regaining consciousness. Most probably, decreased dabigatran clearance due to increased age might have contributed to the fatal course. We suggest withholding anticoagulant therapy in patients with unexplained falls. If anticoagulant therapy is deemed necessary, vitamin-K-antagonists with their potential for laboratory monitoring and reversal of anticoagulant activity should be preferred.\n\nCerebral hemorrhageAnticoagulationDabigatranAtrial fibrillation\n==== Body\n1 Introduction\nDabigatran, a direct thrombin inhibitor, is one of the direct anticoagulant drugs (DOACs) which are increasingly used in patients with atrial fibrillation (AF) for prevention of embolism. Dabigatran has been compared with the vitamin-K-antagonist (VKA) warfarin in the randomized evaluation of long-term anticoagulant therapy trial (RE-LY).[1] In that trial, the rates of ischemic strokes and intracranial haemorrhages were lower with dabigatran than with warfarin.[2] Patients with recurrent falls were excluded from RE-LY.[1] In real life, however, patients who are prone to falls are prescribed DOACs because physicians believe them to be “safer” than VKA. One of the disadvantages of the DOACs (Table 1), the lack of an antidote for prompt reversal of the anticoagulant effect, may become relevant in traumatic brain injury as illustrated by the following case.\n\n2 Case Report\nTThe patient is a 77-years old man. He had had multiple sclerosis for 30 years, hypertension for 10 years, AF for 7 years, and dilated cardiomyopathy for 5 years. Because of his neurologic comorbidity associated with repeated falls, his physicians estimated the bleeding risk as high. He received no anticoagulant therapy until at age 73 years (in 2010) when he suffered from an ischemic stroke with right-sided hemiparesis and oral anticoagulation with phenprocoumon was started. Since 2011 he suffered from increasing cognitive impairment. In 2012, the mini-mental state examination yielded 18/30 points. A therapy with rivastigmin was not tolerated because of diaphoresis. In March 2012, he suffered from two episodes of speech disturbance, amaurosis fugax and right-sided weakness which were interpreted as prolonged reversible ischemic neurologic deficits. Because of unstable international normalised ratio (INR) values, the anticoagulant therapy was switched from phenprocoumon to dabigatran 300 mg/d. Since March 2012 recurrent syncopes occurred. Tachycardia-bradycardia syndrome was diagnosed, and he received a VVIR pacemaker in June 2012. Despite the pacemaker the syncopes recurred during one of which he nearly drowned. Neurologic investigation including electroencephalo-graph (EEG) in March 2014 disclosed no causes of syncopes. The treating physicians suspected a vagovasal etiology, but neither initiated further investigations nor considered changes in the anticoagulant therapy. He was on a chronic medication with nebivolol 5 mg/d, spironolactone 25 mg/d, venlafaxine 75 mg/d and dabigatran 300 mg/d at that time. His CHA2DS2VASc Score was 6.\n\nTable 1. Advantages and disadvantages of the direct oral anticoagulant drugs.\nAdvantage\tDisadvantage\t\nNo need for repeated blood testing\tNo laboratory test for effectiveness of anticoagulation\t\nFixed doses\tElimination dependent on renal (dabigatran) and/or hepatic (factor Xa inhibitors) function\t\nLess bleeding events than with warfarin in trials\tNo antidote\t\nLess stroke/embolism than with warfarin in trials\tUnknown potential for drug- and food interactions\t\nFew known drug-drug interactions\tHigher price than warfarin\t\nNo known food-drug interaction\tIntricate application of dabigatran-capsule\t\nIn June 2014, he fell from his chair without any prodromi and hit his head. He had taken his last dabigatran tablet 2 h before the accident. His wife called for the emergency service who found him soporous with a Glasgow coma scale (GCS) of 12. On admission, he started to vomit requiring intubation. Cerebral computed tomography (CCT) showed extensive subarachnoidal and intraparenchymal hemorrhages, subdural hematoma and brain edema with a midline shift (Figure 1). The results of the blood tests are listed in Table 2. The prolonged thrombin time indicated anticoagulant activity of dabigatran. Interrogation of the pacemaker showed AF and no dysfunction at the time of the fall. Due to the massive bleeding, the midline shift and the neurologic deterioration it was decided to perform surgery 4 h after the fall, 6 h after he had taken the last dabigatran dose. Osteoklastic trepanation and evacuation of the subdural hematoma were carried out, and a left-sided parenchymal probe was inserted. For correction of his anticoagulation therapy he received 3000 IU human prothrombin complex concentrate and 15 µg desmopressin pre-and intraoperatively. The postoperative CCT showed an increase in the size of the haemorrhage (Figure 2). The patient remained comatose with a GCS of 3 and died 7 days later without regaining consciousness.\n\nFigure 1. Cerebral computed tomography two hours after the trauma showing extensive subarachnoidal and intraparenchymal hemorrhages, subdural hematoma and brain edema with a midline shift.\nTable 2. Laboratory findings.\nParameter (normal range)\tD1 15: 00\tD1 19: 35\tD2 07: 51\tD3 06: 44\tD3 18: 21\tD4 06: 43\tD6 07: 24\t\nBUN, 8–23 mg/dL\t17\tNM\t11\t10\tNM\tNM\tNM\t\nCreatinine, < 1.1 mg/dL\t0.93\tNM\t0.96\t0.84\tNM\t0.71\tNM\t\n*Cr clearance, > 90 mL/min\t85\tNM\t82\t94\tNM\t111\tNM\t\nPotassium, 3.5–5.5 mmol/L\t4.2\tNM\t4.1\t4.3\tNM\t3.9\tNM\t\nSodium, 135–150 mmol/L\t136\tNM\t138\t139\tNM\t138\tNM\t\nHaemoglobin, 14–17 g/dL\t14.5\t11.2\t11.9\t11.4\t11.4\t10.7\tNM\t\nThrombocytes, 150–450/nL\t249\t202\t209\t174\t180\t172\tNM\t\nINR\t1.09\tNM\tNM\tNM\tNM\tNM\tNM\t\nPT, 70% –130%\t64\t63\t73.0\t65.0\t63\t62\t76\t\naPTT < 33 s\t52\t54.1\t39.1\t37.3\t36.2\t36.9\t38.4\t\nTT, 14–21 s\t186\tNM\t100.5\tNM\tNM\tNM\tNM\t\nFibrinogen, 1.50-4.50 g/dL\t3.26\tNM\t3.59\tNM\tNM\tNM\tNM\t\nASAT, 0–35 U/L\t34\tNM\t39\t31\tNM\t23\tNM\t\nALAT, 0–35 U/L\t18\tNM\t20\t18\tNM\t15\t52\t\nGamma GT, 0–40 U/L\t41\tNM\t33\t33\tNM\t38\t83\t\nBilirubin, 0.0–1.1 mg/dL\t0.92\tNM\t2.54\t3.26\tNM\t3.39\t2.3\t\nTotal protein, 64–83 g/L\tNM\tNM\t49\tNM\tNM\tNM\tNM\t\n*According to the Cockcroft-Gault formula. ALAT: alanine aminotransferase; aPTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BUN: blood urea nitrogen; Cr: Creatinine; GT: glutamyltransferase; INR: international normalised ratio; PT: prothrombin time; TT: thrombin time; NM: not measured.\n\n3 Discussion\nHead trauma in the presented patient was severe and it is questionable if the outcome would have been different if he had not been anticoagulated. There are indications that the pathophysiology of traumatic intracranial hemorrhages differs from spontaneous intracranial hemorrhage due to extensive endothelial activation exacerbating prothrombotic and proinflammatory signaling pathways in traumatic intracranial hemorrhage.[3]\n\nThe influence of dabigatran on traumatic brain injury has only been investigated in animal models, so far.[4] Little is known about patients who suffered from traumatic brain injury in the DOAC-investigating trials. There are indications from RE-LY that traumatic intracerebral haemorrhages under dabigatran may have a higher mortality then under warfarin.[2] In this trial, 22 traumatic intracranial haemorrhages occurred under dabigatran (intracerebral n = 4, subdural n = 15, subarachnoid n = 3), and 6 of them (27%) were fatal. In the patients randomized to warfarin, 46 traumatic intracranial haemorrhages occurred (intracerebral n = 4, subdural n = 16, subarachnoid n = 4), and only 5 of them (11%) were fatal. No details were reported how these patients were treated and if they underwent surgery.[2]\n\nIn addition to RE-LY, there are case reports which indicate that the therapy of fall-associated brain injuries in patients under dabigatran is difficult since there is no specific antidote available, as listed in Table 3.[5]–[12] From these cases it can be inferred that patients with chronic subdural hematoma under dabigatran have a better prognosis than patients with acute subdural hematoma which is similar to patients under VKA- or antiplatelet-therapy.[13]\n\nFigure 2. Postoperative cerebral computed tomography 26 h after the trauma showing an increase in the size of the hemorrhage of the brain edema.\nTable 3. Traumatic cerebral bleedings reported under dabigatran.\nReferences\tAge/sex\tTrauma\tType of bleeding\tReversal of dabigatran\tSurgery\tDischarge\t\n[5]\t85/F\tMHT\tSDH, MS\tHD attempt failed\tBurr hole drainage\tNeurologically intact\t\n[6]\t94/M\tGLF\tSDH, MS\tFEIBA, HD\tBurr hole drainage\tMild hemiparesis\t\n[7]\t80/M\tGLF\tSDH\tVitamin K\tND\tNeurologically intact\t\n[8]\tNR\tGLF\tIP\tNR\tCraniotomy\tDead\t\n[9]\t83/M\tGLF\tIP, tSAH, SDH\trFVII\tND\tDead\t\n[10]\t88/F\tGLF\ttSAH, SDH\tPCC, rFVII, HD\tND\tRecovered\t\n[11]\t87/F\tNS\tCSDH\tND\tBurr hole evacuation\tFully recovered\t\n[11]\t80/F\tGLF\tCSDH\tPCC\tBurr hole evacuation\tFully recovered\t\n[11]\t86/M\tGLF\tCSDH\tND\tBurr hole evacuation\tFully recovered\t\n[11]\t74/M\tGLF\tCSDH\tND\tBurr hole evacuation\tFully recovered\t\n[11]\t87/F*\tGLF\ttSAH\tND\tND\tNI\t\n[11]\t87/F*\tGLF\tIP\tND\tND\tNI\t\n[12]\t79/F\tGLF\tIP, MS\tND\tND\tDead\t\n[12]\t72/M\tGLF\ttSAH\tFFP\tND\tNeurologically intact\t\n[15]\tNR\tNS\tIP\tFFP, HD platelets\tDone, not specified\tDead\t\nPresent case\t77/M\tGLF\tIP, MS, tSAH, SDH\tPCC, desmopressin\tTrepanation, hematoma evacuation\tDead\t\n*This patient suffered from two falls. CSDH: chronic subdural hematoma; FEIBA: factor VIII inhibitor bypass agent; FFP: fresh frozen plasma; GLF: ground-level fall; HD: hemodialysis; IP: intraparenchymal; MHT: mild head trauma; MS: midline shift; ND: not done; NR: not reported; NS: trauma type not specified; PCC: prothrombin complex concentrate; RfVII: recombinant factor VII; SDH: subdural hematoma; tSAH: traumatic subarachnoid hemorrhage.\n\nParra, et al.[14] reported five patients with closed head injury secondary to ground-level falls under dabigatran. All patients had repeated CCTs after reversal of anticoagulation, and in four patients, new or expanded haemorrhages were seen. Two of these five patients died. During the same time, 15 patients under warfarin (n =12 with AF) and 25 without anticoagulation (n = 0 with AF) were treated after closed head injury and none of these patients died.[3] Alonso, et al.[15] reported about intracranial haemorrhages in AF patients treated with dabigatran or warfarin by analysing healthcare utilization claims in the Truven Health Marketscan Research Database. They reported that 45 of the 101 dabigatran-treated patients suffered from traumatic haemorrhages but traumatic and nontraumatic intracerebral haemorrhages were not compared regarding haemorrhage subtype, therapy or mortality. Among 11 patients with life-threatening dabigatran-related bleeding events, reported by Ross, et al., [16] four patients had traumatic intracerebral haemorrhages and one of them died.\n\nNeurosurgeons are frequently involved in the management of anticoagulation-related intracerebral hemorrhages. Strategies to reverse VKA comprise fresh frozen plasma, prothrombin complex concentrates, vitamin K, and recombinant activated factor VII. However, reversal of anticoagulation may not always result in good clinical outcome which is probably related to the severity of the initial hemorrhage.[17] As compared with VKA, pharmacologic strategies to reverse dabigatran or other DOACs are lacking and experience is limited mostly to case reports as listed in Table 3. Multiple measures are taken, like in our patient, to reverse the anticoagulant effect of dabigatran. This polypragmatic approach is of limited therapeutic success. Since dabigatran has a low protein binding, elimination by haemodialysis or hemofiltration is a possible therapy, however in trauma-patients this measure is difficult to perform and only applied rarely.[6],[10],[16] In our patient, haemodialysis was not carried out because of the rapid progression of the neurologic deterioration necessitating urgent surgery.\n\nAt present, there is no specific antidote available for dabigatran. Idarucizumab, an investigational fully humanized antibody fragment, is under investigation. Data from a, so far unpublished, phase I study showed that idarucizumab was able to achieve immediate, complete and sustained reversal of dabigatran-induced anticoagulation in healthy humans. According to the manufacturer, a global phase III study, RE-VERSE AD™, is under way in patients taking dabigatran who have uncontrolled bleeding or require emergency surgery or procedures.\n\nFrail elderly people, like our patient, were not represented in DOAC-investigating trials due to various exclusion criteria, and only a third of patients in these trials were > 75 years. From RE-LY, a subgroup analysis showed that in patients ≥ 75 years extracranial bleeding risk was higher (4.1%/4.7% per year) under 220/300 mg/d dabigatran vs. 3.4%/year under warfarin.[18] One factor for the increased bleeding risk in elderly patients might be the decreased clearance of dabigatran: dabigatran concentration is increased 1.3-fold in patients aged 65–75 years and 1.7-fold in those ≥ 75 years; these increases correspond to a decreased clearance of 0.66% for each year of age greater than the median age of 68 years.[19]\n\nThe risk of falls is the most frequent reason for not prescribing VKAs to elderly patients.[20] In patients aged ≥ 81 years, the risk of non-accidental falls was 2.5 times higher in patients with AF compared to those without.[21] A history of falls is the strongest risk factor for subsequent bleeding events, strokes and all-cause mortality in elderly AF-patients under anticoagulation.[22,[23] The use of DOACs will neither solve the problem of falls nor of fall-associated traumatic bleeding, as illustrated by the presented case.\n\nIn conclusion, we suggest withholding anticoagulant therapy in patients with unexplained falls as long as no therapy for their falls has been established. If anticoagulant therapy is deemed necessary, VKA should be preferred over DOACs, as long as no antidotes for DOACs and reliable tests for laboratory monitoring are available.\n\nWritten informed consent was obtained from the widow of the patient for publication of this case report and any accompanying images. The author(s) declare that they have no competing interests.\n==== Refs\nReferences\n1 Connolly SJ Ezekowitz MD Yusuf S Dabigatran versus warfarin in patients with atrial fibrillation N Engl J Med 2009 361 1139 1151 19717844 \n2 Hart RG Diener HC Yang S Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial Stroke 2012 43 1511 1517 22492518 \n3 Lok J Leung W Murphy S Intracranial hemorrhage: mechanisms of secondary brain injury Acta Neurochir 2011 111 Suppl S63 S69 \n4 Schaefer JH Leung W Wu L Translational insights into traumatic brain injury occurring during dabigatran or warfarin anticoagulation J Cereb Blood Flow Metab 2014 34 870 875 24549187 \n5 Awad AJ Walcott BP Stapleton CJ Dabigatran, intracranial hemorrhage, and the neurosurgeon Neurosurg Focus 2013 34 E7 23634926 \n6 Chang DN Dager WE Chin AI Removal of dabigatran by hemodialysis Am J Kidney Dis 2013 61 487 489 23219111 \n7 Chen BC Viny AD Garlich FM Hemorrhagic complications associated with dabigatran use Clin Toxicol (Phila) 2012 50 854 857 22970730 \n8 Cotton BA McCarthy JJ Holcomb JB Acutely injured patients on dabigatran N Engl J Med 2011 365 2039 2040 22111735 \n9 Garber ST Sivakumar W Schmidt RH Neurosurgical complications of direct thrombin inhibitors--catastrophic hemorrhage after mild traumatic brain injury in a patient receiving dabigatran J Neurosurg 2012 116 1093 1096 22394293 \n10 Joseph B Ditillo M Pandit V Dabigatran therapy. Minor trauma injuries are no longer minor Am Surg 2014 80 116 118 \n11 Komori M Yasaka M Kokuba K Intracranial hemorrhage during dabigatran treatment Circ J 2014 78 1335 1341 24662438 \n12 Wassef SN Abel TJ Grossbach A Traumatic intracranial hemorrhage in patients taking dabigatran: report of 3 cases and review of the literature Neurosurgery 2013 73 E368 E373 23670031 \n13 Baraniskin A Steffens C Harders A Impact of pre-hospital antithrombotic medication on the outcome of chronic and acute subdural hematoma J Neurol Surg A Cent Eur Neurosurg 2014 75 31 36 23427037 \n14 Parra MW Zucker L Johnson ES Dabigatran bleed risk with closed head injuries: are we prepared? J Neurosurg 2013 119 760 765 23634730 \n15 Alonso A Bengtson LG MacLehose RF Intracranial hemorrhage mortality in atrial fibrillation patients treated with dabigatran or warfarin Stroke 2014 45 2286 2291 24994722 \n16 Ross B Miller MA Ditch K Clinical experience of life-threateningdabigatran-related bleeding at a large, tertiary care, academic medical center: a case series J Med Toxicol 2014 10 223 228 24385325 \n17 Dowlatshahi D Butcher KS Asdaghi N Poor prognosis in warfarin-associated intracranial hemorrhage despite anticoagulation reversal Stroke 2012 43 1812 1817 22556194 \n18 Eikelboom JW Wallentin L Connolly SJ Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial Circulation 2011 123 2363 2372 21576658 \n19 Hunchuck JE Lake JD Dabigatran for stroke prevention in all patients with atrial fibrillation? Pharmacotherapy 2011 31 725 728 21923597 \n20 Rosenman MB Baker L Jing Y Why is warfarin underused for stroke prevention in atrial fibrillation? A detailed review of electronic medical records Curr Med Res Opin 2012 28 1407 1414 22746356 \n21 Sanders NA Ganguly JA Jetter TL Atrial fibrillation: an independent risk factor for nonaccidental falls in older patients Pacing Clin Electrophysiol 2012 35 973 979 22694347 \n22 Banerjee A Clementy N Haguenoer K Prior history of falls and risk of outcomes in atrial fibrillation: The Loire Valley Atrial Fibrillation Project Am J Med 2014 127 972 978 24929021 \n23 Poli D Antonucci E Testa S Bleeding risk in very old patients on vitamin K antagonist treatment: results of a prospective collaborative study on elderly patients followed by Italian Centres for Anticoagulation Circulation 2011 124 824 829 21810658\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1671-5411",
"issue": "12(1)",
"journal": "Journal of geriatric cardiology : JGC",
"keywords": "Anticoagulation; Atrial fibrillation; Cerebral hemorrhage; Dabigatran",
"medline_ta": "J Geriatr Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101237881",
"other_id": null,
"pages": "83-7",
"pmc": null,
"pmid": "25678908",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports",
"references": "24662438;24887656;22556194;21725733;22492518;21810658;23219111;24929021;22111735;24549187;23670031;21576658;22746356;22694347;23427037;22970730;19717844;23634926;24385325;23634730;24994722;21923597;22394293",
"title": "Traumatic fatal cerebral hemorrhage in an old patient with a history of multiple sclerosis under dabigatran: a case report and review of the literature.",
"title_normalized": "traumatic fatal cerebral hemorrhage in an old patient with a history of multiple sclerosis under dabigatran a case report and review of the literature"
} | [
{
"companynumb": "PHHY2015AT014925",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional": null,... |
{
"abstract": "Recognition of progressive multifocal leukoencephalopathy (PML) in patients with an established primary neuroinflammatory condition can be clinically challenging. Delayed or incorrect diagnosis may worsen the course of the disease and result in an inaccurate prognosis. We present an unusual case of a patient with a rapid decline in visual acuity, positive serum ACE and extensive lymphadenopathy who was found to have progressive subcortical lesions and cerebrospinal fluid PCR positive for John Cunningham virus supporting a coincidental diagnosis of PML. The prognosis of PML is affected by the associated condition. Establishing the diagnosis is important for an exact prognosis of the primary condition but also to allow early discontinuation of immunomodulatory treatment. Sarcoidosis-associated PML might have a similar aggressive course to that seen when associated with haematological malignancies.",
"affiliations": "Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK mmelbadri@hotmail.com.;Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.",
"authors": "Elbadri|Maha|M|;Plant|Gordon|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-232636",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(8)",
"journal": "BMJ case reports",
"keywords": "infection (neurology); iris; visual pathway",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001927:Brain Diseases; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012507:Sarcoidosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32847869",
"pubdate": "2020-08-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Progressive multifocal leukoencephalopathy as the first presentation of sarcoidosis.",
"title_normalized": "progressive multifocal leukoencephalopathy as the first presentation of sarcoidosis"
} | [
{
"companynumb": "GB-TEVA-2020-GB-1843750",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPhenylephrine hydrochloride (PE HCl) is widely used for the treatment of nasal congestion, but efficacy at the 10-mg dose is not known for certain. The Food and Drug Administration has requested that sufficiently powered, multicenter, dose-ranging studies be conducted to assess the efficacy and safety of PE HCl.\n\n\nOBJECTIVE\nTo evaluate subjective nasal congestion symptom relief and safety of 4 different doses of PE HCl immediate-release 10-mg tablets and placebo in adults with seasonal allergic rhinitis (SAR).\n\n\nMETHODS\nThis multicenter, phase 2, parallel, open-label trial randomized 539 adults with SAR (but otherwise healthy) to 7 days of treatment with either PE HCl 10-mg tablets at fixed doses of 10, 20, 30, or 40 mg or placebo. The primary efficacy end point was the mean change from baseline over the entire treatment period in daily reflective nasal congestion score. Other efficacy end points and safety were also evaluated.\n\n\nRESULTS\nNone of the PE HCl treatment groups had a statistically significant change from baseline in instantaneous or reflective nasal congestion scores compared with the placebo group. PE HCl was well tolerated at doses of up to 30 mg. At least 1 treatment-emergent adverse event was experienced by 18.4% of the participants, the most common being headache (3.0%).\n\n\nCONCLUSIONS\nPE HCl, at doses of up to 40 mg every 4 hours, is not significantly better than placebo at relieving nasal congestion in adults with SAR. The phenylephrine section of the Food and Drug Administration monograph on over-the-counter cold, cough, allergy, bronchodilator, and antiasthmatic products should be revised accordingly.",
"affiliations": "Allergy & Asthma Medical Group & Research Center, San Diego, Calif.;Sylvana Research, San Antonio, Texas.;Merck & Co, Inc, Kenilworth, NJ. Electronic address: thomas_p_mcgraw@yahoo.com.",
"authors": "Meltzer|Eli O|EO|;Ratner|Paul H|PH|;McGraw|Thomas|T|",
"chemical_list": "D014663:Nasal Decongestants; D010656:Phenylephrine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "3(5)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Dose-ranging trial; Nasal congestion; Oral decongestant; Phenylephrine HCl; Seasonal allergic rhinitis",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D004311:Double-Blind Method; D054796:Drug Dosage Calculations; D005260:Female; D006261:Headache; D006801:Humans; D008297:Male; D008875:Middle Aged; D014663:Nasal Decongestants; D015508:Nasal Obstruction; D010656:Phenylephrine; D017410:Practice Guidelines as Topic; D006255:Rhinitis, Allergic, Seasonal; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration; D055815:Young Adult",
"nlm_unique_id": "101597220",
"other_id": null,
"pages": "702-8",
"pmc": null,
"pmid": "26143019",
