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"abstract": "BACKGROUND\nIn-stent restenosis (ISR) is still a recognized clinical problem in the era of drug-eluting stent (DES). Some previous studies have suggested that circulating eosinophils play an important role in both restenosis and thrombosis after DES implantation. However, the contribution of eosinophils to the pathogenesis of ISR has not yet been concisely clarified.\n\n\nMETHODS\nWe present the case of an 83-year-old male Japanese patient with ISR exacerbated by drug-induced severe eosinophilia. He had previous histories of coronary stent implantations by DES and was referred to our hospital because of erythema with severe eosinophilia (maximum was 6500/μl [48% of total white blood cell count]). Around the same time, the patient developed ISR, for which a stent was deployed 2 years earlier. Arterial wall injury due to the increase in circulating eosinophils was verified in several findings, such as the increase of D-dimer and brain natriuretic peptide. In addition, the histology of the resected tissue from erythema demonstrated that the nuclei of endothelial cells were swollen where eosinophils and lymphocytes heavily infiltrated into the extravascular space, suggesting the presence of vascular injury. This injury due to the increase in circulating eosinophils may have a marked impact on the pathologic process of ISR in DES implantation.\n\n\nCONCLUSIONS\nJust a few anecdotal reports are available of ISR occurring in the setting of hypereosinophilia. The clarification of the mechanism in this patient provides a new effective therapeutic strategy against ISR in the setting of DES implantation.",
"affiliations": "Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.;Department of Dermatology, Jikei University School of Medicine, Tokyo, Japan.;Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.;Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.",
"authors": "Yagi|Hiroki|H|;Amiya|Eisuke|E|;Ando|Jiro|J|;Watanabe|Masafumi|M|;Yanaba|Koichi|K|;Ikemura|Masako|M|;Fukayama|Masashi|M|;Komuro|Issei|I|",
"chemical_list": "D007166:Immunosuppressive Agents; D050257:Tubulin Modulators; D017239:Paclitaxel; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.891106",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "15()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D001706:Biopsy; D017023:Coronary Angiography; D001026:Coronary Artery Bypass; D023903:Coronary Restenosis; D003331:Coronary Vessels; D003937:Diagnosis, Differential; D054855:Drug-Eluting Stents; D004802:Eosinophilia; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D017239:Paclitaxel; D011474:Prosthesis Design; D012720:Severity of Illness Index; D020123:Sirolimus; D050257:Tubulin Modulators",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "397-400",
"pmc": null,
"pmid": "25227966",
"pubdate": "2014-09-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19383735;2801737;21376502;16814667;10636274;8180373;14744976;3538819;19234576;18718813;22878464;17510464;16273582;22901886;1732351",
"title": "In-stent restenosis exacerbated by drug-induced severe eosinophilia after second-generation drug-eluting stent implantation.",
"title_normalized": "in stent restenosis exacerbated by drug induced severe eosinophilia after second generation drug eluting stent implantation"
} | [
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"companynumb": "JP-ACTAVIS-2015-10606",
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"abstract": "Primary adrenal lymphoma (PAL) is rare and known to have a predilection for central nervous system (CNS) relapse. A 70-year-old man with a 2-year history of primary aldosteronism presented because of a fever. He was hypotensive, and his adrenal glands were unequivocally enlarged. PAL was diagnosed. Despite showing an initial response to immunochemotherapy, progressive paralysis ensued. Magnetic resonance imaging findings were negative, and rituximab was ineffective. His debilitated condition hindered further chemotherapy. A postmortem examination revealed lymphoma relapse in the systemic peripheral nerves. The sequential presentation of two rare lymphomas implies that PAL might have a predilection for not only the CNS but also peripheral nerves.",
"affiliations": "Division of Hematology, Department of Internal Medicine, Shinshu University School of Medicine, Japan.;Division of Hematology, Department of Internal Medicine, Shinshu University School of Medicine, Japan.;Division of Hematology, Department of Internal Medicine, Shinshu University School of Medicine, Japan.;Division of Hematology, Department of Internal Medicine, Shinshu University School of Medicine, Japan.;Division of Hematology, Department of Internal Medicine, Shinshu University School of Medicine, Japan.;Department of Diagnostic Pathology, Shinshu University School of Medicine, Japan.;Division of Hematology, Department of Internal Medicine, Shinshu University School of Medicine, Japan.;Division of Hematology, Department of Internal Medicine, Shinshu University School of Medicine, Japan.",
"authors": "Nishikawara|Mayuka|M|;Kawakami|Toru|T|;Sakai|Hitoshi|H|;Kawakami|Fumihiro|F|;Nishina|Sayaka|S|;Uehara|Takeshi|T|;Ishida|Fumihiro|F|;Nakazawa|Hideyuki|H|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000069283:Rituximab",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.4085-19",