"pubdate": "2015",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Oral Phenylephrine HCl for Nasal Congestion in Seasonal Allergic Rhinitis: A Randomized, Open-label, Placebo-controlled Study.",
"title_normalized": "oral phenylephrine hcl for nasal congestion in seasonal allergic rhinitis a randomized open label placebo controlled study"
} | [
{
"companynumb": "US-JNJFOC-20150926813",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENYLEPHRINE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "OBJECTIVE\nDiarrhoea following orthotopic liver transplantation (OLT) is a significant clinical problem associated with mycophenolic acid (MPA). The histological injury pattern associated with MPA in the large bowel is well documented in the literature; however, that in the duodenum is less extensively documented. The aim of this study was to investigate the histological spectrum of duodenal injury specifically in symptomatic OLT patients on MPA, and to compare this with the spectrum in patients with coeliac disease and in normal controls.\n\n\nRESULTS\nWe reviewed our pathology database for all duodenal biopsies from patients on the OLT list over a period of 19 years. Medical records, anti-tissue transglutaminase IgA serology and histology were reviewed. Of the 667 patients who underwent endoscopy, 127 had duodenal biopsies (152 biopsies). Of these, 87.5% were normal. Sixteen showed abnormal histology, and seven (43.8%) of these were on MPA at the time of biopsy. Significant features included coeliac-like changes (shortened villi and increased intraepithelial lymphocyte counts), and novel findings included increased endocrine cell counts, apoptotic counts and lamina propria eosinophil counts in comparison with normal duodenal biopsies.\n\n\nCONCLUSIONS\nPathologists should be aware of the features of MPA-associated duodenal injury, including coeliac-like changes and increased apoptotic counts. In those with abnormal histology, discontinuation or a reduction in the dose of MPA should be discussed.",
"affiliations": "Department of Histopathology, Centre for Colorectal Disease, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland.",
"authors": "Cotter|Maura B|MB|;AbuShanab|Ahmed|A|;Merriman|Raphael|R|;McCormick|Aiden|A|;Sheahan|Kieran|K|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": "10.1111/his.12541",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0309-0167",
"issue": "66(4)",
"journal": "Histopathology",
"keywords": "coeliac-like pathology; duodenum; liver transplantation; mycophenolic acid",
"medline_ta": "Histopathology",
"mesh_terms": "D000368:Aged; D002446:Celiac Disease; D003967:Diarrhea; D004386:Duodenum; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007413:Intestinal Mucosa; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D012189:Retrospective Studies",
"nlm_unique_id": "7704136",
"other_id": null,
"pages": "500-7",
"pmc": null,
"pmid": "25195696",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Coeliac-like duodenal pathology in orthotopic liver transplant patients on mycophenolic acid therapy.",
"title_normalized": "coeliac like duodenal pathology in orthotopic liver transplant patients on mycophenolic acid therapy"
} | [
{
"companynumb": "PHHY2015IE028169",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nConcern exists about the potential for liver injury with therapeutic dosing of acetaminophen in children.\n\n\nOBJECTIVE\nWe systematically reviewed the medical literature to determine the rate at which liver injury has been reported for children prescribed therapeutic doses of acetaminophen (≤75 mg/kg per day orally or intravenously or ≤100 mg/kg per day rectally).\n\n\nMETHODS\nWe searched Medline, Embase, and the Cochrane Central Register of Controlled Trials to locate all studies in which acetaminophen was administered to a defined pediatric population for ≥24 hours and for all case reports of liver injury after therapeutic acetaminophen dosing. Trained reviewers extracted data from each report. Major and minor hepatic adverse events (AEs) were defined prospectively. Causality was assessed by using the Naranjo algorithm.\n\n\nRESULTS\nA total of 62 studies that enrolled 32,414 children were included. No child (0% [95% confidence interval: 0.000-0.009]) was reported to have exhibited signs or symptoms of liver disease, to have received an antidote or transplantation, or to have died. Major or minor hepatic AEs were reported for 10 children (0.031% [95% confidence interval: 0.015-0.057]). The highest transaminase value reported was 600 IU/L. Naranjo scores (2-3) suggested \"possible\" causation. Twenty-two case reports were identified. In 9 cases, the Naranjo score suggested \"probable\" causation (5-6).\n\n\nCONCLUSIONS\nHepatoxicity after therapeutic dosing of acetaminophen in children is rarely reported in defined-population studies. Case reports suggest that this phenomenon may occur, but few reports contain sufficient data to support a probable causal relationship.",
"affiliations": "Rocky Mountain Poison & Drug Center, 777 Bannock St, MC 0180, Denver, CO 80204, USA. eric.lavonas@rmpdc.org",
"authors": "Lavonas|Eric J|EJ|;Reynolds|Kate M|KM|;Dart|Richard C|RC|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2009-3352",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "126(6)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000082:Acetaminophen; D000284:Administration, Oral; D018712:Analgesics, Non-Narcotic; D002648:Child; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008099:Liver; D017093:Liver Failure; D008111:Liver Function Tests",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "e1430-44",
"pmc": null,
"pmid": "21098156",
"pubdate": "2010-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Therapeutic acetaminophen is not associated with liver injury in children: a systematic review.",
"title_normalized": "therapeutic acetaminophen is not associated with liver injury in children a systematic review"
} | [
{
"companynumb": "US-JNJFOC-20150202244",
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{
"abstract": "Patients with long QT syndrome can sometimes present with a ventricular fibrillation (VF) storm. Catheter ablation of culprit premature ventricular complexes responsible for the triggering of the VF episodes may be required in rare cases of electrical storm that do not respond to conventional measures, and this can be life-saving. We describe a case of emergency catheter ablation in a young woman with a normal corrected QT interval, who presented with malignant VF storm for the first time. We also discuss the diagnostic and management challenges involved, as well as the value of genetic testing in refining the diagnosis.",
"affiliations": "Department of Cardiology, National Heart Centre, Singapore.",
"authors": "Yap|Jonathan|J|;Tan|Vern Hsen|VH|;Hsu|Li Fern|LF|;Liew|Reginald|R|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
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"issn_linking": "0037-5675",
"issue": "54(1)",
"journal": "Singapore medical journal",
"keywords": null,
"medline_ta": "Singapore Med J",
"mesh_terms": "D002309:Cardiology; D017115:Catheter Ablation; D004562:Electrocardiography; D005260:Female; D006323:Heart Arrest; D006579:Heterozygote; D006801:Humans; D008133:Long QT Syndrome; D017180:Tachycardia, Ventricular; D016896:Treatment Outcome; D014693:Ventricular Fibrillation; D018879:Ventricular Premature Complexes; D055815:Young Adult",
"nlm_unique_id": "0404516",
"other_id": null,
"pages": "e1-4",
"pmc": null,
"pmid": "23338923",
"pubdate": "2013-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Catheter ablation of ventricular fibrillation storm in a long QT syndrome genotype carrier with normal QT interval.",
"title_normalized": "catheter ablation of ventricular fibrillation storm in a long qt syndrome genotype carrier with normal qt interval"
} | [
{
"companynumb": "SG-B.BRAUN MEDICAL INC.-2093691",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXTROSE\\LIDOCAINE HYDROCHLORIDE"
},
... |
{
"abstract": "Chemotherapy-induced neurotoxicity is a serious complication of cancer treatment. Oxaliplatin, a third-generation platinum drug, has become one of the first-line therapies used in the treatment of metastatic colorectal cancer. Peripheral neuropathy is a common complication of platinum-based chemotherapy. Most commonly a sensory neuropathy occurs with cold-triggered symptoms in the acute phase and numbness and painful paresthesias as a late presentation. Autonomic neurotoxicity and late presentation, months after cessation of the therapy, has rarely been described. We report a patient who clinically presented with a pseudo-obstruction months after treatment with oxaliplatin for metastatic colorectal cancer. Intestinal adhesions and relapsing malignancy were carefully excluded. By exclusion the pseudo-obstruction was attributed to a toxic oxaliplatin-induced autonomic neuropathy which slowly improved during months of follow-up.",
"affiliations": null,
"authors": "Vandamme|M|M|;Pauwels|W|W|;Bleecker|J De|JD|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1179/2295333714Y.0000000110",
"fulltext": null,
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"issn_linking": "1784-3286",
"issue": "70(3)",
"journal": "Acta clinica Belgica",
"keywords": "Autonomic neuropathy,; Metastatic colorectal cancer,; Neurotoxicity,; Oxaliplatin,; Pseudo-obstruction",
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D003082:Colectomy; D003112:Colonic Pseudo-Obstruction; D015179:Colorectal Neoplasms; D005472:Fluorouracil; D006498:Hepatectomy; D006801:Humans; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D009367:Neoplasm Staging; D020258:Neurotoxicity Syndromes; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010288:Parenteral Nutrition; D010523:Peripheral Nervous System Diseases; D016896:Treatment Outcome",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "207-10",
"pmc": null,
"pmid": "25523317",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of delayed oxaliplatin-induced pseudo-obstruction: an atypical presentation of oxaliplatin neurotoxicity.",
"title_normalized": "a case of delayed oxaliplatin induced pseudo obstruction an atypical presentation of oxaliplatin neurotoxicity"
} | [
{
"companynumb": "BE-ACTAVIS-2015-22467",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": null,
... |
{
"abstract": "The data collected in the Australian Register of antiepileptic drugs in pregnancy have been studied in the hope of defining simple items of information that could be recorded at initial interview of pregnant women with epilepsy, and which might allow estimation of the risk of the pregnancy resulting in a malformed foetus. Analysis of the data showed that dose of valproate, but not intake of other commonly used antiepileptic drugs, in the current pregnancy, and a past history of a pregnancy involving a malformed foetus, statistically significantly increased the malformation hazard in the current pregnancy, and that continuing alcohol intake might decrease it. Plotting the hazard against valproate dose in monotherapy, with or without histories of (i) previous pregnancies with foetal malformations (FMs), and (ii) continuing alcohol intake, provided quantitative information concerning the degree of increased risk. It is hoped that this information may help in advising about the risk of foetal malformation (FM) in individual pregnancies.",
"affiliations": "Department of Medicine and Neurosciences, Royal Melbourne Hospital and University of Melbourne, Parkville, Victoria 3050, Australia. Electronic address: vajda@netspace.net.au.;Department of Medicine and Neurosciences, Royal Melbourne Hospital and University of Melbourne, Parkville, Victoria 3050, Australia.;Department of Medicine and Neurosciences, Royal Melbourne Hospital and University of Melbourne, Parkville, Victoria 3050, Australia.;Royal Brisbane and Women's Hospital and University of Queensland, Brisbane, Queensland 4027, Australia.;Royal Brisbane and Women's Hospital and University of Queensland, Brisbane, Queensland 4027, Australia.",
"authors": "Vajda|F J E|FJ|;O'Brien|T J|TJ|;Graham|J|J|;Lander|C M|CM|;Eadie|M J|MJ|",
"chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-1211",
"issue": "108(6)",
"journal": "Epilepsy research",
"keywords": "Alcohol; Antiepileptic drugs; Foetal malformations; Spina bifida; Teratogenesis; Valproate",
"medline_ta": "Epilepsy Res",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000927:Anticonvulsants; D001315:Australia; D004827:Epilepsy; D005260:Female; D006801:Humans; D011247:Pregnancy; D049188:Prenatal Injuries; D016016:Proportional Hazards Models; D012042:Registries; D012306:Risk; D014635:Valproic Acid",
"nlm_unique_id": "8703089",
"other_id": null,
"pages": "1013-7",
"pmc": null,
"pmid": "24880523",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Prediction of the hazard of foetal malformation in pregnant women with epilepsy.",
"title_normalized": "prediction of the hazard of foetal malformation in pregnant women with epilepsy"
} | [
{
"companynumb": "AU-JNJFOC-20140703470",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of cerebral venous thrombosis (CVT) associated with a giant adenomyosis. At admission, the patient demonstrated generalized seizures and consciousness disturbance. Brain fluid-attenuated inversion recovery magnetic resonance imaging revealed a localized, high-intensity region in the left frontal lobe. Subsequent brain angiography showed that right internal carotid angiograms display abrupt termination of the anterior half of the superior sagittal sinus and a filling defect in the lateral part of the left transverse sinus. The patient complicated with iron deficiency anemia (IDA) and adenomyosis with higher levels of serum carbohydrate antigen 125 (CA125) and d-dimer. After 1 year from onset, intermittent severe menalgia and headache persisted, and blood examination revealed abnormal values; the patient was receiving oral medications. Finally, adenomyosis resection was performed with a favorable outcome, and no recurrence was observed during the 2-year follow-up period. We conclude that IDA and increased CA125 levels may have promoted hypercoagulability and CVT. This report emphasizes the possible relationship between CVT and adenomyosis.",
"affiliations": "Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan. Electronic address: kenya.nishioka@gmail.com.;Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.;Department of Neurosurgery, Juntendo University Urayasu Hospital, Chiba, Japan.;Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.;Department of Obstetrics and Gynecology, Juntendo University Urayasu Hospital, Chiba, Japan.;Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.;Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.;Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.",
"authors": "Nishioka|Kenya|K|;Tanaka|Ryota|R|;Tsutsumi|Satoshi|S|;Yamashiro|Kazuo|K|;Nakahara|Mariko|M|;Shimura|Hideki|H|;Hattori|Nobutaka|N|;Urabe|Takao|T|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "23(7)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Cerebral venous thrombosis; adenomyosis; dural sinus; iron deficiency anemia",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D062788:Adenomyosis; D000747:Anemia, Hypochromic; D005260:Female; D006801:Humans; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D012640:Seizures; D012851:Sinus Thrombosis, Intracranial; D016896:Treatment Outcome; D020246:Venous Thrombosis",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "1985-7",
"pmc": null,
"pmid": "24794947",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cerebral dural sinus thrombosis associated with adenomyosis: a case report.",
"title_normalized": "cerebral dural sinus thrombosis associated with adenomyosis a case report"
} | [
{
"companynumb": "JP-MYLANLABS-2014M1009806",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Thyrotoxicosis factitia is a hyperthyroid state due to the accidental or deliberate thyroxine ingestion. It can have many complications depending upon the organ involved. We present a case of a heavy built athlete presenting with cardiac arrest, who was found to be abused the thyroxine hormone for bodybuilding. Electrocardiogram (EKG) was significant for junctional arrhythmias along with interval supraventricular tachycardia (SVT) and bradycardia. The patient ultimately expired due to a failed resuscitation. To our knowledge, this is the first reported case of junctional arrhythmias caused by exogenous thyroxine.",
"affiliations": "Department of Medicine, Abington Hospital - Jefferson Health, Abington, PA, USA.;Department of Medicine, Abington Hospital - Jefferson Health, Abington, PA, USA.;Department of Medicine, Abington Hospital - Jefferson Health, Abington, PA, USA.;Department of Medicine, Abington Hospital - Jefferson Health, Abington, PA, USA.;Presence St Joseph Hopsital, Chicago, IL, USA.;Sunny Downstate Medical Center, New York, USA.",
"authors": "Roomi|Sohaib|S|0000-0001-5998-9309;Ullah|Waqas|W|0000-0002-4850-0309;Iqbal|Iqra|I|0000-0002-7317-6803;Ahmad|Asrar|A|0000-0002-6727-2591;Saleem|Sameer|S|0000-0003-3763-0906;Sattar|Zeeshan|Z|0000-0003-0133-0645",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/20009666.2019.1618668",
"fulltext": "\n==== Front\nJ Community Hosp Intern Med PerspectJ Community Hosp Intern Med PerspectZJCHzjch20Journal of Community Hospital Internal Medicine Perspectives2000-9666Taylor & Francis 161866810.1080/20009666.2019.1618668Case ReportThyrotoxicosis factitia: a rare cause of junctional rhythm and cardiac arrest S. ROOMI ET AL.JOURNAL OF COMMUNITY HOSPITAL INTERNAL MEDICINE PERSPECTIVEShttp://orcid.org/0000-0001-5998-9309Roomi Sohaib ahttp://orcid.org/0000-0002-4850-0309Ullah Waqas ahttp://orcid.org/0000-0002-7317-6803Iqbal Iqra ahttp://orcid.org/0000-0002-6727-2591Ahmad Asrar ahttp://orcid.org/0000-0003-3763-0906Saleem Sameer bhttp://orcid.org/0000-0003-0133-0645Sattar Zeeshan ca Department of Medicine, Abington Hospital - Jefferson Health, Abington, PA, USAb Presence St Joseph Hopsital, Chicago, IL, USAc Sunny Downstate Medical Center, New York, USACONTACT Waqas Ullah waqasullah.dr@gmail.comDepartment of Medicine, Abington Hospital - Jefferson Health, 1200 Old York Rd, Abington, PA19001, USA2019 19 6 2019 9 3 258 263 03 3 2019 09 5 2019 © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Greater Baltimore Medical Center.2019The Author(s)This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 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.ABSTRACT\nThyrotoxicosis factitia is a hyperthyroid state due to the accidental or deliberate thyroxine ingestion. It can have many complications depending upon the organ involved. We present a case of a heavy built athlete presenting with cardiac arrest, who was found to be abused the thyroxine hormone for bodybuilding. Electrocardiogram (EKG) was significant for junctional arrhythmias along with interval supraventricular tachycardia (SVT) and bradycardia. The patient ultimately expired due to a failed resuscitation. To our knowledge, this is the first reported case of junctional arrhythmias caused by exogenous thyroxine.\n\nKEYWORDS\nThyroid diseaseendocrinologyarrhythmiascardiovascular medicine\n==== Body\n1. Introduction\nExogenous intake of thyroid hormone in the form of pills or supplements has various amounts ofthyroid hormone ranging from per capsule T3 content of 0.97 μg and a T4 content of 3.4 μg to 1.1 μg and 4.5 μg, respectively, [1]. It is most commonly used for the treatment of hypothyroidism; however, it has also been used as a recreational drug and has been abused in high quantities by athletes and gymnasts for body fitness. These levels of exogenous thyroid hormone preparations can easily cause alterations in normal hormone levels and even lead to iatrogenic thyrotoxicosis [2]. A number of complications have been observed, but little is known about the types and incidence of arrhythmias due to exogenous thyroxine. We are highlighting an unusual set of cardiac arrhythmias in a fairly healthy athlete who succumbed to the severe complication of exogenous thyroxine.\n\n2. Case presentation\nA 50-year-old female athlete was brought into the emergency department (ED) after a witnessed car accident. Per fiancé she was the only one in the car, was driving normally but all of a sudden she started driving haphazardly. She initially hit the curb on the roadside and was found to be gasped for air, staring into space, and had some irregular, jerky motions. The fiancé tried to pull her out of the car, but she unknowingly hit on the accelerator which led the car to fall into a deep puddle. She was pulled out of the car after this second impact. This time she was completely unresponsive and pulseless. On-site, CPR was started, and EMS was called. She was intubated on the field, had further two rounds of CPR and received six pushes of epinephrine along the way to the hospital. On presenting to the ER, her heart rhythm at this point showed the junctional rhythm. After a few minutes, she again went into the cardiac arrest. CPR was started, and repeat doses of epinephrine were given. Spontaneous circulation was established, but she went into supraventricular narrow complex tachycardia with a heart rate of 180 bpm (bpm) and blood pressure of 110/80. She then received two doses of adenosine and synchronized cardioversion at 100 J with no improvement in tachycardia. She was started on nicardipine gutta(gtt) to slowdown her heart rate, but it was futile, and the heart rate was continuously above 180 bpm, but her BP came down to 100 systolic. She was then started on 5 mg IV lopressor after being transferred to CCU, which resulted in a drastic drop in heart rate and another round of CPR had to be performed for 9 min, followed by two more rounds with the reestablishment of spontaneous circulation and systolic BP by doppler was 40. The patient at this time had bilateral fixed dilated pupils, was unresponsive with variable heart rate and rhythms. Her eyes were red and edematous, but there was no exophthalmos or thyromegaly. Her cardiovascular examination was unremarkable, but the abdomen was mildly distended with a lack of bowel sounds. Chest examination showed bilateral crepitation, while the neurological examination was remarkable for a GCS score of 3/15. Of note, per fiancé, her past medical history was significant for hypothyroidism for which she had been taking thyroid supplements (possibly ‘nature thyroid’) and prescribed levothyroxine. Her family also revealed that she was a very professional gym trainer and had a history of anabolic steroid intake (testosterone, Anavar and Primo). Further history from fiancé indicated that she has been using supplemental products by the name of ‘Killer Bee’s-fat burner’ and thyroxine containing cardine supplements for weight loss and to energy boost up.\n\n3. Investigations\nLaboratory workup revealed hemoglobin of 14 g/dL with a white blood cell count of 8000. Serumcreatinine was 2.07 mg/dL, sodium was 155 mEq/L, serum calcium was 6.7 mg/dL, serum phosphorus was 6.5 mg/dL. Thyroid workup revealed a TSH level of 0.057 mmol/L. These investigations are given in Table 1. Her urine drug screening turned out negative. An arterial blood gas showed pH 7.21 with bicarbonate of 18.9 and pCO2 of 19. Her initial EKG showed junctional rhythm with diffuse ST depressions (Figure 1) whereas her 2D echocardiography showed an ejection fraction of 55–60% and impaired LV relaxation. There was mild mitral and tricuspid regurgitation. Chest X-ray showed mixed interstitial and alveolar opacities within the mid and upper lung zones, more on the left side with no cardiomegaly or mediastinal shifting. Chest CT scan revealed extensive dependent airspace disease which could point out to atelectasis or aspiration pneumonia. A head CT scan was performed which revealed global loss of intracranial sulci, slit-like ventricles, and diminished gray-white differentiation, concerning for global anoxic injury and cerebral edema (Figure 2).10.1080/20009666.2019.1618668-T0001Table 1. Laboratory investigations performed on admission.\n\nS. no\tInvestigation\tResult\tNormal range\t\n1\tHemoglobin\t14 g/dL\t12–14 g/dL\t\n2\tWhite blood cells (WBCs)\t4.2/L\t4.5–11/L\t\n3\tpH\t7.21\t7.35–7.45\t\n4\tBlood urea nitrogen (BUN)\t32 mg/dL\t5–20 mg/dL\t\n5\tLactate\t2.1 mmol/L\t0.5–1 mmol/L\t\n6\tCreatinine\t2.07 mg/dL\t0.7–1.2 mg/dL\t\n7\tSodium\t155 mEq/L\t135–145 mEq/L\t\n8\tPotassium\t4.2 mEq/L\t3.5–5 mEq/L\t\n9\tCalcium\t6.7 mg/dL\t8.5–10.5 mg/dL\t\n10\tPhosphorus\t6.5 mg/dL\t2.5–4.5 mg/dL\t\n7\tCO2\t19\t23–29 mEq/L\t\n8\tAST\t1291 units/L\t10–40 units/L\t\n9\tALT\t732 units/L\t5–40 units/L\t\n10\tAlbumin\t2.5 g/L\t3.5–5.5 g/L\t\n11\tTSH\t0.057 mmol/L\t0.4–4 mmol/L\t\n12\tFree T3\t>30\t75–200 ng/dL\t\n13\tFree T4\t16 ng/dL\t0.7–1.9 ng/dL\t\n14\tPO2\t128 mmHg\t80–100 mmHg\t\n15\tHCO3\t18.9 mEq/L\t22–28 mEq/L\t\n16\tTroponin T\t5.13 ng/mL\t<0.4 ng/mL\t\n10.1080/20009666.2019.1618668-F0001Figure 1. ECG showing the junctional rhythm with some evidence of left ventricular hypertrophy.\n\n10.1080/20009666.2019.1618668-F0002Figure 2. Head non-contrast CT scan showing global loss of intracranial sulci, slit-like ventricles and diminished gray-white differentiation.\n\n\n\n4. Treatment\nAn initial diagnosis of cardiogenic shock was made, and the patient was transferred to the CCU. She was put on broad spectrum antibiotics vancomycin, cefepime and levaquin. Norepinephrine was started as the first pressor as she was unable to maintain her blood pressure due to cardiogenic shock. Her mean arterial pressure (MAP) was 63 after being on norepinephrine. Her cerebral edema was managed gradually by monitoring the serum sodium levels and starting patient on low dose hypertonic saline. It was not considered safe by the neurologists to bring her serum sodium level down quickly, as it could worsen her brain edema. Since there was evidence of acute kidney injury, she was started on aggressive fluid therapy and was started on keppra for seizure prophylaxis. Due to respiratory failure, the patient was kept on ventilatory support.\n\n5. Outcome and follow-up\nDiscussion with the neurologist made it clear that the patient had sustained severe anoxic brain injury with extremely poor prognosis and was brain dead. Planar scintigraphy made evident that there was no detectable blood flow to any part of the brain, and the findings were consistent with brain death. The family was counseled accordingly. She was extubated, and all treatment was withdrawn leading to patient’s sad demise.\n\n6. Discussion\nA hyperthyroid state can be divided into two main categories, thyrotoxicosis, i.e. hyperfunctioning of the thyroid gland or exogenous intake of thyroid hormone. The thyrotoxicosis state is well known for its numerous adverse effects on the body however little is known regarding the exogenous thyroid hormone toxicities. It can have a variety of adverse effects depending on the system involved and the amount of intoxication. Although the symptoms of hyperthyroidism from factitious ingestion can be similar to the symptoms from thyrotoxicosis including weight loss, heat intolerance, tremor, palpitations, anxiety, increased frequency of bowel movements, or shortness of breath, there can be some physical signs specific to a specific cause. For instance, there will be no exophthalmos and thyromegaly in factitious hyperthyroidism while lid lag and stare can be seen in both exogenous and endogenous hyperthyroidism [3]. Our patient’s eyes were red and swollen but since they were reported to be normal before the cardiac arrest that rules out Graves’ disease and suggests that swelling of her eyes was as a result of brain edema after the cardiac arrest. Thyrotoxicosis in old age is notorious for cardiac complications while the adverse events related to factitious hyperthyroidism are still unknown.\n\nFollowing table compares signs and symptoms of exogenous hyperthyroid state versus hyperfunctioning thyroid gland\n10.1080/20009666.2019.1618668-UT0001System\tSymptoms\tSigns\tHyper- functioning thyroid gland\tExogenous hyperthyroid state\t\nCardiovascular\theat intolerance, sweating, and polydipsia,\npalpitations,\tTachycardia, systolic hypertension,\natrial fibrillation, weight loss\tPresent\tPresent\t\nNeuromuscular\tTremors, anxiety,\nReduced sleep,\nNervousness\tHyperactivity,\nHyperreflexia,\nMuscle tenderness\tPresent\tPresent\t\nSkin\tIncreased perspiration\tWarm and moist skin\tPresent\tPresent\t\nGraves dermopathy\tRed, swollen skin on shins and top of feet\tOrange peel like skin called pretibial myxedema\tPresent in Graves disease\tAbsent\t\nOcular\tRedness and swelling in both eyes\tLid lag, lid retraction\tPresent\tPresent\t\nGraves exophthalmos\tpain, dryness and photophobia in both eyes\tConjunctivitis, bulging eyes\tPresent in Graves Disease\tAbsent\t\nNeck\tDsyphagia, dyspnea, cough, neck tightness\tThyromegaly, hoarseness\tPresent\tAbsent\t\n Thyroxine overdose or hyperthyroid state is known to be associated with tachycardia and atrial fibrillation, it can occasionally cause supraventricular tachycardia but there are no data to suggest the mechanism or association of thyroxine-induced junctional rhythm. Our case was unique as the junctional rhythm in the setting of thyroxine overdose was never been reported. Comparison with other reported cases and our approach to the article is described under the heading ‘methods’ In terms of initial presentation, our case was different as the initial presentation was cardiac arrest and unlike other reported cases our patient had junctional rhythm on presentation rather than tachycardia arrhythmias. Management in previously reported cases was with beta blockers, diazepam, and supportive care because they were having supraventricular tachycardia (SVT). One case responded well and recovered, while the other reported by Bacci et al. was an old-aged patient with nonspecific changes who died. Our case was unique not only in terms of presentation but also the management; she required multiple resuscitative measures, intubation and ultimately had brain death. The characteristics of these cases are shown in Table 2 [4,5].10.1080/20009666.2019.1618668-T0002Table 2. Previously reported cases of thyroxine-induced cardiac arrhythmias.\n\nS. no\tAuthor\tAge /Se x\tPresentation\tT3, T4, TSH\tComorbids\tEKG\tEcho\tTreatment\tOutco me\tFU\t\n1\tBacci V et al [4]\t63/F\tLethargy, Unconsciou sness\tT4 1.2 ug/dL\tHypothyroidism\tNSST\tLV dilatation\tResuscitation\tDeath\tN/A\t\n2\tHack JB et al [5]\t34/M\tVomiting, Diaphoresis, Insomnia, Incoherent speech\tT4 13 mcg/dL,\tN/A\tSVT\tN/A\tIntubation, Hydration, Activated charcoal, Haloperidol, Diazepam, Phenobarbital, Propranolol\tRecovered\tN/A\t\n3\tOur case\t50 /F\tCardiac arrest\tT3 > 30 mcg/dL, TSH 0.057 mm ol/L\tHypothyroidis m, Anabolic steroid intake\tDiffuse ST\ndepression\t55–60% EF, Impaired LV relaxation. Mild mitral, tricuspid regurgitation.\tVentilatory support, Antibiotics, Vasopressors, Hypertonic saline, Correction of acidosis, Fluid therapy, Levetiracetam\tDeath\tN/A\t\n\n\nOur case is the third reported case of thyroxine therapy related to any cardiac arrhythmia and the first reported case of junctional rhythm in association with thyroid hormone treatment. Moreover, our case for the first time unmasks the reality that thyroid hormone abuse for weight loss and energy boost up just like steroid hormones in athletes can lead to arrhythmias and surprisingly junctional rhythm. Loose et al. postulated that the myocytes mainly depends on T3 as it does not have significant intracellular deiodinase activity [6]. T3 then travels into the myocytes via channels and reaches the nucleus to alter the genetic expression [7]. This explains the thyrotoxicosis induced cardiac complications, but the ingested thyroxine is mostly in T4 form and is not known for severe cardiac complications. Moreover, thyroxine pills rarely cause any arrhythmias as the dosages are well controlled and monitored in the clinical settings. In our case thyroxine was abused for weight loss and energy boost up causing junctional arrhythmias leading to cardiac arrest. The mechanism of these arrhythmias is unknown; however, the generally observed effects of ingested thyroxine on cardiac myocytes are similar to the effects of catecholamines such as tachycardia, increased contractility, increased stroke volume and ejection fraction [8]. This can eventually cause persistent tachycardia, atrial fibrillation, eventually causing a high output heart failure [9–11]. What caused junctional arrhythmias in our case is unknown. Our patient had raised T4 at presentation in the setting of chronic abuse of thyroxine products indicating its role in the causation of junctional arrhythmias.\n\nPalpitations are the most common presenting symptom of hyperthyroidism, in about 10–25% of the patients, more likely in the population age 60 years and above, and usually caused by atrial arrhythmias, e.g., atrial fibrillation [9]. Almost 55% to 75% of the patients with AF secondary to hyperthyroidism without any underlying cardiac disease usually return to normal sinus rhythm within 3 to 6 months after treatment of hyperthyroidism [12]. Other types of arrhythmias can be sinus tachycardia, ventricular tachycardia, SVT, ventricular fibrillation and rarely cardiac arrest can also happen [13–15]. There has been no report of thyroxine-induced junctional rhythm leading to cardiac arrest reported so far.\n\nThe mechanism responsible for any possible arrhythmias can be generalized to the effect of thyroxine on the cardiac conduction system. Thyroxine causes early repolarization changes and also increases coronary vascular spasm. A study conducted on 403 patients with various kinds of hyperthyroidism evaluated the types of arrhythmias [16]. Eighty-seven patients (21.5%) had cardiac disturbances. The frequency of the arrhythmias was atrial fibrillation (4.00%), ventricular premature beats (2.77%), paroxysmal supraventricular tachycardia (2.23%), atrial flutter (1.00%). Congestive heart failure occurred in 10.42% of the cases [16]. A forensic analysis of six cases of sudden cardiac death revealed increased cardiac weight, dilatation of cardiac chambers, diffuse myocardial hypertrophy and focal areas of necrosis [17]. Our case was unique not only because of its presentation but also because thyroxine was abused rather than being used for medical purposes, and this highlights the importance that it should be taken in the therapeutic range only.\n\nThe management of thyroid induced cardiac arrhythmias can be divided into two steps. Establishing the normal rhythm and hemodynamic stabilization of the patient followed by treating the underlying hyperthyroid state. Beta blockers help in controlling the heart rate and decrease the peripheral conversion of T4 to T3. An antithyroid drug such as propylthiouracil is preferred over methimazole because of the additional effect of blocking T4 to T3 conversion, although there is some disagreement in avoiding methimazole in this setting since no data show the superior efficacy of propylthiouracil in thyroid storm [18]. Inorganic iodine decreases the release of preformed T4 and T3 and should be given 1 h after antithyroid drugs because iodine can increase hormone production by acting as a substrate for the thyroid synthesis of T4 and T3 if synthesis has not already been blocked with antithyroid drugs. In cases of thyroid storm, fever should be treated with paracetamol; salicylates should be avoided because they increase free T3 and free T4 concentrations by inhibiting T3 and T4 binding to serum proteins [19]. Other medications such as bile acids sequestrants, e.g. cholestyramine bind the free intestinal thyroid hormone and help in its fecal excretion in cases of thyroid storm [20]. Glucocorticoids reduce T4 to T3 conversion and treat the potential risk of adrenal insufficiency due to severe thyrotoxicosis [21]. Our patient, however, did not manifest signs of thyroid storm and presented with thyroid-induced cardiac arrest. She ultimately succumbed to the complications and could not be revived.\n\nOur comprehensive search showed only a few reported cases on factitious thyroxine-induced cardiac complications. The available literature was searched systematically by three authors independently to retrieve all available material on thyroid-induced cardiac arrhythmias, cardiac arrest or myocardial complications. A total of 129 articles were initially obtained using the above search strategy. The titles and abstracts of all these articles were screened for their relevance to our study. One hundred and four articles described different cardiac rhythm problems associated with the hyperfunctioning thyroid gland. Seven of the total articles were about amiodarone-induced thyroid gland abnormalities leading to various arrhythmias while only two articles reported cardiac arrhythmias due to iatrogenic thyroid therapy. The schematic of this search is shown in Figure 3. The thyroxine therapy induced cardiac rhythm abnormalities were reported in one female and one male patient previously. All the patients including ours were young except one reported case of non-specific ST changes leading to the cardiac arrest with levothyroxine ingestion reported by Bacci et al. in a 63 years old patient [4]. Interestingly, the thyroxine levels were normal in this patient [5]10.1080/20009666.2019.1618668-F0003Figure 3. Flow Sheet of literature search and thyroxine-induced cardiac arrhythmias.\n\n\n\n7. Conclusions\nThyroxine-induced cardiac arrhythmias can range from sinus tachycardia to ventricular fibrillation, and surprisingly it can cause junctional rhythm due to an unknown mechanism.\n\nThyroxine if abused for weight loss, energy gain or recreational needs can exceed the tolerated dose and can have detrimental effects on heart rhythm.\n\nThyroxine dose regulation and proper disposition are imperative in patients on regular thyroxine therapy for any hypothyroid condition as unexpected side effects are life-threatening.\n\nDisclosure statement\nNo potential conflict of interest was reported by the authors.\n==== Refs\nReferences\n[1] Ohye H , Fukata S , Kanoh M , et al \nThyrotoxicosis caused by weight-reducing herbal medicines . Arch Internal Med . 2005 4 25 ;165 (8 ):831 –834 .15851631 \n[2] Kang GY , Parks JR , Fileta B , et al \nThyroxine and triiodothyronine content in commercially available thyroid health supplements . Thyroid . 2013 10 1 ;23 (10 ):1233 –1237 .23758055 \n[3] Bilezikian JP , Loeb JN. The influence of hyperthyroidism and hypothyroidism on α and β- adrenergic receptor systems and adrenergic responsiveness . Endocr Rev . 1983 10 1 ;4 (4 ):378 –388 .6317368 \n[4] Bacci V , Schussler GC , Bhogal RS , et al \nCardiac arrest after intravenous administration of levothyroxine . Jama . 1981 3 6 ;245 (9 ):920 .\n[5] Hack JB , Leviss JA , Nelson LS , et al \nSevere symptoms following a massive intentional Lthyroxine ingestion . Vet Hum Toxicol . 1999 10 ;41 (5 ):323 –326 .10509439 \n[6] Ioos V , Das V , Maury E , et al \nA thyrotoxicosis outbreak due to dietary pills in Paris . Ther Clin Risk Manag . 2008 12 ;4 (6 ):1375 .19337445 \n[7] Klein I , Danzi S. Thyroid disease and the heart . Curr Probl Cardiol . 2016 2 1 ;41 (2 ):65 –92 .26792255 \n[8] Udovcic M , Pena RH , Patham B , et al \nHypothyroidism and the heart . Methodist Debakey Cardiovasc J . 2017 4 ;13 (2 ):55 .28740582 \n[9] Danzi S , Klein I \nThyroid disease and the cardiovascular system . Endocrinol Metab Clin . 2014 6 1 ;43 (2 ):517 –528 .\n[10] Biondi B Mechanisms in endocrinology: Heart failure and thyroid dysfunction . Eur J Endocrinol . 2012 ;167(5):609–618. \n[11] Panagoulis C , Halapas A , Chariatis E , et al \nHyperthyroidism and the heart . Hellenic J Cardiol . 2008 5 1 ;49 (3 ):169 –175 .18543646 \n[12] Klein I , Danzi S \nThyroid disease and the heart . Circulation . 2007 10 9 ;116 (15 ):1725 –1735 .17923583 \n[13] Klein I , Ojamaa K \nThyroid hormone and the cardiovascular system . N Engl J Med . 2001 2 15 ;344 (7 ):501 –509 .11172193 \n[14] Ueno A , Yamamoto T , Sato N , et al \nVentricular fibrillation associated with early repolarization in a patient with thyroid storm . J Interv Card Electrophysiol . 2010 11 1 ;29 (2 ):93 –96 .20857326 \n[15] Nakashima Y , Kenzaka T , Okayama M , et al \nA case of thyroid storm with cardiac arrest . Int Med Case Rep J . 2014 ;7 :89 .24855394 \n[16] Vlase H , Lungu G , Vlase L \nCardiac disturbances in thyrotoxicosis: diagnosis, incidence, clinical features and management . Endocrinologie . 1991 ;29 (3–4 ):155 –160 .1821073 \n[17] Zhang MZ , Li BX , Zhao R , et al \nForensic analysis of 6 cases of sudden death due to hyperthyroid heart disease . Fa Yi Xue Za Zhi . 2017 10 ;33 (5 ):482 –485 .29275552 \n[18] Burch HB , Wartofsky L \nLife-threatening thyrotoxicosis: thyroid storm . Endocrinol Metab Clin North Am . 1993 6 1 ;22 (2 ):263 –277 .8325286 \n[19] American Thyroid Association and American Association of Clinical Endocrinologists Taskforce on Hyperthyroidism and Other Causes of Thyrotoxicosis , Bahn RS , Burch HB , Cooper DS , et al \nHyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists . Thyroid . 2011 6 1 ;21 (6 ):593 –646 .21510801 \n[20] Kaykhaei MA , Shams M , Sadegholvad A , et al \nLow doses of cholestyramine in the treatment of hyperthyroidism . Endocrine . 2008 12 1 ;34 (1–3 ):52 –55 .18946743 \n[21] Tsatsoulis A , Johnson EO , Kalogera CH , et al \nThe effect of thyrotoxicosis on adrenocortical reserve . Eur J Endocrinol . 2000 3 1 ;142 (3 ):231 –235 .10700716\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2000-9666",
"issue": "9(3)",
"journal": "Journal of community hospital internal medicine perspectives",
"keywords": "Thyroid disease; arrhythmias; cardiovascular medicine; endocrinology",
"medline_ta": "J Community Hosp Intern Med Perspect",
"mesh_terms": null,
"nlm_unique_id": "101601396",
"other_id": null,
"pages": "258-263",
"pmc": null,
"pmid": "31258870",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10509439;10700716;11172193;15851631;17923583;1821073;18543646;18946743;19337445;20857326;21510801;22956554;23758055;24855394;24891175;26792255;28740582;29275552;6317368;7463688;8325286",
"title": "Thyrotoxicosis factitia: a rare cause of junctional rhythm and cardiac arrest.",
"title_normalized": "thyrotoxicosis factitia a rare cause of junctional rhythm and cardiac arrest"
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"companynumb": "US-IBSA PHARMA-TIR-2019-0605",
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"abstract": "BACKGROUND\nNeostigmine is a frequently used acetylcholinesterase inhibitor administered to reverse muscular relaxation caused by nondepolarizing neuromuscular relaxants in patients recovering from general anesthesia. Severe allergic reactions and urticaria are rarely reported following the use of neostigmine bromide, and never with methylsulfate-containing drugs. In this case, bigeminal premature ventricular contractions added to urticaria provides a warning about the possibility of a life-threatening situation.\n\n\nMETHODS\nWe report the case of a 23-year-old Persian woman who presented with bigeminal premature ventricular contractions along with urticarial lesions on her arm and trunk as soon as she was administered neostigmine methylsulfate after undergoing a laparoscopy for ectopic pregnancy.\n\n\nCONCLUSIONS\nThis case report could be of value not only for anesthesiologists who routinely use neostigmine but also for others who administer the pharmaceutical preparation in other situations. The report presents a rare case of drug reaction following neostigmine use. As a result, one should consider any drug a probable cause of drug reaction. The preparation of resuscitative facilities, therefore, is necessary prior to the prescription of the medication.",
"affiliations": "Anesthesia and Critical Care Department, Women Hospital & Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran. yousefshahi@tums.ac.ir.",
"authors": "Yousefshahi|Fardin|F|;Anbarafshan|Mohammad|M|;Khashayar|Patricia|P|",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/1752-1947-5-83",
"fulltext": "\n==== Front\nJ Med Case ReportsJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-5-832135252710.1186/1752-1947-5-83Case ReportDermal reaction and bigeminal premature ventricular contractions due to neostigmine: a case report Yousefshahi Fardin 1yousefshahi@tums.ac.irAnbarafshan Mohammad 2m_anbarafshan@yahoo.comKhashayar Patricia 3patricia.kh@gmail.com1 Anesthesia and Critical Care Department, Women Hospital & Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran2 Anesthesia and Critical Care Department, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran3 General Practitioner, Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences, Tehran, Iran2011 25 2 2011 5 83 83 8 5 2010 25 2 2011 Copyright ©2011 Yousefshahi et al; licensee BioMed Central Ltd.2011Yousefshahi 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 cited.Introduction\nNeostigmine is a frequently used acetylcholinesterase inhibitor administered to reverse muscular relaxation caused by nondepolarizing neuromuscular relaxants in patients recovering from general anesthesia. Severe allergic reactions and urticaria are rarely reported following the use of neostigmine bromide, and never with methylsulfate-containing drugs. In this case, bigeminal premature ventricular contractions added to urticaria provides a warning about the possibility of a life-threatening situation.\n\nCase presentation\nWe report the case of a 23-year-old Persian woman who presented with bigeminal premature ventricular contractions along with urticarial lesions on her arm and trunk as soon as she was administered neostigmine methylsulfate after undergoing a laparoscopy for ectopic pregnancy.\n\nConclusion\nThis case report could be of value not only for anesthesiologists who routinely use neostigmine but also for others who administer the pharmaceutical preparation in other situations. The report presents a rare case of drug reaction following neostigmine use. As a result, one should consider any drug a probable cause of drug reaction. The preparation of resuscitative facilities, therefore, is necessary prior to the prescription of the medication.\n==== Body\nIntroduction\nNeostigmine, generally used in combination with bromide or methylsulfate, is an acetylcholine esterase inhibitor prescribed mainly to reverse the effects of muscular relaxants at the end of operations performed with the patient under general anesthesia. The drug is also used in patients with myasthenia gravis and paralytic ileus [1-3].\n\nIncreased saliva, nausea and vomiting, abdominal cramps, cardiac dysrhythmia and diarrhea are the commonly reported side effects of the drug [4]. Severe allergic reactions and urticaria, however, are rarely reported following the use of neostigmine bromide, and never with methylsulfate-containing drugs [5]. This article presents the case of a pregnant woman who developed a 5 mm wheal on her left forearm after receiving neostigmine during an operation.\n\nCase presentation\nThe patient was a 23-year-old Persian woman who weighed 60 kg. She underwent a laparoscopy at the eighth week of gestation (G1Ab0L0) because of a right adenexal mass and free liquid in her dorsal cul de sac space.\n\nConsidering the patient's medical record, there was no evidence of any underlying diseases or positive history of allergic reactions to food or drugs in her or her close family. She had never undergone any operations before and had no previous exposure to neostigmine. Additionally, there was no positive finding in her medical history, preoperative examinations and laboratory findings (complete blood count, erythrocyte sedimentation rate, blood urea nitrogen, creatinine and liver function tests).