"fulltext": "\n==== Front\nIntern Med\nIntern. Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32132335\n10.2169/internalmedicine.4085-19\nCase Report\nMagnetic Resonance Imaging-negative, Rituximab-resistant Neurolymphomatosis as a Paradoxical Presentation of Relapsed Primary Adrenal Lymphoma\nNishikawara Mayuka 1 Kawakami Toru 1 Sakai Hitoshi 1 Kawakami Fumihiro 1 Nishina Sayaka 1 Uehara Takeshi 2 Ishida Fumihiro 13 Nakazawa Hideyuki 1 \n1 Division of Hematology, Department of Internal Medicine, Shinshu University School of Medicine, Japan\n\n2 Department of Diagnostic Pathology, Shinshu University School of Medicine, Japan\n\n3 Department of Biomedical Laboratory Medicine, Shinshu University School of Medicine, Japan\nCorrespondence to Dr. Hideyuki Nakazawa, hnaka@shinshu-u.ac.jp\n\n\n5 3 2020 \n1 6 2020 \n59 11 1437 1443\n23 10 2019 14 1 2020 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Primary adrenal lymphoma (PAL) is rare and known to have a predilection for central nervous system (CNS) relapse. A 70-year-old man with a 2-year history of primary aldosteronism presented because of a fever. He was hypotensive, and his adrenal glands were unequivocally enlarged. PAL was diagnosed. Despite showing an initial response to immunochemotherapy, progressive paralysis ensued. Magnetic resonance imaging findings were negative, and rituximab was ineffective. His debilitated condition hindered further chemotherapy. A postmortem examination revealed lymphoma relapse in the systemic peripheral nerves. The sequential presentation of two rare lymphomas implies that PAL might have a predilection for not only the CNS but also peripheral nerves. \n\nneurolymphomatosisprimary adrenal lymphomadiffuse large B-cell lymphoma\n==== Body\nIntroduction\nDiffuse large B-cell lymphoma (DLBCL) arise primarily from extranodal sites in about 30% of cases (1,2). Extranodal involvement is a poor prognostic indicator according to the International Prognostic Index score, a commonly used prognostic tool in patients with DLBCL (3). Certain specific anatomical sites of extranodal involvement are also associated with a poorer outcome, including bone marrow, central nervous system (CNS), liver, gastrointestinal tracts and lungs (2), and these sites were incorporated in a recent prognostic stratification of DLBCL, such as NCCN-IPI (4). However, the site-specific prognostic implication of infrequent extranodal lymphomas is not always clear, as their low incidence in surveillance studies may hinder recognition of any statistical significance concerning the prognosis (2).\n\nThe incidence of primary adrenal lymphoma (PAL) is extremely low, although secondary involvement in the adrenal glands has been described as a relapsed site of DLBCL or as a disseminated lesion of intravascular large B-cell lymphoma without organ specificity (5). Previous studies have suggested that PAL may also follow an aggressive clinical course with its predilection for dissemination into the CNS, although the absolute risk of nervous involvement of extranodal lymphomas in general is still being debated (5,6).\n\nNeurolymphomatosis (NL) is another rare extranodal lymphoma with a nerve-seeking manifestation, disseminating primarily into the peripheral nerves (7,8). Although the affected patients commonly present with neuralgia in the involved sites, the definitive diagnosis of NL may often be delayed, since the presenting symptoms are highly variable and a wide range of differential diagnoses must be ruled out, including therapy-related neuropathy (9). Imaging studies, such as magnetic resonance imaging (MRI) and fluorodeoxyglucose-positron emission tomography (FDG-PET), may alert clinicians to the affected sites and guide a biopsy for the pathological diagnosis (10,11). However, the highly invasive nature of a peripheral nerve biopsy as well as the highly progressive clinical course of NL may often preclude the timely diagnosis and implementation of treatment. Indeed, it is not uncommon for NL to be diagnosed by a postmortem examination (8).\n\nWe herein report a case with a sequential presentation of two rare extranodal lymphomas (PAL and NL). The present case merits reporting not only because it implies a novel insight for the anatomical pattern of disease relapse of PAL but also because it may suggest a sanctuary nature of peripheral nerves.\n\nCase Report\nA 70-year-old man presented to a tertiary university hospital because of a 3-month episode of a fever of unknown origin. He had had a history of primary aldosteronism with a unilateral adrenal mass on the right side requiring antihypertensive agents for the past two years. Three months prior to the presentation, the patient started to complain of malaise, chills and a fever, which had persisted and compromised his general well-being.\n\nThe laboratory tests at the referring hospital showed anemia, thrombocytopenia and an elevated level of lactate dehydrogenase (LDH). Computed tomography (CT) revealed bilateral enlargement of the adrenal glands and hepatosplenomegaly (Fig. 1). He was admitted to the university hospital under suspicion of primary adrenal lymphoma (PAL).\n\nFigure 1. Computed tomography (CT) at presentation revealed bilateral enlargement of the adrenal glands (arrowheads) (a). There was hepatosplenomegaly (b), but no ascites was noted.\n\nAt presentation, he had a fever of over 39℃, heart rate of 122 beats per minute and blood pressure of 91/56 mmHg even after cessation of the antihypertensive drugs. The superficial lymph nodes were not palpable, and distention of the abdomen and pretibial pitting edema were noted on a physical examination. CT revealed no nodal diseases, but its cross section showed that the adrenal glands were 4.3 cm×1.6 cm (right) and 4.0 cm×2.5 cm (left) in size, and the spleen was 12.5 cm×3.6 cm in size.\n\nThe laboratory data showed deteriorated anemia, thrombocytopenia, increased LDH and elevated soluble interleukin-2 receptor. Aldosterone was below the lower limit of normal (Table). A random skin incisional biopsy from the chest, abdomen and thighs, showed that he had no lymphomatous infiltrations, including the subcutaneous vasculature (Fig. 2). A bone marrow biopsy revealed diffuse proliferation of large-sized atypical lymphoid cells. Immunohistochemistry showed positivity for CD20, bcl-6 and MUM-1 and negativity for CD5 and CD10. However, anti-CD34 staining revealed no intravascular infiltration (Fig. 3). EBV in situ hybridization was negative. Intravascular lymphoma was ruled out, and extranodal DLBCL, non-germinal center (non-GC) type, was diagnosed.\n\nTable. Laboratory Data at Admission.\n\nBlood Counts\t\tImmunochemistry\t\nWBC\t\t3.19×103\t/μL\t\tTP\t\t4.5\tg/dL\t\nSEG\t\t65\t%\t\tALB\t\t1.7\tg/dL\t\nBND\t\t16\t%\t\tBUN\t\t18.8\tmg/dL\t\nMON\t\t8\t%\t\tCre\t\t1.04\tmg/dL\t\nLYM\t\t9\t%\t\tAST\t\t98\tU/L\t\nUNC\t\t2\t%\t\tALT\t\t40\tU/L\t\nRBC\t\t3.09×106\t/μL\t\tγGT\t\t50\tU/L\t\nHb\t\t8.5\tg/dL\t\tT-Bil\t\t1.15\tmg/dL\t\nPLT\t\t2.8×104\t/μL\t\tALP\t\t533\tU/L\t\n\t\t\t\t\tLDH\t\t586\tU/L\t\nHemostasis\t\tCRP\t\t9.84\tmg/dL\t\nPT\t\t35\ts\t\tFerritin\t\t1,853\tng/mL\t\nAPTT\t\t40.1\ts\t\tsIL-2R\t\t13,157\tU/mL\t\nFDP-DD\t\t8.9\tμg/mL\t\tCOR\t\t24.1\tμg/dL\t\nFIBG\t\t236\tmg/dL\t\tALD\t\t<25.0\tpg/mL\t\n\t\t\t\t\tACTH\t\t8.2\tpg/mL\t\nWBC: white blood cell, SEG: segmented neutrophil, BND: band neutrophil, MON: monocyte, LYM: lymphocyte, UNC: unclassified cell, RBC: red blood cell, Hb: hemoglobin, PLT: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, FIBG: fibrinogen, TP: total protein, ALB: albumin, BUN: blood urea nitrogen, Cre: creatinine, AST: aspartate aminotransferase, ALT: alanine aminotransferase, γGT: γ-glutamyl transpeptidase, T-Bil: total bilirubin, ALP: alkaline phosphatase, LDH: lactate dehydrogenase, COR: cortisol, ALD: aldosterone, sIL-2R: soluble interleukin-2 receptor, ACTH: adrenocorticotropic hormone\n\nFigure 2. A random skin incisional biopsy revealed no lymphomatous infiltration in the vasculature, with similar findings on (a) Hematoxylin and Eosin staining and (b) CD20 preparations.\n\nFigure 3. A bone marrow biopsy showed infiltration of lymphoma cells. (a) Hematoxylin and Eosin staining showed diffuse proliferation of large-sized lymphoma cells. They were CD20-positive (b) and CD10-negative (c) findings. Both bcl-6 (d) and MUM-1 (e) were positive. CD34 staining revealed no intravascular infiltration of lymphoma cells (f). According to the Hans classification, diffuse large B-cell lymphoma, non-GC type, was diagnosed.\n\nA transjugular liver biopsy was also performed, and proliferation of similar lymphoid cells was found. Although a CT-guided adrenal biopsy was planned, it was withheld because the urgent need for treatment outweighed the need for another confirmatory invasive procedure. Since the bilateral adrenal lesions were deemed dominant compared to other nodal and extranodal lesions, the bilaterally enlarged adrenal glands were considered to be the primary sites of involvement.\n\nImmunochemotherapy with cyclophosphamide, doxorubicin, vincristine (VCR), prednisolone and rituximab was started soon after the diagnosis, which was complicated with tumor lysis syndrome, disseminated intravascular coagulation with splenic hemorrhaging and congestive heart failure. The splenic hemorrhaging required catheter intervention. The laboratory data, such as the abnormal LDH, liver enzymes and DIC parameters, returned to the reference range of normal about two weeks after the administration of rituximab, implying that the first course of the R-CHOP-like regimen had been effective. The clinical course is depicted in Fig. 4.\n\nFigure 4. The clinical course. After R-CHOP-like chemotherapy was administered, the abnormal laboratory data, including total bilirubin and LDH, were ameliorated. Although the treatment was complicated with tumor lysis syndrome, disseminated intravascular coagulation with splenic hemorrhaging and cardiac failure, the primary adrenal lymphoma seemed to respond well to the chemotherapy. Soon after the recovery from the complications, however, the patient experienced bilateral neuralgia and progressive paralysis in the limbs, and bulbar paralysis ensued. While neurological signs and symptoms deteriorated, the level of LDH stayed within the upper limit of the reference range of normal, and no other nodal/extranodal lymphoma lesions were observed. The neurological symptoms seemed to have evolved during an on-going response to the chemotherapy outside of the peripheral nerves. CY: cyclophosphamide, VCR: vincristine, DXR: doxorubicin, Rit: rituximab, r-TM: recombinant thrombomodulin, LDH: lactate dehydrogenase\n\nAt 42 days after admission (2 weeks after the completion of the R-CHOP-like therapy), however, the patient started to experience bilateral neuralgia in the upper and lower extremities. Although this neurological symptom was symmetrical, as in the VCR-induced peripheral neuropathy, it developed more proximally and progressed rapidly. While NL was also suspected, his general condition with a very poor performance status precluded further administration of cytotoxic agents. He instead received a second cycle of rituximab on day 43, but his neurologic impairment deteriorated further during the following weeks. He became quadriplegic around day 50, and dysarthria, dysphagia and diplopia also ensued.\n\nPlain MRI of the spinal cord and the brachial plexus on day 40 revealed that he did not have any compressing mass lesions nor any enlargement in the nerve fibers (Fig. 5). Another MRI scan of the brain on day 48 revealed no cerebral disease, but a small lesion was noted in the pons with a high intensity in T2-weighted imaging, which was compatible with central pontine myelinolysis (Fig. 6). The laboratory data, however, revealed no apparent electrolytic imbalance. Another brain MRI scan on day 55 and 67 showed amelioration of the pontine lesion. A cerebrospinal fluid examination showed total protein 178 mg/dL, glucose 108 mg/dL and increased mononuclear cells (87 cells/μL), most of which were T-cells with class-III cytology. The patient ultimately died from aspiration pneumonia on day 77.