\n\nMidazolam (2 mg) and fentanyl (50 μg) plus thiopental (5 mg/kg), atracurium (0.5 mg/kg) and lidocaine (1 mg/kg) were injected to induce anesthesia. The patient received halothane (1.2 minimum alveolar concentration) and oxygen (100%) for anesthesia maintenance. Two minutes before the surgical incision was performed, 25 μg fentanyl was injected; atracurium (0.15 mg/kg) was then administered every 20 minutes during the operation.\n\nThe surgeon suctioned about 500 ml of blood from the patient's abdominal cavity; no blood, however, was transfused during the two-hour, 40-minute operation. The patient's vital signs were monitored throughout the surgery, and no specific complication was reported.\n\nAt the end of the operation, the patient was still in a deep anesthetic stage and did not respond to painful stimuli. Partial muscular force, however, was restored as soon as the inhaled anesthesia was ceased; thereafter neostigmine (0.04 mg/kg) and atropine (0.02 mg/kg) were infused slowly. At this time, the patient developed a 5 mm urticarial lesion along the vein course that quickly spread over the left forearm. The erythematous convex lesions spread in a geographical pattern but were less severe in the neck and chest (Figure 1).\n\nFigure 1 Urticaria lesions in the recovery room 30 minutes after occurrence, when partial resolution is obvious.\n\nBigeminate premature ventricular contractions (PVCs) were also noted at the same time but disappeared spontaneously after a few minutes. It should be noted that the patient's heartbeat (80beats/min), blood pressure (110/60 mmHg) and blood oxygen saturation (SpO2) (98%) were all normal at this time, and there was no sign of wheeze or other abnormal lung sounds in auscultation.\n\nHydrocortisone (200 mg) was prescribed for the lesions. The tracheal tube was removed as soon as the patient became conscious, and she was then transferred to the recovery room. No other complications such as the development of dermal lesions or cardiac dysrhythmia were reported during the patient's hospitalization, and she was discharged in good condition.\n\nA sample of the prescribed neostigmine was sent to the laboratory of the Pharmacology Faculty; further analysis revealed the medication to be neostigmine methylsulfate with 102.85% effective substance (in accordance with USP30 reference) with no other additives.\n\nThe postsurgical echocardiography was reported to be normal. A skin test performed a few months after the operation revealed a 5 mm wheal and 7 mm flare after the patient was exposed to neostigmine; such a reaction, however, was not noted following the exposure to atropine, normal saline and latex. Additionally, histamine exposure was associated with the development of an 8 mm wheal and a 9 mm flare, suggestive of a positive dermal reaction. It should be noted that the patient did not agree to undergo additive complement component C3 or C4 and antinuclear antibody tests.\n\nDiscussion\nDrug reactions presenting as dermal lesions is not a known phenomenon following the use of neostigmine, particularly neostigmine methylsulfate. While the underlying cause of urticaria following allergen exposure may remain unclear in certain cases, the presence of active components, preservatives or conveying combinations (parabens and aldeheids) are often considered the main cause of drug-related urticaria.\n\nIn our case, the absence of any preservatives or conveying combinations in the specific compound, along with the results of the performed skin test, supported the hypothesis that the neostigmine molecule itself had been the main cause of the reported allergic reaction.\n\nArrhythmia, especially PVCs, is common during anesthesia, particularly during the intubation and extubation time, when the blood anesthetic level is lightened and the airway is stimulated. There are many other factors to take into account, including cardiac disease, direct stimulation, toxins and allergens, contributing to arrhythmia during surgery. PVCs are often benign and resolve spontaneously, but rarely are a precursor of life-threatening arrhythmias.\n\nIn the present case, the patient was in deep stages of anesthesia when the muscular block was reversed using a combination of neostigmine and atropine. Considering the fact that there was no noxious stimulation at the very moment or minutes before that, the occurrence of the lesion could be considered an obvious drug eruption.\n\nConclusion\nThis case could be of value not only for anesthesiologists, as physicians who administer neostigmine routinely, but also for others who are involved in pharmaceutical preparation. The current report reveals that neostigmine, similar to many other drugs, may cause a drug reaction. Co-occurrence of bigeminate premature ventricular contractions, therefore, should be viewed as a herald of possible hemodynamic or cardiac catastrophes. Physicians should hence consider any drugs as a probable cause of drug reaction and should be prepared for necessary resuscitative actions in case it occurs.\n\nAbbreviations\nANA: antinuclear antibody; C3: complement component 3; C4: complement component 4; PVCs: premature ventricular contractions;\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent\nWritten informed consent was obtained from the patient and her husband (in the respect of local customs) for publication of this manuscript and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. At same time, it should be noted that unfortunately the patient did not agree to undergo C3, C4 and ANA tests.\n\nAuthors' contributions\nFY was the responsible anesthesiologist for the patient and scientific coordinator in preparing the case report. MA was the responsible anesthesia resident at the time of patient admission, he performed the following laboratory and skin tests and evaluated their impact on the diagnosis. PK performed searches and prepared the first version of the written case report. All authors read and approved the final version of the manuscript.\n\nAcknowledgements\nWe express our gratitude to Professor Abbas Kebriaeezadeh (Departments of Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences) for performing the pharmaceutical analysis of the neostigmine sample. Also, we appreciate our patient and her husband for permitting and helping us in presenting this case.\n==== Refs\nHunter JM Is it always necessary to antagonize residual neuromuscular block? Do children differ from adults? Br J Anaesth 1996 77 707 709 9014619 \nFawcett WJ Neuromuscular block in children Br J Anaesth 1997 78 627 9175986 \nFuchs-Buder T Mencke T Use of reversal agents in day care procedures (With special reference to postoperative nausea and vomiting) Eur J Anaesthesiol 2001 18 Suppl 23 23 29 \nNaguib M Lien CA Miller RD Pharmacology of muscle relaxants and their antagonists Textbook of Anesthesiology 2005 1 6 Philadelphia: Elsevier 511 514 \nSeed MJ Ewan PW Anaphylaxis caused by neostigmine Anaesthesia 2000 55 574 575 10.1046/j.1365-2044.2000.01125.x 10866721\n\n",
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"issn_linking": "1752-1947",
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"publication_types": "D016428:Journal Article",
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"title": "Dermal reaction and bigeminal premature ventricular contractions due to neostigmine: a case report.",
"title_normalized": "dermal reaction and bigeminal premature ventricular contractions due to neostigmine a case report"
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"abstract": "The development of drug-induced lupus remains a matter of concern in patients treated with anti-tumour necrosis factor (TNF) alpha. The incidence of such adverse effects is unknown. We undertook a retrospective national study to analyse such patients. Between June and October 2003, 866 rheumatology and internal medicine practitioners from all French hospital centres prescribing anti-TNF in rheumatic diseases registered on the website of the 'Club Rhumatismes et Inflammation' were contacted by email to obtain the files of patients with TNF-induced systemic lupus erythematosus. Twenty-two cases were collected, revealing two aspects of these manifestations. Ten patients (six patients receiving infliximab, four patients receiving etanercept) only had anti-DNA antibodies and skin manifestations one could classify as 'limited skin lupus' or 'toxidermia' in a context of autoimmunity, whereas 12 patients (nine patients receiving infliximab, three patients receiving etanercept) had more complete drug-induced lupus with systemic manifestations and at least four American Congress of Rheumatology criteria. One patient had central nervous system manifestations. No patients had lupus nephritis. The signs of lupus occurred within a mean of 9 months (range 3-16 months) in patients treated with infliximab and within a mean of 4 months (range 2-5 months) in patients treated with etanercept. In all cases after diagnosis was determined, anti-TNF was stopped and specific treatment introduced in eight patients: two patients received intravenous methylprednisolone, four patients received oral steroids (15-35 mg/day), and two patients received topical steroids. Lupus manifestations abated within a few weeks (median 8 weeks, standard deviation 3-16) in all patients except one with longer-lasting evolution (6 months). At that time, cautious estimations (unpublished data from Schering Plough Inc. and Wyeth Inc.) indicated that about 7700 patients had been exposed to infliximab and 3000 to etanercept for inflammatory arthritides in France. It thus appears that no drug was more implicated than the other in lupus syndromes, whose incidence was 15/7700 = 0.19% with infliximab and 7/3800 = 0.18% with etanercept. Clinicians should be aware that lupus syndromes with systemic manifestations may occur in patients under anti-TNF alpha treatment.",
"affiliations": "Rheumatology Department, Hôpital Robert Ballanger, Aulnay sous Bois, France. m.debandt@ch-aulnay.fr",
"authors": "De Bandt|Michel|M|;Sibilia|Jean|J|;Le Loët|Xavier|X|;Prouzeau|Sebastian|S|;Fautrel|Bruno|B|;Marcelli|Christian|C|;Boucquillard|Eric|E|;Siame|Jean Louis|JL|;Mariette|Xavier|X|;|||",
"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": "England",
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"doi": "10.1186/ar1715",
"fulltext": "\n==== Front\nArthritis Res TherArthritis Research & Therapy1478-63541478-6362BioMed Central London ar17151589904110.1186/ar1715Research ArticleSystemic lupus erythematosus induced by anti-tumour necrosis factor alpha therapy: a French national survey De Bandt Michel 1m.debandt@ch-aulnay.frSibilia Jean 2Le Loët Xavier 3Prouzeau Sebastian 4Fautrel Bruno 5Marcelli Christian 6Boucquillard Eric 7Siame Jean Louis 8Mariette Xavier 9the Club Rhumatismes et Inflammation1 Rheumatology Department, Hôpital Robert Ballanger, Aulnay sous Bois, France2 CHU Hautepierre, Strasbourg, France3 Hôpital Bois-Guillaume, Rouen, France4 Hôpital de Saint Lo, Saint Lo, France5 Hôpital Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris, Paris, France6 CHU côte de Nacre, Caen, France7 Hôpital de Saint Pierre de la Réunion, St Pierre France8 Polyclinique de Riaumont, Liévin, France9 Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France2005 1 3 2005 7 3 R545 R551 29 11 2004 29 12 2004 7 2 2005 10 2 2005 Copyright © 2005 De Bandt et al., licensee BioMed Central Ltd.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 work is properly cited.\n\nThe development of drug-induced lupus remains a matter of concern in patients treated with anti-tumour necrosis factor (TNF) alpha. The incidence of such adverse effects is unknown. We undertook a retrospective national study to analyse such patients.\n\nBetween June and October 2003, 866 rheumatology and internal medicine practitioners from all French hospital centres prescribing anti-TNF in rheumatic diseases registered on the website of the 'Club Rhumatismes et Inflammation' were contacted by email to obtain the files of patients with TNF-induced systemic lupus erythematosus. Twenty-two cases were collected, revealing two aspects of these manifestations. Ten patients (six patients receiving infliximab, four patients receiving etanercept) only had anti-DNA antibodies and skin manifestations one could classify as 'limited skin lupus' or 'toxidermia' in a context of autoimmunity, whereas 12 patients (nine patients receiving infliximab, three patients receiving etanercept) had more complete drug-induced lupus with systemic manifestations and at least four American Congress of Rheumatology criteria. One patient had central nervous system manifestations. No patients had lupus nephritis. The signs of lupus occurred within a mean of 9 months (range 3–16 months) in patients treated with infliximab and within a mean of 4 months (range 2–5 months) in patients treated with etanercept. In all cases after diagnosis was determined, anti-TNF was stopped and specific treatment introduced in eight patients: two patients received intravenous methylprednisolone, four patients received oral steroids (15–35 mg/day), and two patients received topical steroids. Lupus manifestations abated within a few weeks (median 8 weeks, standard deviation 3–16) in all patients except one with longer-lasting evolution (6 months). At that time, cautious estimations (unpublished data from Schering Plough Inc. and Wyeth Inc.) indicated that about 7700 patients had been exposed to infliximab and 3000 to etanercept for inflammatory arthritides in France. It thus appears that no drug was more implicated than the other in lupus syndromes, whose incidence was 15/7700 = 0.19% with infliximab and 7/3800 = 0.18% with etanercept.\n\nClinicians should be aware that lupus syndromes with systemic manifestations may occur in patients under anti-TNF alpha treatment.\n==== Body\nIntroduction\nTherapy with anti-tumour necrosis factor (TNF) alpha is effective for rheumatoid arthritis (RA) [1,2], with an estimated 500,000 patients being treated worldwide. The possible occurrence of drug-induced autoimmune disorders remains a matter of concern [3]because induction of autoantibodies is frequently observed in patients treated with TNF alpha inhibitors [4]. Of concern is the possible induction of lupus-like (or drug-induced lupus) syndromes, but few cases have been reported [5-7]. In all reported cases, the signs disappeared after treatment was stopped. The incidence of cases is unknown.\n\nWe report here the results of a French national survey revealing 22 cases of drug-induced lupus erythematosus (systemic lupus erythematosus [SLE]) in French patients being treated with anti-TNF alpha for inflammatory arthritides.\n\nMethods\nBetween June and October 2003, the 'Club Rhumatismes et Inflammation', a section of the French Society of Rheumatology, carried out a retrospective survey among all French rheumatologists and specialists in internal medicine to uncover cases of SLE with anti-TNF alpha treatment (infliximab or etanercept at that time). Eight hundred and sixty-six rheumatology and internal medicine practitioners from all the French hospital centres prescribing anti-TNF in rheumatic diseases, registered on the website of the Club Rhumatismes et Inflammation , were contacted four times by email at 1-month intervals to obtain the files of patients with TNF-induced SLE. The study included all the patients ever known to have developed an SLE-like illness during anti-TNF treatment and not only those who developed an SLE-like illness during the 3-month study period.\n\nAs the prescription for anti-TNF alpha is limited to the hospitals in France, all the units of rheumatology using biologics were contacted. Eighteen units gave positive results, 22 gave negative results and very few (<10) did not participate. As all the units of rheumatology using biologics were contacted and most of them participated in the study, we can estimate that the survey involved almost all of the French patients treated with anti-TNF for arthritides. At that time, cautious estimations indicated that about 7700 patients had been exposed to infliximab and 3800 had been exposed to etanercept for inflammatory arthritides in France (unpublished data from Schering Plough Inc. and Wyeth Inc.).\n\nAs there are no recognized criteria for drug-induced lupus [8], we considered diagnosis in the case of: a patient with anti-TNF alpha treatment for inflammatory arthritides; a temporal relationship between clinical manifestations and anti-TNF alpha treatment; the presence of at least four American Congress of Rheumatology (ACR) criteria of SLE [9]. Musculoskeletal symptoms were taken into account only if they reappeared with other lupus symptoms in a patient in whom they had previously disappeared under anti-TNF therapy, and isolated positive results for antinuclear antibodies (ANA) or anti-dsDNA antibodies were not considered for diagnosis, given their high frequency in patients under this therapy. Telephone calls were made to collect information in the case of missing data. Physicians were asked to provide information about the clinical status of the patients and the presence of lupus criteria. Information about the immunological status of the patients was requested (before and after the onset of the manifestations as well as after drug discontinuation).\n\nThe biological tests used for the detection of autoantibodies were an indirect immunofluorescent assay for ANA, an ELISA or Farr assay for anti-DNA antibodies, Ouchterlony's method for anti-extractable nuclear antigens (anti-ENA), and an ELISA for anti-histone, anti-Ro, anti-La, anti-SM, anti-RNP, anti-JO1, anti-Topo 1, and anticardiolipin antibodies (ACL).\n\nResults\nA total of 32 patients was collected, three of which had been previously described [5]. Ten patients were ruled out due to improper diagnosis of lupus syndrome, due to pre-existing lupus syndrome or due to mixed connective tissue disease before introduction of anti-TNF alpha therapies. We observed two types of manifestations among the remaining patients.\n\nTen patients (six patients treated with infliximab, four patients treated with etanercept) had a diagnosis of 'anti-TNF-induced SLE' based on three ACR criteria (Table 1). None of these patients had previous signs of lupus before treatment except one with isolated positive ANA. All of them had RA with joint erosions. The mean age at onset of RA was 39 years (range 24–57 years), and the mean disease duration before onset of 'SLE' was 13 years (range 6–31 years). All patients had been treated with a mean of five disease-modifying antirheumatic drugs, including methotrexate in all cases. Before anti-TNF therapy, no patients had clinical sign of lupus, one had positive isolated ANA (1/160) without any other lupus criteria, and no patients had anti-DNA or low complement. At the time of treatment, all patients were being treated with steroids (mean 8 mg/day, range 4–16 mg/day) and methotrexate. No patient had any other drug known as a lupus-inducing drug.\n\nThe only signs were isolated skin lesions (Table 2): pruritic rash (two cases), butterfly rash (three cases), photosensitivity (two cases), purpura (two cases), chilblains (one case), in a context of autoimmunity with positive ANA and anti-dsDNA antibodies. In all cases the clinical manifestations led to ceasing the treatment with anti-TNF alpha, and the signs abated quickly thereafter (<1 month). Despite the presence of three manifestations or criteria for systemic lupus we did not consider that these patients had drug-induced SLE, but rather that they presented toxidermia associated with ANA. Moreover, all of these clinical manifestations are not specific for lupus. Unfortunately no skin biopsy was performed.\n\nBiological signs were positive results for ANA in all patients (new onset or rise in titre, range 1/160–1/250°; three patients with a speckled pattern, seven patients with a diffuse pattern). A new onset of positive results for anti-dsDNA antibodies in the 10 patients was noted by ELISA. None had any other biological and/or immunological manifestations of lupus. No confounding agent was involved in the occurrence of ANA and anti-dsDNA.\n\nTwelve other patients (10 females, two males; nine patients receiving infliximab, three patients receiving etanercept) had a diagnosis of drug-induced systemic lupus supported by the presence of at least four ACR criteria (Tables 2 and 3). Eleven patients had erosive and destructive RA and one patient had severe psoriatic arthritis. The mean age at onset of RA was 36 years (range 14–54 years), and the mean disease duration before onset of SLE was 16 years (range 3–40 years). All patients had been treated with a mean of five disease-modifying antirheumatic drugs (range 2–8), including methotrexate in all cases.\n\nBefore anti-TNF therapy, no patients had clinical sign of lupus, three had positive ANA (range 1/160–1/1280), one of these (the patient with the highest level of ANA) had one time a limit positive anti-dsDNA titre (ELISA test, 46 UI; normal value <40), and nine had negative results. The two other patients with positive ANA had positive anti-Ro antibodies, and a clinical history of secondary Sjögren syndrome. None of the three patients with positive ANA had any other sign or lupus criteria (Table 2). Eleven patients had a typical history of severe and erosive RA and one patient a history of severe psoriatic arthritis. At the time of treatment, all patients were being treated with steroids (mean 9 mg/day; range 5–15 mg/day) and methotrexate (except one patient on etanercept alone).\n\nClinical signs were skin manifestations in 11 patients (papules, alopecia, rash, butterfly rash, photosensitivity), general manifestations in nine patients (fever, weight loss, asthenia), reappearance of polyarthritis in six patients, inflammatory myalgias in four patients, serositis in three patients, deep vein thrombosis (twice) in one patient, lung disease (life-threatening pneumonitis) with pleuritis in one patient, and neuritis of the third cranial nerve in one patient. No case of nephritis was found. The mean ACR criteria number was 5.5 (range 4–7).\n\nSkin lesions were largely symmetrical (arm, face, trunk) and not at injection sites (in the case of etanercept). Histological analysis (four patients) revealed atrophy of the epidermis, necrosis of some keratinocytes, and perifollicular and perivascular lymphocytic infiltration in the dermis without vasculitis. No indirect immunofluorescent test was performed. The patient with deep vein thrombosis also had positive ACL antibodies. Articular symptoms were taken into account only if they reappeared with other lupus symptoms in a patient in whom they had previously disappeared under anti-TNF therapy and/or were different from previous complaints.\n\nThe patient with optical neuritis had no previous sign of multiple sclerosis before treatment with infliximab; she had an isolated neuritis of the third cranial nerve, with malar rash and autoantibodies. The lumbar puncture was normal. Magnetic resonance imaging showed an isolated hyper signal of the third cranial nerve. Extensive research for other manifestations of multiple sclerosis was performed without success. The presence of the neurological manifestations with other clinical signs and autoimmunity led to the diagnosis of drug-induced lupus.\n\nBiological signs were positive results for ANA in all patients (new onset or rise in titre, range 1/160–1/2560°; four with a speckled pattern, eight with a diffuse pattern), and positive results for anti-dsDNA antibodies (new onset) in 11 patients by ELISA. Among the 11 patients tested with ELISA: five had anti-IgM antibodies and six had a positive test with no more detail; among them, three patients were tested by Farr assay and were positive. The patient without anti-DNA had a high titre of ANA, positive anti-ENA and anti-histone antibodies. Positive anti-ENA antibodies were present in five patients (two patients with previously known anti-SS-A/Ro antibodies, three patients with newly detected anti-ENA antibodies with an unidentified aspect), anti-histone in two patients and anti-cardiolipin in six patients. Leucopenia (blood count <4000/mm3), thrombopenia (blood count <100,000/mm3), lymphopenia (blood count <1500/mm3) and positive Coombs test (without haemolytic anaemia) were present in five patients, four patients, two patients and one patient, respectively. Elevated muscle enzymes were present in three of four patients with inflammatory myalgias. One patient had isolated elevated creatinin phosphokinase. No patient had muscle weakness. Transient low levels of C4 were detected in four cases (nine tested).