\n\nFigure 5. Plain MRI of the brachial plexus on day 40 showed that he had no compressing mass lesions and no enlargement in the nerve fibers.\n\nFigure 6. Brain MRI showed a high intensity on T2-weighted imaging in the pons (arrowhead).\n\nA postmortem examination revealed large-sized lymphoma cells infiltrating the systemic peripheral nerve fibers, including bilateral sympathetic nerves, bilateral brachial plexuses and nerve roots at C5, C7 and C8 (Fig. 7). Group atrophy was found in the iliopsoas and other skeletal muscles adjacent to the lumber plexuses. Lymphomatous infiltration was also observed in the perivascular areas and subpleural areas of the lungs and the Glisson sheath in the hepatoduodenal ligament, mesentery and other connective tissues. The right adrenal gland showed remnants of lymphoma cells and adenoma. No lymphomatous involvement was observed in the bone marrow or CNS. Local gliosis with edema was observed at the central pons, which was compatible with the pathological changes of central pontine myelinolysis. The spleen had a 3-cm hematoma, but there was no lymphomatous infiltration. Intravascular lymphoma was not detected in any organs. Nodal lesions were not detected. The residual lymphoma cells showed identical immunophenotypes to those at the presentation. Neurolymphomatosis as relapsed disease of PAL was thus confirmed.\n\nFigure 7. The postmortem examination revealed neurolymphomatosis. Hematoxylin and Eosin staining of the brachial plexus showed large lymphoma cells infiltrating into the nerve fibers, ×20 (a) and ×200 (b). The lymphoma cells were CD20-positive (c).\n\nDiscussion\nPAL is defined as having the following: (a) adrenal gland involvement, (b) no history of lymphoma elsewhere and (c) adrenal lesions unequivocally dominant if there are other nodal/extranodal lesions (5). In the present case, an adrenal biopsy was withheld at the discretion of the physicians, as the need to promptly implement chemotherapy outweighed the need for another confirmatory biopsy with its procedural risks. Despite the lack of a biopsy of the glands, however, the present case was still considered to have PAL because of the glands' dominant size with bilaterality, the pathological diagnosis of extranodal DLBCL being established with the concurrent bone marrow and liver biopsies and the subsequent adrenal response to immunochemotherapy.\n\nRashidi et al. described some of the demographic, clinical and pathological features commonly found in 187 cases with PAL (5). Among the common features described, B symptoms and a high LDH level as well as bilaterality of adrenal lesions were also found at the presentation in the present case. Adrenal insufficiency at the presentation was another frequent characteristic, being shared by 60% of cases with PAL in previous studies (5,12). However, the present case was preceded by a two-year history of primary aldosteronism, which was a rather atypical presentation for PAL. Such a functional transition of the adrenal glands from a hypertensive to hypotensive state in a short period of time might have been the result of a pathological change in the glands of the present case, with a functional benign adenoma potentially being overridden by an unfunctional highly aggressive lymphoma.\n\nNeurolymphomatosis frequently poses a diagnostic dilemma, as it may often present as an isolated neuropathy without other overt lymphomatous development (10). One of the most remarkable features of the present case was that the NL, as a relapsed disease, had developed during a seemingly ongoing response to chemotherapy at other anatomical sites. Because the initial presentation of NL occurred shortly after the previous round of chemotherapy for PAL, it was a diagnostic challenge to rule out other possible differential diagnoses, such as demyelinating polyneuropathies, VCR-induced neuropathy and virus-associated neuropathy (9,10).\n\nImaging studies, such as MRI and FDG-PET, may alert clinicians to affected sites and facilitate the timely diagnosis and intervention, although the suboptimal sensitivity and specificity of these modalities have also been described (10,11). Indeed, 45% of NL cases were not diagnosed until a postmortem examination, according to a previous review that included case reports published before the introduction of FDG-PET (8). In the present case, non-enhanced MRI of the brachial plexus did not reveal any compressing lesions, enlargement or laterality in the nerve fibers while the bilateral neuropathy was developing aggressively. The unavailability of FDG-PET in the present case might have been part of the reason a pre-mortem diagnosis of neurolymphomatosis was quite challenging. Enhanced MRI or FDG-PET might have been helpful for identifying the localization of peripheral nerve involvement, and their performance should be encouraged when indicated.\n\nAbe et al. summarized the brain MRI changes of 33 patients with intravascular lymphoma and found that hyperintense lesions in the pons were present in 57% of patients, which might have diagnostic implications (13). In the present case, a similar pontine lesion was found on MRI near the onset of neurolymphomatosis, although intravascular lymphoma was ruled out during the initial diagnostic workup for PAL and the autopsy. Such pontine lesions might also be pertinent to PAL and neurolymphomatosis.\n\nOf note: the paradoxical response to immunochemotherapy encountered in the present case may not be exceptional for NL (9,11). Indeed, such a response or treatment resistance of NL seems to be in accordance with the presumed notion that a blood-peripheral-nerve barrier might have prevented the penetration of immunochemotherapeutic agents, as the blood-brain barrier does, making the peripheral nerves sanctuary sites (11).\n\nThis is the first case report to describe a peripheral nervous relapse of PAL. While rare, PAL is a nerve-seeking lymphoma, and more than 10% of cases have been previously reported to relapse in CNS (5). The present case is unique in that the neurolymphomatosis was isolated nervous involvement of PAL without CNS disease. Intravascular lymphoma is another nerve-seeking lymphoma that tends to develop as CNS disease as a result of systemic spread, and the biological similarity between primary CNS lymphoma and intravascular lymphoma has been described (1). However, data on the biological and immunophenotypic associations between NL and PAL are lacking. The sequential presentation of two extremely rare extranodal lymphomas (PAL and NL) in the present case might highlight the possible predilection of PAL for peripheral nerves as well. Because of the time-consuming nature of the accrual of extremely rare extranodal lymphomas like the present case, an analysis of the genetic-phenotypic associations might facilitate our understanding of the site-specific biology and prognosis of PAL and NL.\n\nIn summary, this is the first case report of peripheral nervous relapse of PAL. The sequential presentation of the rare extranodal lymphomas PAL and neurolymphomatosis may support novel insight into the anatomical pattern of disease relapse of PAL as well as the sanctuary nature of peripheral nerves.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Ollila TA , Olszewski AJ \nExtranodal diffuse large B cell lymphoma: molecular features, prognosis, and risk of central nervous system recurrence\n. Curr Treat Options Oncol \n19 : 38 , 2018 .29931605 \n2. Castillo JJ , Winer ES , Olszewski AJ \nSites of extranodal involvement are prognostic in patients with diffuse large B-cell lymphoma in the rituximab era: an analysis of the Surveillance, Epidemiology and End Results database\n. Am J Hematol \n89 : 310 -314\n, 2014 .24273125 \n3. International Non-Hodgkin's Lymphoma Prognostic Factors P . A predictive model for aggressive non-Hodgkin's lymphoma\n. N Engl J Med \n329 : 987 -994\n, 1993 .8141877 \n4. Zhou Z , Sehn LH , Rademaker AW , et al \nAn enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era\n. Blood \n123 : 837 -842\n, 2014 .24264230 \n5. Rashidi A , Fisher SI \nPrimary adrenal lymphoma: a systematic review\n. Ann Hematol \n92 : 1583 -1593\n, 2013 .23771429 \n6. Ferreri AJ \nRisk of CNS dissemination in extranodal lymphomas\n. Lancet Oncol \n15 : e159 -e169\n, 2014 .24694639 \n7. Grisariu S , Avni B , Batchelor TT , et al \nNeurolymphomatosis: an International Primary CNS Lymphoma Collaborative Group report\n. Blood \n115 : 5005 -5011\n, 2010 .20368468 \n8. Baehring JM , Damek D , Martin EC , Betensky RA , Hochberg FH \nNeurolymphomatosis\n. Neuro Oncol \n5 : 104 -115\n, 2003 .12672282 \n9. Gan HK , Azad A , Cher L , Mitchell PLR \nNeurolymphomatosis: diagnosis, management, and outcomes in patients treated with rituximab\n. Neuro-Oncology \n12 : 212 -215\n, 2009 .20150388 \n10. Bourque PR , Warman Chardon J , Bryanton M , Toupin M , Burns BF , Torres C \nNeurolymphomatosis of the brachial plexus and its branches: case series and literature review\n. Can J Neurol Sci \n45 : 137 -143\n, 2018 .29307326 \n11. Matsue K , Hayama BY , Iwama K , et al \nHigh frequency of neurolymphomatosis as a relapse disease of intravascular large B-cell lymphoma\n. Cancer \n117 : 4512 -4521\n, 2011 .21448935 \n12. Mozos A , Ye H , Chuang WY , et al \nMost primary adrenal lymphomas are diffuse large B-cell lymphomas with non-germinal center B-cell phenotype, BCL6 gene rearrangement and poor prognosis\n. Mod Pathol \n22 : 1210 -1217\n, 2009 .19525926 \n13. Abe Y , Narita K , Kobayashi H , et al \nClinical value of abnormal findings on brain magnetic resonance imaging in patients with intravascular large B-cell lymphoma\n. Ann Hematol \n97 : 2345 -2352\n, 2018 .30141061\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "59(11)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "diffuse large B-cell lymphoma; neurolymphomatosis; primary adrenal lymphoma",
"medline_ta": "Intern Med",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D017809:Fatal Outcome; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008279:Magnetic Resonance Imaging; D008297:Male; D009364:Neoplasm Recurrence, Local; D000077162:Neurolymphomatosis; D000069283:Rituximab",
"nlm_unique_id": "9204241",
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"pages": "1437-1443",
"pmc": null,
"pmid": "32132335",
"pubdate": "2020-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19525926;29931605;23771429;30141061;29307326;12672282;20150388;24273125;21448935;24694639;8141877;20368468;24264230",
"title": "Magnetic Resonance Imaging-negative, Rituximab-resistant Neurolymphomatosis as a Paradoxical Presentation of Relapsed Primary Adrenal Lymphoma.",
"title_normalized": "magnetic resonance imaging negative rituximab resistant neurolymphomatosis as a paradoxical presentation of relapsed primary adrenal lymphoma"
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"abstract": "Clozapine was the widely accepted gold standard treatment for treatment resistant psychotic symptoms. Clozapine has efficacy of about 50% and some responding patients have to discontinue it due to serious adverse effects. The search for novel agents to use for clozapine-non-responders continues. One such possible agent is the non-dopaminergic antipsychotic pimavanserin, an inverse agonist of serotonin 5-HT2A receptors which was recently approved for the hallucinations and delusions of Parkinson's Disease Psychosis. We report here the successful results of using pimavanserin in patients with refractory hallucinations and delusions who failed to respond to clozapine. We also report similar results in refractory psychosis patients who did not receive clozapine.\n\n\n\nWe present ten cases of patients with schizophrenia and schizoaffective disorder with refractory hallucinations and delusions who received a trial of pimavanserin when clozapine or multiple antipsychotics failed. Six of ten patients had not responded to a clozapine trial. The subjects' ages ranged between 21 and 77 years and were followed up for several months.\n\n\n\nAll 10 patients with refractory hallucinations and delusions showed marked response to pimavanserin 34 mg/day within 4-8 weeks, with continuation of the response for several months of follow-up. Improvements in negative symptoms and social functioning were also observed in several patients.\n\n\n\nThis series of 10 cases of patients with refractory psychosis who responded to pimavanserin is an important new finding that has never been reported before. Controlled studies comparing clozapine and pimavanserin in refractory schizophrenia are warranted to confirm these clinical observations.",