\n\nThe signs of SLE occurred in a mean of 9 months in patients treated with infliximab and 4 months in patients treated with etanercept. In all cases, after the diagnosis was determined, the treatment was stopped and the manifestations then abated within a few weeks (median 8 weeks, range 3–16 weeks), except one (patient 12, Table 2) with a longer lasting evolution (6 months) before resolution. She had persistent asthenia, immunological and haematological abnormalities before resolution. But after 6 months all the signs abated. Biological signs normalized within a few months: in eight patients the ANA results were negative, and in four they were reduced; in nine patients, anti-dsDNA results were negative, and in three patients they were reduced.\n\nRecovery was spontaneous without treatment in four cases. Steroids were needed in the eight other patients: two patients received topical steroids for skin lesions, two patients received intravenous methylprednisolone, and four patients received oral steroids (15–30 mg/day) for intense general signs. In no patient did SLE signs reappear.\n\nCautious estimations at that time (unpublished data from Schering Plough Inc. and Wyeth Inc.) indicated that about 7700 patients had been exposed to infliximab and 3800 patients had been exposed to etanercept for inflammatory arthritides in France. The incidence of lupus syndromes was thus the same with infliximab (15/7700 = 0.19%) and with etanercept (7/3800 = 0.18%).\n\nDiscussion\nWe report on 22 patients treated with anti-TNF alpha for severe RA or psoriatic arthritis (15 patients receiving infliximab and seven patients receiving etanercept) with no previous sign of lupus disease who developed clinical and biological manifestations of drug-induced lupus.\n\nWe are aware that the scientific interest of a retrospective analysis is of limited value compared with a prospective study. However, at that time only isolated case reports were available. As far as we know, this survey is the only one providing further information about the clinical problem of drug-induced lupus. We hope that the national observatories and registers that have been settled in various countries around the world will precisely and prospectively answer the question of anti-TNF-induced lupus.\n\nAnalysis of the cases revealed two subgroups of patients. The first group of patients was considered by the referring physician as 'drug-induced lupus'. In our opinion these patients had what we term 'toxidermia' – that is, isolated skin manifestations in a context of autoimmunity and the absence of systemic manifestations. We are aware that some colleagues will feel uneasy with the term 'toxidermia' and would prefer to qualify these patients as 'incomplete lupus with isolated skin manifestations'. We do understand the reserve about the expression 'toxidermia' rather than 'drug-induced lupus erythematosus'. We preferred to be rigorous with the diagnosis of SLE and to use a more stringent definition (at least four ACR criteria for SLE) to describe a core of patients. Indeed, patients treated with anti-TNF (mostly infliximab rather than etanercept) have frequent and isolated skin manifestations with positive autoantibodies. The frequency of these clinical pictures is unknown but seems important regarding the frequency of autoantibodies (up to 50% for ANA, 25% for ACL and 15% for anti-DNA with infliximab) and of skin manifestations [3-7,10-12]. Do all these patients only have toxidermia in a context of autoimmunity or 'limited drug-induced skin lupus'?\n\nThe second group of 12 patients had what we considered true 'drug-induced SLE' with at least four ACR criteria and systemic manifestations, with a very acute and complete syndrome, associating general manifestations and clinical and biological signs of lupus. All 12 patients fulfilled the ACR criteria for SLE [9], and did not simply have drug-induced skin toxidermia in a context of autoimmunity. Clinicians should thus be aware that lupus syndromes may occur in patients under anti-TNF alpha treatment and may be complicated by central nervous system signs. However, withdrawal of the drug leads to an abatement of the signs.\n\nACL antibodies were detected in six patients whereas only one patient had developed thrombosis. The occurrence of ACL antibodies in anti-TNF alpha-treated patient is well documented [13]: up to 25% of RA patients with anti-TNF develop IgG or IgM ACL, but thrombosis is observed in much fewer patients (about 4%). It is also known that TNF has potent anti-thrombotic properties [14]. It is therefore conceivable that the association of ACL antibodies and inhibition of TNF could lead to an increase number of thrombosis. Should we routinely look for ACL antibodies in our patients?\n\nThe imputability of anti-TNF therapy in inducing lupus syndrome is probable, given the temporal relationship between the onset of signs with treatment and the resolution following withdrawal of the drug in all cases. No confounding agent (such as statins) was involved in patients with myositis, myalgias or elevated creatinin phosphokinase. No other drug, known as a lupus-inducing-drug, was present in any patient.\n\nThe incidence of anti-TNF-induced lupus is difficult to evaluate. We estimated that we covered most, if not all, cases in France as of October 2003. It is possible we have missed some cases, as in all retrospective studies. However, with the opportunity to use the quite unique organized system that is the Club Rhumatismes et Inflammation website, which encompasses most if not all the physicians interested in biologics and systemic diseases, we think these missing cases are scarce. Moreover, we sent four email recall letters at 1-week intervals to detect the cases. The estimation of the number of exposed patients to the drugs is always difficult, even by the pharmaceutical companies themselves. At the time, cautious estimations from Schering Plough Inc. and Wyeth Inc. allowed one to determine the number of exposed patients to each of the drugs from the beginning of the clinical trials until the time of the study, but did not allow one to determine the length of exposition in terms of the number of patients-years. Therefore, with these estimations, it appears that no drug was more implicated than the other in lupus syndromes.\n\nInterestingly, no case of lupus nephritis was observed in this survey. However, one case of etanercept-associated renal disease has been recently described (active urine sediment, new onset of anti-Ro, anti-Sm and anti-RNP antibodies) but no biopsy has been performed. In that case signs abated shortly after drug discontinuation [15].\n\nThe mechanism of induction remains unclear. One hypothesis could be an increase of apoptotic particles and antigens from apoptotic cells. It has been shown that RA patients had no circulating nucleosomes at the steady state and some of them had significantly higher levels of plasma nucleosomes after receiving infliximab [16]. The accumulation of nucleosomes could possibly enhance the development of autoantibodies in subjects with appropriate genetic backgrounds.\n\nAnother hypothesis is that the suppression of the T-helper type 1 response by TNF blockers could favour a T-helper type 2 response leading to SLE, but this hypothesis needs to be tested in man. Neutralization of TNF alpha was tested in mice undergoing acute graft versus host disease using the parent-into-F1 model [17]. Monoclonal antibody against TNF alpha blocked the lymphocytopenic features characteristic of acute graft versus host disease and induced a lupus-like chronic graft versus host disease phenotype (lymphoproliferation and autoantibody production). These effects resulted from complete inhibition of detectable anti-host cytotoxic T lymphocytes. In that model the authors showed that in vivo blockade of TNF alpha preferentially inhibited the production of interferon gamma and blocked interferon-gamma-dependent upregulation of Fas; and that cytokines such as IL-10, IL-6, or IL-4 were not inhibited. These results suggest that a therapeutic TNF alpha blockade may promote humoral autoimmunity by selectively inhibiting the induction of a cytotoxic T lymphocyte response that would normally suppress autoreactive B cells.\n\nA final hypothesis is the role of bacterial infections. They are increased with TNF blockers and are also powerful stimulants leading to polyclonal B-lymphocyte activation and autoantibody production. Some cases of positive anti-DNA following infection after etanercept have been reported [18]. Interestingly, the titre returned to normal values after antibiotic treatment.\n\nIn conclusion, we collected 22 cases of 'anti-TNF alpha-induced lupus' based on the ACR lupus criteria in a retrospective national survey, allowing us to better define the clinical aspects of these manifestations. Given the frequency of autoantibodies in anti-TNF alpha-treated patients, we proposed to identify two subsets of patients. The first group only had skin manifestations and anti-DNA antibodies. Do these patients have 'toxidermia' in a context of autoimmunity or true 'limited drug-induced skin lupus'? Should they stop or continue treatment with anti-TNF alpha? We do not have the answer, and we let the reader decide. Whereas the second group has true drug-induced SLE (with at least four ACR criteria) and systemic manifestations (serositis, cranial neuritis). In all cases anti-TNF was stopped after diagnosis was determined, and specific manifestations abated within a few weeks. Clinicians should be aware that lupus syndromes with systemic manifestations may occur in patients receiving anti-TNF alpha treatment.\n\nAbbreviations\nACL = anticardiolipin antibodies; ACR = American Congress of Rheumatology; ANA = antinuclear antibodies; ELISA = enzyme-linked immunosorbent assay; ENA = extractable nuclear antigens; IL = interleukin; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; TNF = tumour necrosis factor.\n\nCompeting interests\nThe author(s) declare that there are no competing interests.\n\nAuthors' contributions\nMDB had the original idea for the work, collected all the data, analysed the data and wrote the paper. JS, XLL, SP, BF, ChM, EB and JLS were all in charge of the patients, reviewed the charts, and gathered and collected the data. XM participated in the data analysis and the writing of the work.\n\nAcknowledgements\nEthic approval was given for the study by the advisory board of the Club Rhumatismes et Inflammation and the 'Société Française de Rhumatologie'. The following physicians referred cases of patients with only three signs of lupus: F Simon, T Pham, J Dupuis, I Chary-Valckenaere, M Longy-Boursier, T Schaeverbecke, V Goeb, Ch Richet, B Moura and J Bonidan.\n\nFigures and Tables\nTable 1 General presentation of the 10 patients with 'limited skin lupus' or toxiderma in a context of autoimmunity\n\nPatient\tBefore anti-TNF alpha treatment\t\tDuring onset of symptoms\t\n\t\t\n\tDisease\tAutoantibody\tClinical signs of lupus\tTreatment\tDuration of treatment (months)\tClinical signs of lupus\tBiological signs of lupus\t\n1\tRA, erosive\tRF+\tNone\tETA\t36\tSkin\tANA+, dsDNA+\t\n2\tRA, erosive\tRF+\tNone\tINF\t6\tSkin\tANA+, dsDNA+\t\n3\tRA, erosive\tRF+, ANA+ 1:160°\tNone\tINF\t18\tSkin\tANA+, dsDNA+\t\n4\tRA, erosive\tRF-\tNone\tETA\t5\tSkin\tANA+, dsDNA+\t\n5\tRA, erosive\tRF+\tNone\tINF\t7\tSkin\tANA+, dsDNA+\t\n6\tRA erosive\tRF+\tNone\tETA\t5\tSkin\tANA+, dsDNA+\t\n7\tRA, erosive\tRF+\tNone\tINF\t11\tSkin\tANA+, dsDNA+\t\n8\tRA, erosive\tRF+\tNone\tINF\t3\tSkin\tANA+, dsDNA+\t\n9\tRA, erosive\tRF+\tNone\tETA\t12\tSkin\tANA+, dsDNA+\t\n10\tRA, erosive\tRF+\tNone\tINF\t13\tSkin\tANA+, dsDNA+\t\nANA, antinuclear antibodies; dsDNA, double-strand DNA; ETA, etanercept; INF, infliximab; RA, rheumatoid arthritis; RF, rheumatoid factor; TNF, tumour necrosis factor; +, positive; -, negative.\n\nTable 2 General presentation of the 12 patients with 'complete lupus'\n\nPatient\tBefore anti-TNF alpha treatment\t\tDuring onset of symptoms\t\n\t\t\n\tDisease\tAutoantibody\tClinical signs of lupus\tTreatment\tDuration of treatment (months)\tClinical signs of lupusa\tBiological signs of lupus\t\n1\tRA, RF+, erosive\tNone\tNone\tINF\t27\tGeneral, skin, serositis, lung\tANA+, dsDNA+, ACL+, leucopenia, thrombopenia, ENA+\t\n2\tRA, RF+, erosive\tANA+, Ro+\tNone\tINF\t4\tGeneral, skin (3), arthritis\tANA+, dsDNA+, histone +\t\n3\tRA, RF+, erosive\tANA+, Ro+\tNone\tINF\t2\tSkin, myalgias, arthritis\tANA+, dsDNA+, ENA+,\t\n4\tRA, RF-, erosive\tNone\tNone\tETA\t4\tGeneral, skin (2), myositis\tANA+, dsDNA+, ACL+, low C4, ENA+\t\n5\tRA, RF+, erosive\tNone\tNone\tINF\t4\tSkin (3), myositis, arthritis, pericarditis\tANA+, dsDNA+, ACL+, CPK, lymphopenia\t\n6\tRA, RF+, erosive\tANA+, dsDNA+ limit value\tNone\tETA\t5\tGeneral, skin\tANA+, dsDNA+, thrombopenia, leucopenia\t\n7\tRA, RF+, erosive\tNone\tNone\tINF\t10\tGeneral, serositis, myositis\tANA+, dsDNA+, ACL+, leucopenia, thrombopenia, CPK,\t\n8\tRA, RF+\tNone\tNone\tETA\t2\tPhlebitis, skin\tANA+, dsDNA+, leucopenia, ACL+, thrombopenia\t\n9\tPsoriatic arthritis\tNone\tNone\tINF\t14\tGeneral, skin, neurological\tANA+, dsDNA+\t\n10\tRA, RF+, erosive\tNone\tNone\tINF\t16\tGeneral, Skin, arthritis\tANA+, dsDNA+\t\n11\tRA, RF+, erosive\tNone\tNone\tINF\t12\tGeneral, skin (3), arthritis, myositis\tANA+, dsDNA+, ENA+, CPK\t\n12\tRA, RF+, erosive\tNone\tNone\tINF\t10\tGeneral, skin, arthritis\tANA+, dsDNA+, CPK, ENA+, ACL+, low C4, histone+, leucopenia, lymphopenia, Coombs test+\t\nACL, positive anticardiolipin antibodies; ANA, antinuclear antibodies; CPK, creatin phospokinase or muscle enyme, elevated muscle enzymes; dsDNA, double-strand DNA; ENA, positive anti-extractable nuclear antigens antibodies; ETA, etanercept; general, general manifestations (fever, weight loss, asthenia); histone, positive anti-histone antibodies; INF, infliximab; RA, rheumatoid arthritis; RF, rheumatoid factor; TNF, tumour necrosis factor; +, positive; -, negative.\n\naThe skin manifestations were as follows (number in parentheses indicates number of skin manifestations observed in one patient): maculo papular rash observed in six patients, butterfly rash observed in five patients, alopecia present in one patient, photosensitivity observed in five patients, purpuric lesions observed in two patients. One patient had no skin manifestations, seven patients had one sign, one patient had two different signs, and three patients had three skin manifestations.\n\nTable 3 Signs of systemic lupus erythematosus (SLE) in 12 patients under anti-tumour necrosis factor alpha treatment\n\nSign of SLE\tNumber of patients\t\nSkin (≥ 1 SLE skin criteria)\t11\t\nGeneral (fever, weight loss, asthenia)\t9\t\nMusculoskeletal (arthritis, myositis, myalgias)\t10 (6 arthritis, 3 myositis, 1 myalgia)\t\nSerositis, lung, neuritis, phlebitis; haematological abnormalities, elevated muscle enzymes\t3, 1, 1 and 1, respectively; 12 and 3, respectively\t\nAntibody testing\t\t\n Positive for ANA (>1/160)\t12\t\n Positive for anti-dsDNA antibodies (>40 UI)\t11\t\n Positive anti-ENA, anti-histone, anti-cardiolipid\t5, 2 and 6, respectively\t\nRecovery\t\t\n After treatment withdrawn (with/without steroids)\t12 (4 and 8)\t\n Delay in recovery (median and range)\t8 weeks (3–16 weeks)\t\nTen females, two males; nine patients treated with infliximab and three patients treated with etanercept. ANA, antinuclear antibodies; dsDNA, double-strand DNA; ENA, positive anti-extractable nuclear antigensantibodies.\n==== Refs\nGarrison L McDonnell N Etanercept: therapeutic use in patients with rheumatoid arthritis Ann Rheum Dis 1999 58 suppl 1 I65 I69 10577976 \nMaini R St Clair EW Breedveld F Furst D Kalden J Weisman M Smolen J Emery P Harriman G Feldmann M Lipsky P Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group Lancet 1999 354 1932 1939 10622295 10.1016/S0140-6736(99)05246-0 \nPisetski DS Tumor necrosis factor alpha blockers and the induction of anti-DNA antibodies Arthritis Rheum 2000 43 2381 2382 11083257 10.1002/1529-0131(200011)43:11<2381::AID-ANR1>3.0.CO;2-M \nLouis M Rauch J Armstrong M Fitzcharles M-A Induction of autoantibodies during prolonged treatment with infliximab J Rheumatol 2003 30 2557 2562 14719194 \nDe Bandt M Vittecoq O Descamps V Le Loet X Meyer O Anti-TNF alpha-induced systemic lupus erythematosus Clin Rheumatol 2003 22 56 61 12605321 10.1007/s10067-002-0654-5 \nShakoor N Michalska M Harris CA Block JA Drug-induced systemic lupus erythematosus associated with etanercept therapy Lancet 2002 359 579 580 11867114 10.1016/S0140-6736(02)07714-0 \nDe Rycke L Kruithof E Van Damme N Hoffman IEA Van den Bossche N Van den Bosch F Veys EM De Keyser F Antinuclear antibodies following infliximab treatment in patients with rheumatoid arthritis or spondylarthropathy Arthritis Rheum 2003 48 1015 1023 12687543 10.1002/art.10876 \nMongey AB Hess E Lahita R Drug and environmental lupus: clinical manifestations and differences Systemic Lupus Erythematosus 1999 3 New York: Academic Press \nHochberg MC Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus Arthritis Rheum 1997 40 1725 \n letter\n 9324032 \nSchaible TF Treatment of inflammatory diseases: safety of long-term use of infliximab Presse Med 2001 30 610 613 11317923 \nDevos SA Van Den Bossche N De Vos M Naeyaert JM Adverse skin reactions to anti-TNF-alpha monoclonal antibody therapy Dermatology 2003 206 388 390 12771494 10.1159/000069965 \nFlendrie M Creemers MC Welsing PM den Broeder AA van Riel PL Survival during treatment with tumour necrosis factor blocking agents in rheumatoid arthritis Ann Rheum Dis 2003 62 suppl 2 ii30 ii33 14532145 \nJonsdottir T Forslid J van Vollenhoven A Harju A Brannemark S Klareskog L van Vollenhoven RF Treatment with tumour necrosis factor alpha antagonists in patients with rheumatoid arthritis induces anticardiolipin antibodies Ann Rheum Dis 2004 63 1075 1078 15066863 10.1136/ard.2003.018093 \nCambien B Bergmeier W Saffaripour S Mitchell HA Wagner DD Antithrombotic activity of TNF-alpha J Clin Invest 2003 112 1589 1596 14617760 10.1172/JCI200319284 \nCarlson E Rothfield N Etanercept-induced like lupus syndrome in a patient with rheumatoid arthritis Arthritis Rheum 2003 48 1165 1166 12687569 10.1002/art.11033 \nD'Auria F Rovere-Querini P Giazzon M Ajello P Baldissera E Manfredi A Sabbadini M Accumulation of plasma nucleosomes upon treatment with anti-tumour necrosis factor-alpha antibodies J Intern Med 2004 255 409 418 14871466 10.1111/j.1365-2796.2003.01298.x \nVia CS Shustov A Rus V Lang T Nguyen P Finkelman FD In vivo neutralization of TNF-alpha promotes humoral autoimmunity by preventing the induction of CTL J Immunol 2001 167 6821 6826 11739498 \nFerraccioli G Mecchia F Di Poi E Fabris M Anticardiolipin antibodies in rheumatoid patients treated with etanercept or conventional combination therapy: direct and indirect evidence for a possible association with infections Ann Rheum Dis 2002 61 358 361 11874843 10.1136/ard.61.4.358\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1478-6354",
"issue": "7(3)",
"journal": "Arthritis research & therapy",
"keywords": null,
"medline_ta": "Arthritis Res Ther",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D000068800:Etanercept; D005260:Female; D005602:France; D006306:Health Surveys; D006801:Humans; D007074:Immunoglobulin G; D000069285:Infliximab; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101154438",
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"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "10577976;9324032;11083257;11317923;11739498;11867114;11874843;12605321;12687543;12687569;12771494;14532145;14617760;14719194;14871466;15066863;10622295",
"title": "Systemic lupus erythematosus induced by anti-tumour necrosis factor alpha therapy: a French national survey.",
"title_normalized": "systemic lupus erythematosus induced by anti tumour necrosis factor alpha therapy a french national survey"
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"abstract": "Lung Transplant recipients are at increased risk of complicated diverticular disease. We aim to assess the rate of diverticular surgery in a postlung transplantation population and identify risk factors for surgery. We performed a retrospective cohort study of lung transplant recipients from 2007 to 2011. Demographic variables were evaluated with the Mann-Whitney U and chi-squared tests. Cox regression was performed to evaluate 1- and 2-year landmark survival, assess predictor variables of diverticular surgery and evaluate impact of surgery on CLAD development. Of 17 of 158 patients (10.7%) underwent diverticular-related surgery. Surgical patients had significantly worse survival than nonsurgical patients at 1 year [aHR 2.93 (1.05-8.21), P = 0.041] and 2 year [aHR 4.17 (1.26-13.84), P = 0.020] landmark analyses. Transplant indication of alpha-1 antitrypsin disease and cystic fibrosis were significantly associated with the need for diverticular surgery. Emergent surgery was associated with poorer survival [aHR 5.12(1.00-26.27), P = 0.050]. Lung transplant patients requiring surgery for complicated diverticular disease have significantly poorer survival than those who do not require surgery. Surgery was more common in patients transplanted for A1AT and CF. Optimal assessment and risk stratification of diverticular disease is necessary to prevent excessive morbidity and mortality following transplantation.",
"affiliations": "Department of Medicine, Division of Pulmonary and Critical Care, Washington University in St. Louis, St. Louis, MO, USA.;Department of Public Health, Loyola University Chicago Health Science Division, Maywood, IL, USA.;Department of Internal Medicine, Division of Pulmonary and Critical Care, Loyola University Chicago Health Science Division, Maywood, IL, USA.;Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA.;Department of Internal Medicine, Division of Pulmonary and Critical Care, Loyola University Chicago Health Science Division, Maywood, IL, USA.;Department of Internal Medicine, Division of Pulmonary and Critical Care, Loyola University Chicago Health Science Division, Maywood, IL, USA.",
"authors": "Tague|Laneshia K|LK|https://orcid.org/0000-0002-6243-1901;Adams|William|W|;Young|Katherine A|KA|;Kwon|Oh Jin|OJ|;Mahoney|Erin|E|;Lowery|Erin M|EM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/tri.13417",
"fulltext": null,
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"issn_linking": "0934-0874",
"issue": "32(7)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": "diverticular disease; lung transplantation; surgical complications",
"medline_ta": "Transpl Int",
"mesh_terms": "D000368:Aged; D003550:Cystic Fibrosis; D004238:Diverticulitis; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy; D008171:Lung Diseases; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome; D019896:alpha 1-Antitrypsin Deficiency",
"nlm_unique_id": "8908516",
"other_id": null,
"pages": "739-750",
"pmc": null,
"pmid": "30793380",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": "10932672;11147030;14979513;15261179;15285520;15821195;16377497;16741596;16885691;17889204;1854245;18996378;19005733;19152450;19416776;20694839;21400068;21497510;21764603;22008890;22062360;22354135;22551769;22564266;22777341;23835442;24681032;24709270;24722781;24912859;25127673;25242125;25351931;25659085;2667501;27240131;27448095;27517729;27555756;27582783;27772669;29024071;29214770;29221800;29682542;29846608;5540835;6333217;7564451;7727475;8784016;9229300",