"affiliations": "Saint Louis University, Department of Psychiatry and Behavioral Neuroscience, St. Louis, MO, United States of America. Electronic address: henry.nasrallah@health.slu.edu.;Saint Louis University, Department of Psychiatry and Behavioral Neuroscience, St. Louis, MO, United States of America.;Saint Louis University, Department of Psychiatry and Behavioral Neuroscience, St. Louis, MO, United States of America.",
"authors": "Nasrallah|Henry A|HA|;Fedora|Rissa|R|;Morton|Robert|R|",
"chemical_list": "D014150:Antipsychotic Agents; D010880:Piperidines; D058830:Serotonin 5-HT2 Receptor Antagonists; D014508:Urea; D003024:Clozapine; C510793:pimavanserin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.schres.2019.02.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-9964",
"issue": "208()",
"journal": "Schizophrenia research",
"keywords": "Clozapine; Pimavanserin; Refractory hallucinations and delusions; Schizophrenia; Serotonin 5HT-2A inverse agonist",
"medline_ta": "Schizophr Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents; D003024:Clozapine; D003702:Delusions; D004351:Drug Resistance; D005260:Female; D006212:Hallucinations; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D011618:Psychotic Disorders; D012189:Retrospective Studies; D012559:Schizophrenia; D058830:Serotonin 5-HT2 Receptor Antagonists; D014508:Urea; D055815:Young Adult",
"nlm_unique_id": "8804207",
"other_id": null,
"pages": "217-220",
"pmc": null,
"pmid": "30837203",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of clozapine-nonresponsive refractory hallucinations and delusions with pimavanserin, a serotonin 5HT-2A receptor inverse agonist.",
"title_normalized": "successful treatment of clozapine nonresponsive refractory hallucinations and delusions with pimavanserin a serotonin 5ht 2a receptor inverse agonist"
} | [
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"companynumb": "US-MYLANLABS-2019M1061059",
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{
"abstract": "Antiangiogenic therapy is a proven therapeutic modality for refractory gastric and gastroesophageal junction adenocarcinoma. This trial assessed whether the addition of a high affinity angiogenesis inhibitor, ziv-aflibercept, could improve the efficacy of first-line mFOLFOX6 (oxaliplatin, leucovorin, and bolus plus infusional 5- fluorouracil) in metastatic esophagogastric adenocarcinoma.\n\n\n\nPatients with treatment-naive metastatic esophagogastric adenocarcinoma were randomly assigned (in a 2:1 ratio) in a multicenter, placebo-controlled, double-blind trial to receive first-line mFOLFOX6 with or without ziv-aflibercept (4 mg/kg) every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS).\n\n\n\nSixty-four patients were randomized to receive mFOLFOX6 and ziv-aflibercept (43 patients) or mFOLFOX6 and a placebo (21 patients). There was no difference in the PFS, overall survival, or response rate. Patients treated with mFOLFOX6/ziv-aflibercept tended to be more likely to discontinue study treatment for reasons other than progressive disease (P = .06). The relative dose intensity of oxaliplatin and 5-fluorouracil was lower in the mFOLFOX6/ziv-aflibercept arm during the first 12 and 24 weeks of the trial. There were 2 treatment-related deaths due to cerebral hemorrhage and bowel perforation in the mFOLFOX6/ziv-aflibercept cohort.\n\n\n\nZiv-aflibercept did not increase the anti-tumor activity of first-line mFOLFOX6 in metastatic esophagogastric cancer, potentially because of decreased dose intensity of FOLFOX. Further evaluation of ziv-aflibercept in unselected, chemotherapy-naive patients with metastatic esophagogastric adenocarcinoma is not warranted.",
"affiliations": "Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.;Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts.;Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.;Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.;Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.;Steele Laboratories for Tumor Biology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.;Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.;Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.;Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.;Vernon Cancer Center, Newton-Wellesley Hospital, Newton, Massachusetts.;Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.;Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.;Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.;Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.;Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.;Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.;Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.;Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.;Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.;Steele Laboratories for Tumor Biology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.;Steele Laboratories for Tumor Biology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.;Steele Laboratories for Tumor Biology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.;Yale Cancer Center, Yale Medical School, New Haven, Connecticut.;Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.",