"title": "Association between diverticular disease requiring surgical intervention and mortality in the postlung transplant population - a retrospective cohort study.",
"title_normalized": "association between diverticular disease requiring surgical intervention and mortality in the postlung transplant population a retrospective cohort study"
} | [
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"abstract": "BACKGROUND\nScleral buckling (SB) is usually considered an extraocular operation premeditated to have a low risk of sympathetic ophthalmia (SO). Here we report a rare case of presumed SO in a young female patient following SB.\n\n\nMETHODS\nA nineteen-year-old female patient was referred for visual loss in her left eye due to macula off inferior long-standing rhegmatogenous retinal detachment (RRD). The best corrected visual acuity (BCVA) was 20/400 in the left eye. SB with 360 degrees encircling band, an inferior segmental tire with one spot cryoretinopexy at the break site, and subretinal fluid drainage was performed. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient referred to the hospital 6 weeks later with severe visual loss in both eyes as counting finger 1 m. Patient examination indicated bilateral multifocal serous retinal detachment (SRD) and vitreous cells. The patient, diagnosed with SO, received intravenous corticosteroid pulse therapy and mycophenolate mofetil for treatment. The inflammation was controlled and SRD resolved after a 5-day intravenous treatment without being relapsed after 6 months. Consequently, BCVA became 20/20 and 20/50 in the right and left eye, respectively, after 6 months. The findings of systemic workup were negative for any extraocular disease or systemic involvement.\n\n\nCONCLUSIONS\nSince SB is a procedure without manipulating intraocular tissues, it is considered to impose a low risk for SO. This report presented SO occurrence after successful SB. Some factors may induce SO, including inciting the choroid and retinal pigment epithelium with cryoretinopexy or perforating for drainage.",
"affiliations": "Eye Research Center, Khatam-al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Qarani Boulevard, Mashhad, 9195965919, Iran.;Eye Research Center, Khatam-al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Qarani Boulevard, Mashhad, 9195965919, Iran.;Eye Research Center, Khatam-al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Qarani Boulevard, Mashhad, 9195965919, Iran.;Eye Research Center, Khatam-al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Qarani Boulevard, Mashhad, 9195965919, Iran.;Eye Research Center, Khatam-al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Qarani Boulevard, Mashhad, 9195965919, Iran. mojtaba_abrishami@yahoo.com.",
"authors": "Hosseini|Seyedeh Maryam|SM|;Shoeibi|Nasser|N|;Azimi Zadeh|Mahdieh|M|;Ghasemi|Mahdi|M|;Abrishami|Mojtaba|M|http://orcid.org/0000-0003-2001-7929",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1186/s12348-020-00233-z",
"fulltext": "\n==== Front\nJ Ophthalmic Inflamm Infect\nJ Ophthalmic Inflamm Infect\nJournal of Ophthalmic Inflammation and Infection\n1869-5760 Springer Berlin Heidelberg Berlin/Heidelberg \n\n233\n10.1186/s12348-020-00233-z\nBrief Report\nPersumed sympathetic Ophthalmia after scleral buckling surgery: case report\nHosseini Seyedeh Maryam Shoeibi Nasser Azimi Zadeh Mahdieh Ghasemi Mahdi http://orcid.org/0000-0003-2001-7929Abrishami Mojtaba mojtaba_abrishami@yahoo.com grid.411583.a0000 0001 2198 6209Eye Research Center, Khatam-al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Qarani Boulevard, Mashhad, 9195965919 Iran \n22 2 2021 \n22 2 2021 \n2021 \n11 412 6 2020 20 12 2020 © The Author(s) 2021Open 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/.Background\nScleral buckling (SB) is usually considered an extraocular operation premeditated to have a low risk of sympathetic ophthalmia (SO). Here we report a rare case of presumed SO in a young female patient following SB.\n\nCase presentation\nA nineteen-year-old female patient was referred for visual loss in her left eye due to macula off inferior long-standing rhegmatogenous retinal detachment (RRD). The best corrected visual acuity (BCVA) was 20/400 in the left eye. SB with 360 degrees encircling band, an inferior segmental tire with one spot cryoretinopexy at the break site, and subretinal fluid drainage was performed. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient referred to the hospital 6 weeks later with severe visual loss in both eyes as counting finger 1 m. Patient examination indicated bilateral multifocal serous retinal detachment (SRD) and vitreous cells. The patient, diagnosed with SO, received intravenous corticosteroid pulse therapy and mycophenolate mofetil for treatment. The inflammation was controlled and SRD resolved after a 5-day intravenous treatment without being relapsed after 6 months. Consequently, BCVA became 20/20 and 20/50 in the right and left eye, respectively, after 6 months. The findings of systemic workup were negative for any extraocular disease or systemic involvement.\n\nConclusion\nSince SB is a procedure without manipulating intraocular tissues, it is considered to impose a low risk for SO. This report presented SO occurrence after successful SB. Some factors may induce SO, including inciting the choroid and retinal pigment epithelium with cryoretinopexy or perforating for drainage.\n\nKeywords\nSympathetic ophthalmiaScleral bucklingUveitisCryoretinopexyCase reportissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\nSympathetic ophthalmia (SO) is a rare bilateral diffuse granulomatous panuveitis that may occur after surgery or trauma to one eye, as penetrating injury and exposure of the uvea [1]. The incidence of SO is reported ranging 0.01–0.5% after intraocular surgery [1–5]. Surgeries with manipulation and irritation of the choroid and retina are considered as risk factors [1]. The interval between the ocular injury and the onset of SO varies greatly, from a few days to decades, with most of the cases occurring within 3 months after the injury to the exciting eye and 90% during the first year [2–4]. The inciting ocular surgery varies, including cataract extraction, secondary intraocular lens placement, trabeculectomy, vitrectomy, cyclodestruction, iridectomy, and evisceration [1]. Recently, there has been an increasing trend of SO incidence after intraocular and vitreoretinal surgeries [6].\n\nScleral buckling (SB) is usually considered an extraocular operation, a privilege over vitrectomy, and SO is presumed to have a very low risk after SB. Here we report an unusual rare case of SO following successful SB surgery which was combined with subretinal fluid drainage (SRFD) and cryoretinopexy.\n\nCase presentation\nA nineteen-year-old female was referred for visual loss and superior visual field defect in her left eye (LE). Best corrected visual acuity (BCVA) was 20/20 and 20/400 in the right eye (RE) in the LE, respectively. The anterior segment examination was within normal limits except for the detection of Shaffer sign in the LE. The results of the fundus examination revealed macula off inferior long-standing rhegmatogenous retinal detachment (RRD), 3 h of proliferative vitreoretinopathy (PVR), retinal break, and lattice degeneration. The patient had no history of head or ocular trauma or any intraocular surgery. SB with 360 degrees encircling silicone band (silicone band type 240, FCI Inc., Paris, France) and inferior segmental silicone tire (asymmetrical silicone tire type 276, FCI Inc., Paris, France) with one spot cryoretinopexy at the break site, and SRFD due to chronicity of the RRD was performed. During this process, SRFD was not inadvertent. Scleral thinning was performed after passing the band and tire. Moreover, the needle of polyester spatula suture (Mersilene, Ethicon LLC, Johnson and Johnson Inc., USA) was used to drain the fluid after the cauterization of the choroid. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient was followed up receiving a topical antibiotic (Chlobiotic, Sina Darou, Tehran, Iran) and topical corticosteroid (Bethasonate, Sina Darou, Tehran, Iran) for 3 weeks.\n\nThe patient referred to the hospital with severe visual loss in both eyes 6 weeks later. On examination, BCVA of both eyes was counting finger at one meter and the anterior segment was within normal limits, except 1+ anterior chamber and anterior vitreous cells in both eyes. Bilateral multifocal serous retinal detachment (SRD) was obvious in funduscopy (Fig. 1a, b). The results of enhanced depth imaging optical coherence tomography (EDI-OCT) (Spectralis HRA +OCT, Heidelberg Engineering, Heidelberg, Germany) revealed multilobular SRD, septated subretinal spaces, hyperreflective dot reflexes in subretinal fluid, choroidal thickening, and retinal pigment epithelium undulation (Fig. 1c, d). Chorioscleral junction was not detected due to diffuse severe choroidal thickening. According to the results of examination and imaging, as well as the absence of any other ocular trauma history except for SB surgery, the diagnosis of SO was presumed incited by SB surgery. Therefore, the patient was admitted and received high-dose (1 g/day) intravenous methylprednisolone treatment for 5 days. This five-day pulse therapy led to the control of inflammation and the significant resolution of SRD (Fig. 1e, f). The patient underwent all systemic work-ups for common causes of choroiditis, including sarcoidosis, tuberculosis, syphilis, and autoimmunity markers were inconclusive. Moreover, familial, drug, and past medical history were unremarkable. After pulse therapy, oral prednisolone (50 mg/day) and mycophenolate mofetil (MMF) (2 g/day) were initiated. On the fourth day, fluorescein angiography showed no significant dye pooling except for mild leakage; also, it revealed mixed hypo- and hyper-fluorescent dots scattered at the posterior poles presumably due to choroidal hypoperfusion and abnormal leakage. Since indocyanine green angiography (ICGA) was not available at that time, it was not performed at the first presentation of SO. Prednisolone tapered rapidly due to the increased blood glucose, and subtenon triamcinolone acetonide (TriamHEXAL, Hexal AG, Holzkirchen, Germany) (40 mg/1 cc) was injected bilaterally. Induced diabetes was controlled with oral medication which was stopped after 1 month. Prednisolone was reached to 5 mg/d at the end of the second month with continuing MMF (2 g/d). The blood glucose was checked frequently, which was within normal limits during the follow-up and did not relapse during 6-months follow-ups. Following one-year treatment with MMF 2 g/d and prednisolone 5 mg/d, inflammation was reduced considerably and the retina was attached completely in both eyes. Final BCVA was obtained as 20/20 and 20/50 in the RE and LE, respectively. After 3 months of immunosuppressive treatment, ICGA disclosed only a few hypofluorescent dark dots in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma (Fig. 2).\nFig. 1 Fundus photography of the right (a) and the left (b) eye reveals bilateral disc swelling and multifocal serous retinal detachment at the posterior pole. Enhanced depth imaging optical coherent tomography (EDI-OCT) of the right (c) and the left (d) eye at the first presentation after the development of sympathetic ophthalmia (SO) discloses multi-lobular serous retinal detachment, septate subretinal spaces, hyperreflective dots in subretinal fluid, choroidal thickening, and undulation of the retinal pigment epithelium. The results of EDI-OCT of the right (e) and left (f) eye shows the significant response with resolution of serous retinal detachment and decreased choroidal thickening 5 days after pulse corticosteroid therapy\n\nFig. 2 Indocyanine green angiography of the right (a, b) and the left eye (d, e) at the third month disclosed only a few hypofluorescent dark dots (HDD) in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma. Enhanced depth imaging optical coherent tomography of the right (c) and left (f) eyes at 3 months follow-up showed complete response with resolution of serous retinal detachment and decreased choroidal thickening and inflammation\n\n\n\nDiscussion\nHere, we report a rare case of SO following uncomplicated SB surgery accompanied by cryoretinopexy and SRFD. In this regard, it is recommended that SO be taken into consideration in any case of bilateral panuveitis associated with multiple SRD and a history of penetrating ocular surgery.\n\nIn several studies, the occurrence of SO has been reported after vitreoretinal surgery [2, 4–6]. It is postulated that trauma to the uveal tract in the context of inadvertent perforation, SRFD, or cryotherapy during SB surgery might be related to deliberate uveal antigens, melanin or outer photoreceptor antigens resulting to access to the lymphatic systems of the conjunctival tissue. This process may associated to exciting of delayed hypersensitivity reaction inside the eye [4–6]. The mechanism of hypersensitivity in the sympathizing eye may be due to the exposure of the uveal tissue to the conjunctival lymphatic system leading to a cell-mediated immune response [6]. This mechanism, owing to more uveal incarceration, can explain the relationship between an increase in the trend of transconjunctival sutureless vitrectomy application and a growth in the incidence of SO following vitreoretinal surgery [6]. In our case, SRFD seemingly increased the risk of uveal exposure to conjunctival lymphatic tissue. In a study conducted by Kilmartin et al., it was reported that RRD surgery was the most common procedure associated with the development of SO, with the risk of SO after vitrectomy being as twice as that of external scleral buckling, without any gender predilection [7].\n\nThe onset of SO symptoms after the operation usually occurs between 3 weeks and 6 months after surgery due to delayed hypersensitivity [8]. Regarding the subject in this study, SO was developed 6 weeks later. In a case series study carried out by Ozbek et al. [4], three cases of SO incidence occurred following SB; however, two patients had combined vitrectomy with SB. In the aforementioned research, SO occurred only in one case after encircling buckle combined with 360 indirect retinal photocoagulations and SRFD, in contrast to our case that had only one cryoretinopexy spot and one drainage site. In another similar case report by Parvaresh and Falavarjani, SO was found in a case with a history of SB revision after 4 years. In this case, the second surgery was combined with SRFD and cryoretinopexy [9]. Nonetheless, in our case, SO happened in the first operation without any surgical history.\n\nIn a recent study performed by Tyagi et al., the incidence of SO following vitreoretinal surgery was estimated at 0.038% of all vitrectomy cases, and vice versa, 9% of all cases of SO had vitreoretinal surgery [6]. In this research, 75% of cases underwent multiple ocular surgeries before the development of SO [6]. Furthermore, the most common anterior segment was non-granulomatous uveitis in 50% of subjects, in contrast to SRD occurring in 62.5% of cases [6]. In our case, it was found that anterior segment inflammation was less severe than the posterior segment chorioretinal findings.\n\nMost of the cases presented in studies [4–9] had simultaneous SB and vitrectomy, previous trauma, or multiple surgeries. Nevertheless, the subject of our report had no extensive retinal or uveal tissue manipulation and no combined surgery or previous surgery, highlighting the importance of this report. One of the underlying reasons for this susceptibility might be related to the Asian ethnicity and higher prevalence of Vogt-Koyanagi-Harada (VKH) in this region.\n\nOne of the most important differential diagnoses of our case is related to VKH which is a common uveitis etiology with similar clinical and imaging findings with SO [1, 10]. Although sympathizing eye in SO presents clinically with nongranulomatous uveitis at first, it progresses to granulomatous uveitis afterward [8]. shows three successive stages: posterior uveitis, anterior segment involvement associated with posterior uveitis, and finally anterior granulomatous uveitis. Both anterior and posterior uveitis are present in SO patients within 2 weeks of disease onset [8]. Generally, the main differentiating clue between SO and VKH is the history of prior surgery or trauma in SO. Considering this, in our case, clinical features were more similar to SO than to VKH, as our patient had no systemic sign or symptom attributed to VKH or other systemic diseases causing choroiditis.\n\nThe results of SO imaging, based on FAG, revealed multiple hyperfluorescent pinpoints leakages associated with late pooling resembling VKH and hypofluorescent foci during the early phase of angiography. Moreover, the late phase of FAG showed hyperfluorescence similar to acute posterior multifocal placoid pigment epitheliopathy [10]. In our case, apparently due to the performance of FAG 4 days after the steroid therapy, hyperfluorscence was less prominent than hypofluorescence that was compatible with the location of granuloma and cellular infiltration. The most common features of ICGA imaging are multiple hypocyanescent spots. In the acute phase of SO, EDI-OCT discloses multiple SRD associated with hyperreflective septa, massive choroidal thickening, and loss of normal choroidal vascular architectures, as well as irregular photoreceptor outer segments similar to what was observed in the acute phase of VKH. The visual outcome is worse in SO as compared with VKH disease [8]. Moreover, BCVA was improved in our case due to early diagnosis and prompt, aggressive, and adequate treatment.\n\nIn conclusion, the diagnosis of sympathetic ophthalmia should be taken into account in any case of bilateral uveitis or bilateral SRD following scleral buckling with uveal tract violation, such as cryopexy or SRFD.\n\nAbbreviations\nBCVABest corrected visual acuity\n\nEDI-OCTEnhanced depth imaging optical coherent tomography\n\nOCTOptical coherent tomography\n\nFAGFluorescein angiography\n\nICGAIndocyanine green angiography\n\nRERight eye\n\nLELeft eye\n\nSRDSerous retinal detachment\n\nRRDRhegmatogenous retinal detachment\n\nRPERetinal pigment epithelium\n\nSBScleral buckling\n\nSRFDSubretinal fluid drainage\n\nSOSympathetic ophthalmia\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThe authors would like to express their gratitude to Zahra Emaverdian MSc., Sepideh Nazari Noghabi MSc., Roghaye Kahani BSc., and Roya Gholamzadeh BSc. at Khatam-al-Anbia Eye Hospital, Mashhad, Iran. Moreover, the researchers appreciate the kind supports of Captain Mohammad Mahdi Sarshar.\n\nAuthors’ contributions\nAll the authors contributed significantly to this research and agreed to be accountable for all aspects of the work. SMH took part in patient’s participating in clinical analysis, and interpretation of imaging, and revising the draft. NS, MG, MAz helped to gather the patient’s evaluations and draft the manuscript. MAb participated in the acquisition of clinical data, clinical analysis and interpretation, and revising and finalizing the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThe authors received no funding. It is the authors’ own work, not funded by government or academicals institutes.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study can be provided by the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nNot Applicable.\n\nConsent for publication\nA consent form was obtained from the patient for imaging, data publication, and identifying clinical details.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Arevalo FJ Garcia RA Al-Dhibi HA Sanchez JG Suarez-Tata L Update on sympathetic ophthalmia Middle East Afr J Ophthalmol 2012 19 13 21 10.4103/0974-9233.92111 22346110 \n2. Gass JDM Sympathetic ophthalmia following vitrectomy Am J Ophthalmol 1982 93 552 558 10.1016/S0002-9394(14)77368-4 7081353 \n3. Bilyk JR Enucleation, evisceration, and sympathetic ophthalmia Curr Opin Ophthalmol 2000 11 372 386 10.1097/00055735-200010000-00015 11148706 \n4. Ozbek Z Arikan G Yaman A Oner H Bajin MS Saatci AO Sympathetic ophthalmia following vitreoretinal surgery Int Ophthalmol 2010 30 221 227 10.1007/s10792-009-9313-z 19588077 \n5. Pollack AL McDonald HR Ai E Green WR Halpern LS Jampol LM Sympathetic ophthalmia associated with pars plana vitrectomy without antecedent penetrating trauma Retina. 2001 21 2 146 154 10.1097/00006982-200104000-00008 11321141 \n6. Tyagi M Agarwal K Reddy Pappuru RR Dedhia C Agarwal H Nayak S Sympathetic Ophthalmia after Vitreoretinal surgeries: incidence, clinical presentations and outcomes of a rare disease Semin Ophthalmol 2019 34 3 157 162 10.1080/08820538.2019.1610464 31055985 \n7. Kilmartin DJ Dick AD Forrester JV Sympathetic ophthalmia risk following vitrectomy: should we counsel patients? Br J Ophthalmol 2000 84 5 448 449 10.1136/bjo.84.5.448 10781505 \n8. Yang P Liu S Zhong Z Du L Ye Z Zhou W Kijlstra A Comparison of clinical features and visual outcome between sympathetic Ophthalmia and Vogt-Koyanagi-Harada disease in Chinese patients Ophthalmology. 2019 126 9 1297 1305 10.1016/j.ophtha.2019.03.049 30959067 \n9. Parvaresh MM Falavarjani KG Presumed sympathetic ophthalmia after scleral buckling surgery Retin Cases Brief Rep 2013 7 4 331 333 25383825 \n10. Mahajan S Invernizzi A Agrawal R Biswas J Rao NA Gupta V Multimodal imaging in sympathetic Ophthalmia Ocul Immunol Inflamm 2017 25 2 152 159 10.1080/09273948.2016.1255339 27960610\n\n",
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"keywords": "Case report; Cryoretinopexy; Scleral buckling; Sympathetic ophthalmia; Uveitis",
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"title": "Persumed sympathetic Ophthalmia after scleral buckling surgery: case report.",
"title_normalized": "persumed sympathetic ophthalmia after scleral buckling surgery case report"
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"abstract": "Raynaud's phenomenon (RP) is a medical condition characterized by vasospasm of the digital vessels in the fingers and toes. The prevalence of RP in the general population is estimated at 3-5% and can vary based on climate. It is classified into primary and secondary RP based on causality. RP has been reported in some cases diagnosed with coronavirus disease 2019 (COVID-19) infection. We report the case of a 14-year-old Caucasian female who presented during the pandemic with chief complaints of suicidal ideations and attempted suicide and had a history of attention-deficit hyperactivity disorder (ADHD) and persistent RP after a stimulant trial. After an initial failure of treatment with lisdexamfetamine, she was switched to methylphenidate hydrochloride (MPH). Within two months of starting MPH, the patient noticed skin discoloration of the lower legs and feet along with numbness. The discoloration of skin was mainly limited to her feet and gradually moved up her legs. She was advised to discontinue the MPH, but her symptoms persisted for four more months until her admission. Other etiologies were ruled out by multi-specialties and during her hospitalization. She was started on atomoxetine and buspirone with appropriate dose titration. Post-discharge from the hospital, no improvement was observed in the patient's RP at an outpatient follow-up performed within a month. The development of RP following MPH treatment and its persistence after stopping MPH is a fascinating event. Clinicians should be aware of the potential rare side effects of stimulants and stimulant-like medications, including vascular, hematological, and dermatological effects. Adolescents with ADHD may be particularly distressed by the COVID-19 pandemic and display increased behavioral issues. Stress can be a trigger for RP; therefore, minimizing stress in at-risk patients is essential.",
"affiliations": "Psychiatry, Penn State College of Medicine, Hershey, USA.;Psychiatry, University of Virginia, Charlottesville, USA.;Pediatrics, Pediatric Group of Acadiana, Lafayette, USA.",
"authors": "Laboe|Christopher|C|;Batchelder|Emma|E|;Vasireddy|Deepa|D|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.17647\nDermatology\nPediatrics\nPsychiatry\nPersistent Raynaud's Phenomenon Following Methylphenidate Hydrochloride Use During the COVID-19 Pandemic\nMuacevic Alexander\nAdler John R\nLaboe Christopher 1\nBatchelder Emma 2\nVasireddy Deepa 3\n1 Psychiatry, Penn State College of Medicine, Hershey, USA\n2 Psychiatry, University of Virginia, Charlottesville, USA\n3 Pediatrics, Pediatric Group of Acadiana, Lafayette, USA\nDeepa Vasireddy deepa26vasi@gmail.com\n1 9 2021\n9 2021\n13 9 e176471 9 2021\nCopyright © 2021, Laboe et al.\n2021\nLaboe et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/69323-persistent-raynauds-phenomenon-following-methylphenidate-hydrochloride-use-during-the-covid-19-pandemic\nRaynaud's phenomenon (RP) is a medical condition characterized by vasospasm of the digital vessels in the fingers and toes. The prevalence of RP in the general population is estimated at 3-5% and can vary based on climate. It is classified into primary and secondary RP based on causality. RP has been reported in some cases diagnosed with coronavirus disease 2019 (COVID-19) infection. We report the case of a 14-year-old Caucasian female who presented during the pandemic with chief complaints of suicidal ideations and attempted suicide and had a history of attention-deficit hyperactivity disorder (ADHD) and persistent RP after a stimulant trial. After an initial failure of treatment with lisdexamfetamine, she was switched to methylphenidate hydrochloride (MPH). Within two months of starting MPH, the patient noticed skin discoloration of the lower legs and feet along with numbness. The discoloration of skin was mainly limited to her feet and gradually moved up her legs. She was advised to discontinue the MPH, but her symptoms persisted for four more months until her admission. Other etiologies were ruled out by multi-specialties and during her hospitalization. She was started on atomoxetine and buspirone with appropriate dose titration. Post-discharge from the hospital, no improvement was observed in the patient's RP at an outpatient follow-up performed within a month. The development of RP following MPH treatment and its persistence after stopping MPH is a fascinating event. Clinicians should be aware of the potential rare side effects of stimulants and stimulant-like medications, including vascular, hematological, and dermatological effects. Adolescents with ADHD may be particularly distressed by the COVID-19 pandemic and display increased behavioral issues. Stress can be a trigger for RP; therefore, minimizing stress in at-risk patients is essential.\n\nraynaud’s phenomenon\nmethylphenidate hydrochloride\ncovid-19\nstimulant\nadhd\nsuicide and depression\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\npmcIntroduction\n\nRaynaud's phenomenon (RP) is a medical condition characterized by vasospasm of the digital vessels in the fingers and toes. RP exacerbation occurs by cold, stress, and medications, resulting in changes in the color of the digits, ranging from white to blue to red [1]. The blanching is a result of vasoconstriction/occlusion of precapillary arterioles. Cyanosis occurs due to the deoxygenation of trapped blood in post-capillary venules. Rubor manifests when the ischemia resolves, leading to hyperemia [1]. The prevalence of RP in the general population is estimated at 3-5% and can vary based on climate [2]. An unidentified trigger can lead to a condition known as primary RP. If there is an attributable cause, such as a disease or medication, then the condition is known as secondary RP [1]. Secondary causes include connective tissue diseases and drugs, such as non-selective beta-blockers and stimulants [3]. RP has been reported in some cases diagnosed with coronavirus disease 2019 (COVID-19) infection [4]. It is noteworthy that medical and psychiatric illnesses reported during the COVID-19 pandemic have had varied and unprecedented types of presentations. Numerous studies have documented exacerbation and different manifestations of diseases either due to pandemic-related stress or due to infection and post-infection sequelae [2,5,6]. In this report, we discuss the case of a 14-year-old Caucasian female who presented with chief complaints of suicidal ideations and attempted suicide by overdosing on ibuprofen tablets and had a history of attention-deficit hyperactivity disorder (ADHD) and persistent RP after a stimulant trial. The patient’s identity has been kept confidential in the manuscript.\n\nCase presentation\n\nThe patient was a 14-year-old Caucasian female with a psychiatric history of ADHD and generalized anxiety disorder and no other past medical history. She presented in August 2020 during the COVID-19 pandemic with worsening depression, anxiety, and inattention, following the exacerbation of suicidal ideations secondary to pandemic-related stress and isolation, which had led her to take a handful of ibuprofen pills. The COVID-19 pandemic was described by the patient as a huge stressor, leading to worsening depression and anxiety. At admission, the patient was negative for COVID-19 when tested as part of the initial screening. After being medically cleared, she was admitted to inpatient psychiatry. She had no other past medical, allergic, and surgical history and no history of psychiatric or medical hospitalization. The patient was not on any medications at the time of admission. Baseline investigations including EKG, complete blood count, comprehensive metabolic panel, and thyroid panel were within normal limits.\n\nOn admission, a diagnosis of major depressive disorder (MDD), first episode, severe and ADHD-inattentive type was established. The patient had been diagnosed with ADHD approximately a year ago and started on a trial of lisdexamfetamine. The lisdexamfetamine had been initiated at a dose of 10 mg/day and titrated up to 30 mg/day within a month, and she had continued with this dosage for two months. She had experienced no side effects due to lisdexamfetamine. The patient and her parents had felt that the lisdexamfetamine was not helping with her inattention, and after two months, she had discontinued lisdexamfetamine and switched to methylphenidate hydrochloride (MPH). About six months before the admission, MPH had been initiated and titrated to 60 mg/day within one month. Within two months of starting MPH, the patient had noticed skin discoloration of the lower legs and feet. She had been evaluated by Cardiology and Psychiatry on an outpatient basis and advised to stop MPH. The patient had continued to have waxing and waning of lower leg discoloration that had been nontender and blanched upon palpation for four months until her admission. Her symptoms occurred approximately once per day, usually in the afternoon and with varying duration. Discoloration of the skin had been mainly limited to her feet and had gradually moved up her legs. She believed the discoloration worsened with exposure to cold and was not associated with stress. She experienced numbness of her lower legs and feet but no other accompanying symptoms with the discoloration. She did not have a history of substance use or smoking. Given the multitude of causes of RP, we enquired about any family history of RP, autoimmune diseases, connective tissue diseases, rheumatological, cardiovascular, or neurological diseases, which was negative (Figure 1).\n\nFigure 1 Differential diagnosis and nonpharmacological treatment of Raynaud's phenomenon*\n\n*[7]\n\nADHD: attention-deficit hyperactivity disorder\n\nAccording to a review of the patient's prior history, she had not had a COVID-19 test prior to this admission and the COVID-19 symptom list had been negative within six months leading up to the admission. Around the time of admission, she had a cardiology follow-up with EKG, ultrasound with Doppler of the lower legs, and echocardiography, which were all negative. She had normal blood chemistry and hematology results ruling out other causes of RP. The patient did not have a history of previous use of other psychotropic medications before her admission. During her hospitalization, she was started on atomoxetine 10 mg daily to treat her depression and inattention and the dose was gradually titrated up to 40 mg. Atomoxetine's action as a selective norepinephrine reuptake inhibitor suggested its efficacy as an antidepressant and it was deemed an appropriate option for the patient. She responded well to this medication with no side effects. She was also started on buspirone and titrated up to 10 mg twice daily for her anxiety symptoms. The patient did well with cognitive behavioral therapy skills and other behavioral modification and relaxation techniques that she learned while in the inpatient unit. Post-discharge from the hospital, it was found that there was no improvement in the patient's RP at an outpatient follow-up conducted within a month. The patient continued to remain compliant with her outpatient psychiatry and cardiology appointments.\n\nDiscussion\n\nIt appears that psychostimulants reduce the diameter of the vasculature, which can create filling defects, thereby leading to hypertension [8]. Changes in blood pressure can lead to changes in shearing forces that could damage blood vessels. A case series looking at stimulants leading to RP in adolescents found elevated anti-histone antibodies to measure drug-induced vasculopathy. It was still unclear if the stimulants were a direct cause of the RP or other associated factors [9]. The development of RP following MPH treatment and its persistence after the discontinuation of MPH is a fascinating event. Although the pathogenesis of RP is not well understood, one of the proposed mechanisms is that excess catecholamine release results in a net vasoconstrictive effect [10]. MPH causes a release of catecholamines due to its impact on dopaminergic and noradrenergic systems [11]. Dose-related RP effects while on MPH have been previously reported [10]. The authors were able to identify only one published case series within the past decade describing the relationship between MPH and RP [3]. Another distinct possibility is a latent COVID-19 infection or exacerbation of symptoms of RP secondary to increased anxiety and depression caused by the sense of isolation due to the pandemic [5,12,13]. A previously documented case describes a 19-year-old female who initially developed mild RP that worsened in severity over three years while on MPH and was subsequently diagnosed with systemic sclerosis [3]. Upon discontinuation of the MPH, there was no improvement in her RP symptoms.\n\nIn our patient, the reported discoloration and numbness of feet and lower legs started two months after initiating an MPH trial; however, the same effects did not occur with a two-month trial of lisdexamfetamine. Another interesting observation was the persistence of RP despite stopping the offending agent, which has not been previously reported in the case of stimulants causing RP. One explanation of our patient's uniform, bilateral lower leg, and foot discoloration could be that alpha-2 receptors are more prominent on the distal arteries [14]. It is possible that increased sympathetic noradrenergic nerve activity in response to cold or mental stress occurred at the time of MPH use, in contrast with the lisdexamfetamine trial, resulting in the presence of uniform, bilateral lower legs and feet discoloration [9,14]. Clinicians should be aware of the rare but potential side effects of stimulants and stimulant-like medications, including vascular, hematological, and dermatological effects when selecting medications and considering the side effect profiles of individual drugs [15,16]. RP is associated with other vasoconstrictive medications, including beta-blockers, clonidine, ergot alkaloids, dopaminergic agonists, selective serotonin reuptake inhibitors, cyclosporin, cocaine, and various cancer chemotherapies [17]. The synergistic impact of RP risk and stimulant medication with other RP-associated therapies should be considered when initiating treatment for ADHD. A primary care survey performed during the COVID-19 pandemic measuring depression and suicide risk in adolescents aged 12 to 21 years showed that depression and suicide concerns have increased among adolescents, particularly female adolescents [18]. Adolescents with ADHD may be particularly distressed by the COVID-19 pandemic and display increased behavioral issues [19]. Particular emphasis needs to be placed on increasing social connectivity for teenagers and young adults in these times of enforced social isolation [20].\n\nConclusions\n\nClinician anticipation and awareness of RP as a potential side effect of MPH may lead to earlier recognition and discontinuation of the medication, thereby reducing this effect. It is of paramount importance to perform more studies to identify specific biological and environmental factors leading to the presentation of RP as a result of psychostimulant use in adolescents and young adults. Clinicians need to be mindful of the extreme stress such patients are under, especially secondary to the social isolation in the times of the COVID-19 pandemic. Stress can be a trigger for RP; therefore, minimizing stress in at-risk patients is essential.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Raynaud's phenomenon-an update on diagnosis, classification and management Clin Rheumatol Pauling JD Hughes M Pope JE 3317 3330 38 2019 31420815\n2 Epidemiology of Raynaud’s phenomenon Raynaud’s Phenomenon Maundrell A Proudman SM 21 35 New York, NY Springer 2015\n3 Systemic sclerosis induced by CNS stimulants for ADHD: a case series and review of the literature Autoimmun Rev Meridor K Levy Y 102439 19 2020 31734401\n4 Case report: systemic sclerosis after Covid-19 infection Front Immunol Fineschi S 686699 12 2021 34262566\n5 Posttraumatic stress disorder exacerbation as a result of public masking in times of COVID-19 Prim Care Companion CNS Disord Jolly TS Pandian GS Batchelder E Jain A 20 22 2020\n6 COVID-19 and obsessive-compulsive disorder: the nightmare just got real Prim Care Companion CNS Disord Jain A Bodicherla KP Bashir A Batchelder E Jolly TS 20 23 2021\n7 Raynaud's phenomenon N Engl J Med Wigley FM Flavahan NA 556 565 375 2016 27509103\n8 Blood pressure in children with attention deficit/hyperactivity disorder Paediatr Child Health Grisaru S Yue M Samuel SM Chaput KH Hamiwka LA 0 8 23 2018 http://org.ezaccess.libraries.psu.edu/10.1093/pch/pxx207\n9 Methylphenidate and dextroamphetamine-induced peripheral vasculopathy J Clin Rheumatol Syed RH Moore TL 30 33 14 2008 18431096\n10 OROS-methylphenidate-induced Raynaud's phenomenon: a dose-related side effect J Child Adolesc Psychopharmacol Bayram Ö Hergüner S 521 522 25 2015 26222712\n11 Association between treatment with central nervous system stimulants and Raynaud's syndrome in children: a retrospective case-control study of rheumatology patients Arthritis Rheum Goldman W Seltzer R Reuman P 563 566 58 2008 18240233\n12 COVID-19-induced vestibular neuritis, hemi-facial spasms and Raynaud's phenomenon: a case report Cureus Vanaparthy R Malayala SV Balla M 0 12 2020\n13 Mental health crisis secondary to COVID-19-related stress: a case series from a child and adolescent inpatient unit Prim Care Companion CNS Disord Jolly TS Batchelder E Baweja R 20 22 2020\n14 Mechanisms of Raynaud's disease Vasc Med Cooke JP Marshall JM 293 307 10 2005 16444858\n15 Lisdexamfetamine-associated tonsure trichotillomania (Epub ahead of print) J Clin Psychopharmacol Jolly T Waxmonsky J Baweja R 2020\n16 Bupropion-induced severe leukocytosis Cureus Jolly TS Singh J Baweja R 0 12 2020\n17 Drug-induced Raynaud's phenomenon: beyond β-adrenoceptor blockers Br J Clin Pharmacol Khouri C Blaise S Carpentier P Villier C Cracowski JL Roustit M 6 16 82 2016 26949933\n18 COVID-19 and adolescent depression and suicide risk screening outcomes (Epub ahead of print) Pediatrics Mayne SL Hannan C Davis M 2021\n19 ADHD management during the COVID-19 pandemic: guidance from the European ADHD Guidelines Group Lancet Child Adolesc Health Cortese S Asherson P Sonuga-Barke E 412 414 4 2020 32311314\n20 Rapid systematic review: the impact of social isolation and loneliness on the mental health of children and adolescents in the context of COVID-19 J Am Acad Child Adolesc Psychiatry Loades ME Chatburn E Higson-Sweeney N 1218 1239 59 2020 32504808\n\n",
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"abstract": "To date, only twenty cases of cutaneous legionellosis have been reported. Cutaneous legionellosis has heterogeneous manifestations including abscesses, nodules, and cellulitis. The detection of most cutaneous Legionella species requires specific diagnostic cultures and assays. Herein, we report a case of cutaneous legionella in a hematopoietic cell transplantation recipient with culture-negative nodules unresponsive to empiric antibiotics. We also discuss the varied morphology of cutaneous legionellosis and important diagnostic considerations.",
"affiliations": "Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY Department of Dermatology, Weill Cornell Medical College, New York, NY. markovaa@mskcc.org.",
"authors": "Vaidya|Toral|T|;Schmidt|Elizabeth|E|;Papanicolaou|Genovefa|G|;Hauser|Jocelyn|J|;Lezcano|Cecilia|C|;Tang|Yi-Wei|YW|;Markova|Alina|A|",
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"fulltext": "\n==== Front\n9610776\n20594\nDermatol Online J\nDermatol Online J\nDermatology online journal\n1087-2108\n\n32815687\nnihpa1726211\nArticle\nCutaneous Legionella infections in allogeneic hematopoietic cell transplantation recipients\nVaidya Toral MPH 1\nSchmidt Elizabeth PA-C 2\nPapanicolaou Genovefa MD 23\nHauser Jocelyn PhD 4\nLezcano Cecilia MD 5\nTang Yi-Wei MD PhD 46\nMarkova Alina MD 17\n1 Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA\n2 Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA\n3 Department of Medicine, Weill Cornell Medical College, New York, New York, USA\n4 Clinical Microbiology Service, Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA\n5 Dermatopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA\n6 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA\n7 Department of Dermatology, Weill Cornell Medical College, New York, New York, USA\nCorresponding Author: Alina Markova MD, Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 16 East 60th Street, New York, NY 10022, markovaa@mskcc.org\n22 7 2021\n15 6 2020\n15 6 2020\n23 8 2021\n26 6 13030/qt05f926n7https://creativecommons.org/licenses/by-nc-nd/4.0/ Licensehttps://creativecommons.org/licenses/by-nc-nd/4.0/\nTo date, only twenty cases of cutaneous legionellosis have been reported. Cutaneous legionellosis has heterogeneous manifestations including abscesses, nodules, and cellulitis. The detection of most cutaneous Legionella species requires specific diagnostic cultures and assays. Herein, we report a case of cutaneous legionella in a hematopoietic cell transplantation recipient with culture-negative nodules unresponsive to empiric antibiotics. We also discuss the varied morphology of cutaneous legionellosis and important diagnostic considerations.\n\ncutaneous legionellosis\nhematopoietic cell transplantation recipients\n==== Body\nIntroduction\n\nLegionella species are opportunistic pathogens in humans. Cutaneous legionellosis is an uncommon but important differential diagnosis to consider in immunocompromised patients. Herein, we report a hematopoietic cell transplantation recipient with cutaneous legionella, the varied morphology of cutaneous legionellosis and important diagnostic considerations.\n\nCase Synopsis\n\nA 50-year-old woman with acute myeloid leukemia developed fever, dry cough, and painful erythematous nodules with turbid drainage and surrounding erythema on bilateral lower extremities on day +78 following peripheral blood stem cell transplantation (PBSCT), Figure 1. Sputum culture identified pharyngeal flora and empiric levofloxacin for one week was initiated. Incision and drainage of nodules was performed. Bacterial, fungal, and mycobacterial wound cultures were negative, though Gram stain revealed 1+ Gram-negative rods (GNR). While awaiting wound culture results, trimethoprim/sulfamethoxazole for 10 days and topical mupirocin was initiated for pustular skin/soft tissue infection. Pulmonary symptoms resolved and skin nodules size, drainage, and pain decreased. Following treatment, cutaneous nodules recurred on day +112. Skin 4mm punch biopsies of a left shin nodule revealed a dense acute inflammatory infiltrate with necrotic debris and forms suspicious for bacterial rods on Brown-Hopps stain, some of which appeared intracellular (Figure 2). Periodic acid Schiff diastase and acid-fast bacillistains were negative. Biopsy tissue bacterial Gram stain again revealed 1+ GNR, and culture demonstrated 3+ coagulase-negative staphylococci, consistent with skin flora. Fungal and mycobacterial cultures were negative. A 28-day levofloxacin course was initiated given GNRs on Gram stain and prior improvement on levofloxacin. Broad-range 16S rRNA gene amplification and sequencing of biopsy tissue confirmed Legionella. Because antimicrobials previously used had activity against Legionella, no additional treatment was initiated. Skin lesions resolved following treatment completion.\n\nCase Discussion\n\nTo the best of our knowledge, to date there are twenty confirmed cases of cutaneous legionellosis (Table 1). Seventy percent (N=14) cases occurred in females and 30% (N=6) occurred in males. Patient age of onset ranged from three to 73 years old (average 51.2±21.4 years). Skin manifestations are varied, though abscesses (N=5) and nodules (N=5) were the most common presentations, followed by cellulitis (N=4), ulcers (N=2), bullae (N=1), pustules (N=1), panniculitis (N=1), and diffuse erythema (N=1). Approximately 50% of cutaneous cases were associated with pulmonary legionellosis and spread hematogenously [1]. In non-pulmonary cases, direct inoculation with contaminated water may be the infectious source; the patient in this case bathed in well water.\n\nEighty percent of cases (N=16) were associated with immunosuppression, a risk factor for legionellosis [2]. The majority of these patients (N=9) had a history of hematologic or solid organic malignancy. Systemic antibiotics were initiated in all cases (Table 1). The majority of cases resulted in resolved infection (N=12) or improved cutaneous lesions (N=3). Three of these patients died following presentation. Of these, one death was related to infection (necrotizing soft tissue chest infection) and two were not related to infection (multi-organ failure following worsening respiratory distress, and severe adenoviral hepatitis).\n\nLegionella pneumonias are commonly caused by L. pneumophila serogroup-1 [3], which can be detected by urine antigen testing. However, most cutaneous cases are non-serogroup-1 L. pneumophila or non-L. pneumophila species and therefore require specific diagnostic cultures and assays. Buffered charcoal yeast extract agar is the gold standard and may be used as a “test of cure” for treatment efficacy monitoring. PCR assays targeting 16S rRNA and mip genes are more sensitive for species detection than culture [4]. Though environmental Legionella species could have caused contamination, repeated treatment response with recurrence after treatment discontinuation and visualization of forms suggestive of bacterial rods within tissue biopsy including possibly phagocyted forms in this case are supportive of true infection.\n\nConclusion\n\nCutaneous legionellosis is an uncommon but important infection in the differential diagnosis to consider in immunocompromised patients with culture-negative cutaneous lesions with histologic rods, particularly when the infection is unresponsive to empiric antibiotics. Careful history and early initiation of macrolides or fluoroquinolones may reduce associated morbidity.