"authors": "Cleary|James M|JM|0000-0001-7213-3951;Horick|Nora K|NK|;McCleary|Nadine Jackson|NJ|0000-0003-2377-8301;Abrams|Thomas A|TA|;Yurgelun|Matthew B|MB|;Azzoli|Christopher G|CG|;Rubinson|Douglas A|DA|;Brooks|Gabriel A|GA|;Chan|Jennifer A|JA|;Blaszkowsky|Lawrence S|LS|;Clark|Jeffrey W|JW|;Goyal|Lipika|L|;Meyerhardt|Jeffrey A|JA|;Ng|Kimmie|K|;Schrag|Deborah|D|;Savarese|Diane M F|DMF|;Graham|Christopher|C|;Fitzpatrick|Bridget|B|;Gibb|Kathryn A|KA|;Boucher|Yves|Y|;Duda|Dan G|DG|;Jain|Rakesh K|RK|;Fuchs|Charles S|CS|;Enzinger|Peter C|PC|",
"chemical_list": "D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.32029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "125(13)",
"journal": "Cancer",
"keywords": "and oxaliplatin (FOLFOX); angiogenesis; esophageal cancer; fluorouracil; folinic acid; gastric cancer; ziv-aflibercept",
"medline_ta": "Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D004311:Double-Blind Method; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D002955:Leucovorin; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D011379:Prognosis; D013274:Stomach Neoplasms; D015996:Survival Rate",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "2213-2221",
"pmc": null,
"pmid": "30913304",
"pubdate": "2019-07-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "26539453;24292447;24094768;25517747;25002722;21486442;25240821;27091810;27765757;24445500;21844504;23742877;26884585;27382098;27697982;22949147;24557418",
"title": "FOLFOX plus ziv-aflibercept or placebo in first-line metastatic esophagogastric adenocarcinoma: A double-blind, randomized, multicenter phase 2 trial.",
"title_normalized": "folfox plus ziv aflibercept or placebo in first line metastatic esophagogastric adenocarcinoma a double blind randomized multicenter phase 2 trial"
} | [
{
"companynumb": "US-PFIZER INC-2019146908",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
... |
{
"abstract": "Allergic reaction-associated acute coronary syndrome picture is defined as Kounis syndrome. Although drug use is the most common cause of allergic reaction, foods and environmental factors may also play a role in the etiology. Herein, a case with acute coronary syndrome that developed two times at 8-month interval due to pseudoephedrine use for upper respiratory tract infection is presented.",
"affiliations": "Ear, Nose and Throat Clinic, Rize Training and Research Hospital, Islampasa Mah., Sehitler Caddesi, No. 74, 53020 Rize, Turkey.;Department of Cardiology, Faculty of Medicine, Yüzüncü Yıl University, 65080 Van, Turkey.;Private Lokman Hekim Van Hospital, 65100 Van, Turkey.",
"authors": "Celiker|Metin|M|;Tuncer|Mustafa|M|;Sekeralmaz|Ali|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2014/742905",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2014/742905Case ReportA Case with Repeated Recurrent Acute Coronary Syndrome due to Pseudoephedrine Use: Kounis Syndrome Çeliker Metin \n1\n\n*\nTuncer Mustafa \n2\nŞekeralmaz Ali \n3\n1Ear, Nose and Throat Clinic, Rize Training and Research Hospital, Islampasa Mah., Sehitler Caddesi, No. 74, 53020 Rize, Turkey2Department of Cardiology, Faculty of Medicine, Yüzüncü Yıl University, 65080 Van, Turkey3Private Lokman Hekim Van Hospital, 65100 Van, Turkey*Metin Çeliker: meceliker@hotmail.comAcademic Editor: B. Wedi\n\n2014 11 11 2014 2014 7429054 9 2014 16 10 2014 Copyright © 2014 Metin Çeliker et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Allergic reaction-associated acute coronary syndrome picture is defined as Kounis syndrome. Although drug use is the most common cause of allergic reaction, foods and environmental factors may also play a role in the etiology. Herein, a case with acute coronary syndrome that developed two times at 8-month interval due to pseudoephedrine use for upper respiratory tract infection is presented.\n==== Body\n1. Introduction\nKounis syndrome, which is an entity of allergic reaction-associated acute coronary syndrome, is defined as allergic angina/allergic myocardial infarction. This syndrome, which is related to the mediators released from mast cells, was first defined in 1991 by Kounis and Zavras [1]. In 1998, Braunwald [2] reported that vasospastic angina might be associated with allergic reactions. Etiological factors include drug use, foods, and environmental agents. Nonsteroid anti-inflammatory drugs, antibiotics, and sedative and anesthetic agents used for anesthesia are the drugs that have been most frequently associated with Kounis syndrome. To the best of our knowledge, the number of cases with acute coronary syndrome repeated due to the same agent is quite limited in the literature. Herein, a case with acute coronary syndrome that developed two times at 8-month interval due to pseudoephedrine use for upper respiratory tract infection is presented.\n\n2. Case Presentation\nA 43-year-old male patient was admitted to our Emergency Service with chest pain and pain in the left arm lasting for 1 hour. On his physical examination, arterial blood pressure was 100/60 mmHg and pulse rate was 89/min. Cardiovascular auscultation revealed no additional heart sound or murmur. Respiratory system examination was unremarkable. Electrocardiography (ECG) of the patient that was performed in the Emergency Service revealed 90/min sinus rhythm and 1 mm ST depression on the leads D2, D3, aVF, V4, V5, and V6 (Figure 1). The patient was transferred to the Coronary Intensive Care Unit with the diagnosis of acute coronary syndrome without ST elevation. He received 300 mg acetylsalicylic acid (ASA) and 300 mg clopidogrel load via oral route and 5000 IU heparin via intravenous route, and nitroglycerin perfusion was started. Chest pain of the patient relieved and ST depression