\n\nPotential conflicts of interest\n\nThis study was supported in part by a grant from the National Cancer Institute, National Institutes of Health, given to the Memorial Sloan Kettering Cancer Center (P30-CA008748). Dr. Markova is supported by a Dermatology Foundation Career Development Award.\n\nFigure 1. Clinical presentation of cutaneous legionellosis in a 50-year-old female with painful erythematous, compressible nodules.\n\nFigure 2. A) Diffuse predominantly neutrophilic inflammatory infiltrate is present in dermis. H&E, 30×. B) Higher magnification showing neutrophils, fibrinoid debris, and possible bacterial forms (arrow). H&E, 600×. C) Brown-Hopps stain highlights a cluster of gram-negative rods (inset), 600×.\n\nTable 1. Clinical characteristics of 20 confirmed cases of cutaneous legionellosis.\n\nCase\tAge\tGender\tSkin manifestation\tPulmonary infection\tMicrobiology\tTreatment\tImmuno-compromised\tInfection outcome\tRef\t\n1\t46\tF\tAbscess\tYes\tL. pneumophila serogroup 3\tErythromycin\tYes (treated with high dose corticosteroid therapy for idiopathic diffuse proliferative glomerulonephritis)\tResolved\t[5]\t\n2\t71\tM\tUlcer\tNo\tL. pneumophila serogroup 4\tErythromycin\tNo\tResolved\t[6]\t\n3\t62\tF\tAbscess\tNo\tL. micdadei\tErythromycin\tYes (treated with prednisone and cyclophosphamide for rapidly progressive glomerulonephritis secondary to necrotizing vasculitis)\tResolved\t[7]\t\n4\t39\tF\tCellulitis\tNo\tL. micdadei\tErythromycin\tYes (renal transplantation)\tResolved\t[8]\t\n5\t66\tM\tCellulitis\tYes\tL. pneumophila\tErythromycin\tYes (follicular lymphoma)\tResolved\t[9]\t\n6\t73\tF\tAbscess\tNo\tL. cincinnatiensis\tClarithromycin\tYes (immunoglobulin A gammopathy, lymphoma)\tResolved\t[10]\t\n7\t9\tF\tAbscess\tNo\tL. micdadei\tClarithromycin\tNo\tResolved\t[11]\t\n8\t63\tF\tBullae\tYes\tL. pneumophila\tCefazolin, imipenem/cilastatin, tobramycin\tNo\tDeath\t[12]\t\n9\t68\tF\tNodule\tNo\tL. maceachernii\tLevofloxacin\tYes (treated with prednisone and methotrexate for polymyalgia rheumatica)\tLesions persisted\t[13]\t\n10\t65\tF\tCellulitis\tYes\tL. pneumophila serogroup 1\tVancomycin, cefepime, erythromycin\tYes (treated with high-dose corticosteroids for Interstitial lung disease and idiopathic thrombocytopenic purpura)\tRelapsing disease, death\t[14]\t\n11\t48\tM\tUlcer\tYes\tL. pneumophila serogroup 5\tTigecycline, moxifloxacin\tYes (liver transplantation)\tImproved\t[15]\t\n12\t66\tF\tCellulitis\tNo\tL. feeleii\tAmoxicillin-clavulanate, levofloxacin\tYes (chronic lymphocytic leukemia)\tUnclear\t[16]\t\n13\t27\tF\tNodule\tYes\tL. pneumophila serogroup 8\tAzithromycin\tYes (pre-B - cell acute lymphoblastic leukemia)\tRelapsing disease, death\t[3]\t\n14\t72\tM\tAbscess\tYes\tL. pneumophila serogroup 1\tLevofloxacin\tYes (rectal adenocarcinoma with lung metastasis)\tResolved\t[17]\t\n15\t70\tF\tNodules\tNo\tL. longbeachae\tCiprofloxacin, azithromycin, rifampin\tYes (long-term corticosteroids for immune thrombocytopenia)\tResolved\t[18]\t\n16\t44\tM\tDiffuse erythema\tYes\tL. pneumophila serogroup 1\tCeftriaxone, doxycycline, moxifloxacin\tNo\tResolved\t[19]\t\n17\t23\tF\tPustules\tNo\tL. feeleii\tMoxifloxacin\tYes (cardiac transplantation)\tResolved\t[1]\t\n18\t3\tM\tNodule\tNo\tL. anisa\tLevofloxacin\tYes (familial hemophagocytic lymphohistiocytosis)\tResolved\t[20]\t\n19\t38\tF\tPanniculitis\tNo\tL. pneumophila\tAzithromycin, ciprofloxacin\tYes (treated with prednisolone and azathioprine for systemic lupus erythematosus and myasthenia gravis)\tImproved\t[21]\t\n20\t50\tF\tNodule\tYes\tLegionella subtype indeterminate\tTrimethoprim-sulfamethoxazole, levofloxacin\tYes (acute myeloid leukemia)\tImproved\t-\n==== Refs\nReferences\n\n1. Verykiou S , Goodhead C , Parry G , Meggitt S . Legionella feeleii: an unusual organism associated with cutaneous infection in an immunocompromised patient. Clin Exp Dermatol. 2018;43 :300–302.29277927\n2. Chow JW , Yu VL . Legionella: a major opportunistic pathogen in transplant recipients. Semin Respir Infect. 1998;13 :132–9. Review.9643391\n3. Padrnos LJ , Blair JE , Kusne S , DiCaudo DJ , Mikhael JR . Cutaneous legionellosis: case report and review of the medical literature. Transpl Infect Dis. 2014;16 :307–14.24628820\n4. Stølhaug A , Bergh K . Identification and differentiation of Legionella pneumophila and Legionella spp. with real-time PCR targeting the 16S rRNA gene and species identification by mip sequencing. Appl Environ Microbiol. 2006;72 :6394–8.16957269\n5. Arnow PM , Boyko EJ , Friedman EL . Perirectal abscess caused by Legionella pneumophila and mixed anaerobic bacteria. Ann Intern Med. 1983;98 :184–5.6824252\n6. Brabender W , Hinthorn DR , Asher M , Lindsey NJ , Liu C . Legionella pneumophila wound infection. JAMA. 1983;250 :3091–2.6644990\n7. Ampel NM , Ruben FL , Norden CW . Cutaneous abscess caused by Legionella micdadei in an immunosuppressed patient. Ann Intern Med. 1985;102 :630–2.3885816\n8. Kilborn JA , Manz LA , O’Brien M , Necrotizing cellulitis caused by Legionella micdadei. Am J Med. 1992;92 :104–6.1731498\n9. Waldor MK , Wilson B , Swartz M . Cellulitis caused by Legionella pneumophila. Clin Infect Dis. 1993;16 :51–3.8448318\n10. Gubler JG , Schorr M , Gaia V , Zbinden R , Altwegg M . Recurrent soft tissue abscesses caused by Legionella cincinnatiensis. J Clin Microbiol. 2001 ;39 :4568–70.11724886\n11. Qin X , Abe PM , Weissman SJ , Manning SC . Extrapulmonary Legionella micdadei infection in a previously healthy child. Pediatr Infect Dis J. 2002;21 :1174–6.12508793\n13. Losanoff JE , Metzler MH , Richman BW , Cotton BA , Jones JW . Necrotizing chest wall infection after blunt trauma: case report and review of the literature. J Trauma. 2002;53 :787–9. Review.12394886\n14. Chee CE , Baddour LM . Legionella maceachernii soft tissue infection. Am J Med Sci. 2007;334 :410–3.18004100\n15. Han JH , Nguyen JC , Harada S , Baddour LM , Edelstein PH . Relapsing Legionella pneumophila cellulitis: a case report and review of the literature. J Infect Chemother. 2010;16 :439–42.20526646\n17. Valve K , Vaalasti A , Anttila VJ , Vuento R . Disseminated Legionella pneumophila infection in an immunocompromised patient treated with tigecycline. Scand J Infect Dis. 2010;42 :152–5.19916901\n18. Loridant S , Lagier JC , La Scola B . Identification of Legionella feeleii cellulitis. Emerg Infect Dis. 2011;17 :145–6.21192884\n19. Barigou M , Cavalie L , Daviller B , Isolation on Chocolate Agar Culture of Legionella pneumophila Isolates from Subcutaneous Abscesses in an Immunocompromised Patient. J Clin Microbiol. 2015;53 :3683–5.26292305\n21. Grimstead D , Tucker D , Harris K , Turner D . Cutaneous Legionella longbeachae Infection in Immunosuppressed Woman, United Kingdom. Emerg Infect Dis. 2015;21 :1426–8.26197048\n22. Thalanayar PM , Holguin F . Rash, disseminated intravascular coagulation and legionella: Episode 10 and a rewind into the past. Respir Med Case Rep. 2015;15 :95–100.26236615\n23. Franco-Garcia A , Varughese TA , Lee YJ , Diagnosis of Extrapulmonary Legionellosis in Allogeneic Hematopoietic Cell Transplant Recipients by Direct 16S Ribosomal Ribonucleic Acid Sequencing and Matrix-Assisted Laser Desorption/lonization Time-of-Flight Mass Spectrometry. Open Forum Infect Dis. 2017;4 :ofx140.28852679\n24. Chitasombat MN , Ratchatanawin N , Visessiri Y . Disseminated extrapulmonary Legionella pneumophila infection presenting with panniculitis: case report and literature review. BMC Infect Dis. 2018;18 :467.30223775\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1087-2108",
"issue": "26(6)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D002648:Child; D003937:Diagnosis, Differential; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D007875:Legionella; D007876:Legionellosis; D008297:Male; D008875:Middle Aged; D017192:Skin Diseases, Bacterial",
"nlm_unique_id": "9610776",
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"pmid": "32815687",
"pubdate": "2020-06-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "6824252;19916901;28852679;30223775;18004100;1731498;12508793;24628820;9643391;12394886;11724886;29277927;6644990;26236615;26197048;20526646;21192884;16957269;3885816;26292305;8448318",
"title": "Cutaneous Legionella infections in allogeneic hematopoietic cell transplantation recipients.",
"title_normalized": "cutaneous legionella infections in allogeneic hematopoietic cell transplantation recipients"
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"abstract": "Flavopiridol and lenalidomide have activity in refractory CLL without immunosuppression or opportunistic infections seen with other therapies. We hypothesized that flavopiridol treatment could adequately de-bulk disease prior to lenalidomide therapy, decreasing the incidence of tumor flare with higher doses of lenalidomide. In this Phase I study, the maximum tolerated dose was not reached with treatment consisting of flavopiridol 30 mg m(-2) intravenous bolus (IVB) + 30 mg m(-2) continuous intravenous infusion (CIVI) cycle (C) 1 day (D) 1 and 30 mg m(-2) IVB + 50 mg m(-2) CIVI C1 D8,15 and C2-8 D3,10,17 with lenalidomide 15 mg orally daily C2-8 D1-21. There was no unexpected toxicity seen, including no increased tumor lysis, tumor flare (even at higher doses of lenalidomide) or opportunistic infection. Significant clinical activity was demonstrated, with a 51% response rate in this group of heavily pretreated patients. Biomarker testing confirmed association of mitochondrial priming of the BH3 only peptide Puma with response.",
"affiliations": "Division of Hematology, Department of Internal Medicine, The Ohio State University, Comprehensive Cancer Center, The Ohio State University, College of Pharmacy, The Ohio State University, Ohio.",
"authors": "Maddocks|Kami|K|;Wei|Lai|L|;Rozewski|Darlene|D|;Jiang|Yao|Y|;Zhao|Yuan|Y|;Adusumilli|Mikhil|M|;Pierceall|William E|WE|;Doykin|Camille|C|;Cardone|Michael H|MH|;Jones|Jeffrey A|JA|;Flynn|Joseph|J|;Andritsos|Leslie A|LA|;Grever|Michael R|MR|;Byrd|John C|JC|;Johnson|Amy J|AJ|;Phelps|Mitch A|MA|;Blum|Kristie A|KA|",
"chemical_list": "D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib; D013792:Thalidomide; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
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"issn_linking": "0361-8609",
"issue": "90(4)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D049109:Cell Proliferation; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005419:Flavonoids; D006801:Humans; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010880:Piperidines; D012008:Recurrence; D013792:Thalidomide; D016896:Treatment Outcome; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "7610369",
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"pages": "327-33",
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"pubdate": "2015-04",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "17003373;17088571;17640369;17954615;17995965;18192508;18427150;18334676;18216293;18981292;19734418;19826119;18708993;21072184;21523725;21606960;22033517;21879809;23063124;23300276;24030098;24092807;24451410;10554012;10811119;10887097;12153166;12451473;12702569;14630924;9427698;10384139;15467457;15930354;15916806;16344317;16750498;16569772;17021321;16840727;17576924",
"title": "Reduced occurrence of tumor flare with flavopiridol followed by combined flavopiridol and lenalidomide in patients with relapsed chronic lymphocytic leukemia (CLL).",
"title_normalized": "reduced occurrence of tumor flare with flavopiridol followed by combined flavopiridol and lenalidomide in patients with relapsed chronic lymphocytic leukemia cll"
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"abstract": "Melioidosis is caused by the environmental bacterium Burkholderia pseudomallei and can present with severe sepsis. Predisposing risk factors are present in 80% of cases. Monoclonal antibodies are increasingly prescribed for varied medical conditions. This report describes the first known case of melioidosis in a patient whose only risk factor for disease is treatment with a monoclonal antibody. Prescribers of monoclonal antibodies and other immunosuppressants should ensure that their patients are aware of the potential risk of melioidosis prior to travel and the precautions that should be taken.",
"affiliations": "Department of Infectious Diseases and Northern Territory Medical Program, Royal Darwin Hospital, Darwin, Northern Territory, Australia.",
"authors": "Commons|R J|RJ|;Grivas|R|R|;Currie|B J|BJ|",
"chemical_list": "D000890:Anti-Infective Agents; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D019980:Amoxicillin-Potassium Clavulanate Combination; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D000068879:Adalimumab",
"country": "Australia",
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"doi": "10.1111/imj.12610",
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"issn_linking": "1444-0903",
"issue": "44(12a)",
"journal": "Internal medicine journal",
"keywords": "Burkholderia pseudomallei; immunosuppression; melioidosis; monoclonal antibody; psoriatic arthritis",
"medline_ta": "Intern Med J",
"mesh_terms": "D000068879:Adalimumab; D019980:Amoxicillin-Potassium Clavulanate Combination; D000890:Anti-Infective Agents; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015535:Arthritis, Psoriatic; D016957:Burkholderia pseudomallei; D006801:Humans; D008297:Male; D008554:Melioidosis; D008875:Middle Aged; D012307:Risk Factors; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "101092952",
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"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Melioidosis in a patient on monoclonal antibody therapy for psoriatic arthritis.",
"title_normalized": "melioidosis in a patient on monoclonal antibody therapy for psoriatic arthritis"
} | [
{
"companynumb": "AU-ABBVIE-15K-008-1390827-00",
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{
"abstract": "The DRESS (drug rash, eosinophilia and systemic symptoms) syndrome, also known as DIHS (drug-induced hypersensitivity syndrome), is a severe idiosyncratic reaction to several drugs, mainly antiepileptics and antibiotics, which can occasionally produce acute liver failure. In this article we present two cases of the DRESS syndrome presenting with severe acute hepatitis, including the first case of DRESS associated with levetiracetam. Although both cases finally resolved with good outcomes, DRESS can lead to acute liver failure and has a bad prognosis when liver damage is present. Rapid diagnosis is crucial since withdrawal of the offending drug is the key of treatment, while the potential role of corticosteroids is discussed.",
"affiliations": "Institut de Malalties Digestives, Hospital Clínic, CIBER de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.",
"authors": "Lens|Sabela|S|;Crespo|Gonzalo|G|;Carrión|Jose A|JA|;Miquel|Rosa|R|;Navasa|Miquel|M|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D004338:Drug Combinations; C028423:Salazopyrine; D012460:Sulfasalazine; D000077287:Levetiracetam; D005944:Glucosamine; D010889:Piracetam",
"country": "Mexico",
"delete": false,
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"issn_linking": "1665-2681",
"issue": "9(2)",
"journal": "Annals of hepatology",
"keywords": null,
"medline_ta": "Ann Hepatol",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D056486:Chemical and Drug Induced Liver Injury; D004338:Drug Combinations; D004342:Drug Hypersensitivity; D004802:Eosinophilia; D005260:Female; D005944:Glucosamine; D006801:Humans; D000077287:Levetiracetam; D008099:Liver; D010889:Piracetam; D012720:Severity of Illness Index; D012460:Sulfasalazine; D013577:Syndrome; D016896:Treatment Outcome",
"nlm_unique_id": "101155885",
"other_id": null,
"pages": "198-201",
"pmc": null,
"pmid": "20526017",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Severe acute hepatitis in the DRESS syndrome: Report of two cases.",
"title_normalized": "severe acute hepatitis in the dress syndrome report of two cases"
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{
"companynumb": "ES-LUPIN PHARMACEUTICALS INC.-2015-02667",
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"activesubstance": {
"activesubstancename": "VALPROIC ACID"
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{
"abstract": "A 63-year-old man was hospitalized for immune check-point inhibitors (ICIs) medicated pneumonitis, secondary to treatment with pembrolizumab for non-small cell lung cancer. He was treated with high dose steroids, mycophenolate mofetil, empiric broad spectrum antibiotics and empiric trimethoprim-sulfamethoxazole and intravenous immunoglobulin. Despite the aforementioned treatment, his condition continued to deteriorate. The patient was admitted to the intensive care unit. While intubated, he underwent bronchoscopy and lavage, which was analyzed for potential infectious agents. Cytomegalovirus (CMV) pneumonia was diagnosed and treated. He passed away despite antiviral treatment and maximal supportive care. CMV infection should be suspected in patients failing to recover from toxicities of ICIs with appropriate immunosuppression.",
"affiliations": "Department of Oncology, Galilee Medical Centre, Nahariya 22100, Israel.;Department of Oncology, Galilee Medical Centre, Nahariya 22100, Israel.;Department of Radiology, Galilee Medical Centre, Nahariya 22100, Israel.;Department of Oncology, Galilee Medical Centre, Nahariya 22100, Israel.",
"authors": "Badran|Omar|O|;Ouryvaev|Anton|A|;Baturov|Veronika|V|;Shai|Ayelet|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2021.2282",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "14(6)",
"journal": "Molecular and clinical oncology",
"keywords": "cytomegalovirus pneumonia; immunosuppressive therapy; immunotherapy; non-small cell lung cancer",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "120",
"pmc": null,
"pmid": "33903826",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "31597674;31008047;29442540;22658127;31871778;27682069;29658856;2690289;30618738;14500230;23753231;31762218;11477447;26371282;8606241;29320654;24086067;28246107",
"title": "Cytomegalovirus pneumonia complicating immune checkpoint inhibitors-induced pneumonitis: A case report.",
"title_normalized": "cytomegalovirus pneumonia complicating immune checkpoint inhibitors induced pneumonitis a case report"
} | [
{
"companynumb": "IL-ALKEM LABORATORIES LIMITED-IL-ALKEM-2021-03704",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "OBJECTIVE\nThe International Lamotrigine Pregnancy Registry monitored for a signal of a substantial increase in the frequency of major congenital malformations associated with lamotrigine exposures in pregnancy over an 18-year period. Key methodological lessons are discussed.\n\n\nMETHODS\nThe strengths and weaknesses of the Registry were assessed using quantifiable methodological and operational parameters including enrollment, completeness of exposure and outcome data reporting, and lost to follow-up. The choice of comparator groups and stopping rules for registry closure were critically evaluated.\n\n\nRESULTS\nThe reliance on voluntary reporting was associated with a clustered geographical distribution of registered pregnancies. The enrollment rate increased over time with new approvals and indications for lamotrigine and publication of interim data. Reporter burden was minimized through a streamlined data collection approach resulting in a high level of completeness of exposure and primary outcome data. Lost to follow-up rates were high (28.5% overall) representing a major limitation; incentives to increase the completeness of reporting failed to reduce rates. A lack of an internal comparator group complicated data interpretation; but external comparisons with multiple external groups allowed an assessment of consistency of outcome data across multiple data sources. A lack of a priori closure criteria prolonged the life of the Registry, and consideration of regulatory guidelines on this subject is encouraged at the time of conception of future registries.\n\n\nCONCLUSIONS\nA successful pregnancy exposure registry requires ongoing flexibility and continuous re-assessment of enrollment, recruitment, and retention methods and the availability of comparison data, throughout its lifecycle.",
"affiliations": "University of North Carolina Wilmington, Wilmington, NC, USA; INC Research LLC, Wilmington, NC, USA.",
"authors": "Sinclair|Susan|S|;Cunnington|Marianne|M|;Messenheimer|John|J|;Weil|John|J|;Cragan|Janet|J|;Lowensohn|Richard|R|;Yerby|Mark|M|;Tennis|Patricia|P|",
"chemical_list": "D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine",
"country": "England",
"delete": false,
"doi": "10.1002/pds.3659",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-8569",
"issue": "23(8)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": "birth defects; lamotrigine; methodology; pharmacoepidemiology; pregnancy; registry",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000927:Anticonvulsants; D005260:Female; D006801:Humans; D007391:International Cooperation; D000077213:Lamotrigine; D059012:Lost to Follow-Up; D017891:Pharmacoepidemiology; D011247:Pregnancy; D012042:Registries; D014227:Triazines",
"nlm_unique_id": "9208369",
"other_id": "HHSPA677055",
"pages": "779-86",
"pmc": null,
"pmid": "24974947",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "11297704;18448870;18062721;2292249;2707392;17261678;14703783;2500206;2909875;16157661;3111880;15509250;15509251;21606453;21670385;22551726;15108247;12366730;10553991;20564430",
"title": "Advantages and problems with pregnancy registries: observations and surprises throughout the life of the International Lamotrigine Pregnancy Registry.",
"title_normalized": "advantages and problems with pregnancy registries observations and surprises throughout the life of the international lamotrigine pregnancy registry"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US05917",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": null,
... |
{
"abstract": "The authors report a 51-year-old women with pharmacoresistant partial epilepsy who tolerated well valproate monotherapy and in combination with several other antiepileptic drugs, but developed symptoms and signs of reversible hepatic failure under a combination of valproate and topiramate. Symptoms resolved after discontinuation of VPA. This case provides further anecdotal evidence that topiramate may increase the risk of liver failure when given in combination with other potentially hepatotoxic antiepileptic drugs.",
"affiliations": "Neurosciences Department University Hospital of Luxemboug, Luxembourg.",
"authors": "Bumb|Anja|A|;Diederich|Nico|N|;Beyenburg|Stefan|S|",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D014635:Valproic Acid",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "5(3)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": null,
"medline_ta": "Epileptic Disord",
"mesh_terms": "D000927:Anticonvulsants; D056486:Chemical and Drug Induced Liver Injury; D004359:Drug Therapy, Combination; D004828:Epilepsies, Partial; D005260:Female; D005632:Fructose; D006801:Humans; D002532:Intracranial Aneurysm; D008111:Liver Function Tests; D008875:Middle Aged; D011183:Postoperative Complications; D000077236:Topiramate; D014635:Valproic Acid",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "157-9",
"pmc": null,
"pmid": "14684351",
"pubdate": "2003-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Adding topiramate to valproate therapy may cause reversible hepatic failure.",
"title_normalized": "adding topiramate to valproate therapy may cause reversible hepatic failure"
} | [
{
"companynumb": "LU-VISTAPHARM, INC.-VER201801-000325",
"fulfillexpeditecriteria": "1",
"occurcountry": "LU",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": n... |
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