improved. Routine biochemistry analyses were performed. His chest pain restarted an hour later, and the patient was transferred to the catheterization laboratory for coronary angiography. He underwent right-left selective coronary angiography through the right femoral route. Coronary angiography revealed no significant stenosis in the left anterior descending artery and its branches, circumflex artery and its branches, and right coronary artery and its branches, which could explain the clinical picture (Figure 2). When his medical history was reevaluated, it was learned that he had received pseudoephedrine-containing drug for upper respiratory tract infection. On his blood biochemistry analyses, leukocyte count was 18.000/mm3, hematocrit was 44%, neutrophil was 86%, lymphocyte was 7.8%, eosinophil was 5.1%, troponin T level was 7.11 ng/mL (reference: 0.003–0.014 ng/mL), creatinine kinase (CK) level was 3,445 U/L, CK-MB was 515 U/L, postprandial blood glucose was 115 mg/dL, low-density lipoprotein level was 125 mg/dL, and creatinine level was 0.8 mg/dL. After coronary angiography, the patient who was transferred to the Intensive Care Unit for monitoring had no complaint under medical treatment. The patient, who had had upper respiratory system complaints 3 days ago and received a cold medicine containing pseudoephedrine, was considered to have Kounis syndrome since his coronary angiography was normal. Physical examination revealed no complaint or sign of allergic reaction. On his transthoracic echocardiographic examination, left ventricular ejection fraction was measured to be 65%. Regional wall motion impairment or any other pathology was not determined. Since his cardiac enzymes decreased and he had no complaints during monitoring, he was discharged on the 4th day with ASA 100 mg and atorvastatin 40 mg treatments; he was asked to return for a control visit one month later. The patient was readmitted to our Emergency Service eight months later with similar complaints and it was learned that he had again received a cold medicine containing pseudoephedrine. Anti-ischemic, antiaggregant, and anticoagulant treatments were commenced; ST-T segment changes on his ECG improved and his chest pain relieved.\n\nResults of cardiac enzyme and other blood biochemistry analyses revealed that leukocyte count was 12,000/mm3, neutrophil was 44%, lymphocyte was 51%, eosinophil was 3.2%, troponin was 2.52 ng/mL (reference: 0.003–0.014 ng/mL), CK was 1,309 U/L, CK-MB was 145 U/L, and high-sensitivity C-reactive protein was 15 mg/L. As was at his previous admission, physical examination of the patients revealed no complaint or sign of allergic reaction. His transthoracic echocardiography demonstrated normal left ventricular function with no regional wall motion impairment.\n\nControl coronary angiography was not performed since he was diagnosed with Kounis syndrome at his previous admission, his complaints clinically relieved, and he was hemodynamically stable. The patient, cardiac enzymes of whom decreased and who was free of cardiac complaints during monitoring, was discharged on the 3rd day with ASA and statin treatments. He was referred to the Immunology Polyclinic as he was considered to have allergic angina (Kounis syndrome).\n\n3. Discussion\nThis paper presented a case, who developed Kounis syndrome (allergic angina/allergic myocardial infarction) for two times at 8-month interval each occurring after pseudoephedrine use for upper respiratory tract infection.\n\nEtiological factors of Kounis syndrome include drugs, foods, and environmental agents (insect bite, snakebite, etc.). Although nonsteroidal anti-inflammatory drugs, antibiotics, sedative and anesthetic agents used for anesthesia, and iodine-contrast substances are the drugs that have been most frequently associated with Kounis syndrome [3–5], any kind of drug has the potential of inducing allergic reaction and causing Kounis syndrome. To the best of our knowledge, there is one case of pseudoephedrine-induced Kounis syndrome in the literature. In that case, acute coronary syndrome with ST segment elevation developed following the use of a cold medicine and hypokinesis of the apical septum was detected on the magnetic resonance imaging of the left ventricle [6]. To our knowledge, our patient was the first case in whom recurrent Kounis syndrome developed due to pseudoephedrine use. Vasoactive mediators (histamine, leukotriene, and serotonin) and proteases (tryptase, chymase) are released both locally and into the systemic circulation by mast cell degranulation after contact with the allergens that have a role in the etiology [7]. Among these mediators, histamine and leukotrienes may lead to coronary events via vasoconstriction, whereas proteases lead to coronary events via metalloprotein activation, collagen reduction, and the potential of inducing atheromatous plaque erosion. Moreover, histamine plays a role in thrombocyte aggregation via thrombocyte activation [8, 9]. In our case, pseudoephedrine, a nonselective alpha- and beta-adrenergic receptor activator, might lead to myocardial injury by causing coronary artery spasm.\n\nKounis syndrome has two subtypes. Type 1 has no underlying coronary artery disease or risk factor. Vasoactive mediators that appear due to acute allergic reaction lead to coronary spasm. Chest pain secondary to ischemia and changes in ECG occur. Clinical picture may present in a wide spectrum ranging from unstable angina pectoris to sudden cardiac death. Cardiac enzymes may either be normal or reflect acute myocardial infarction. Type 2 comprises preexisting atheromatous plaque or coronary artery disease. Mediator that is released during acute allergic reaction may cause erosion or rupture of atheromatous plaque. In recent years, a third type has been defined due to widespread use of drug-eluting stents in percutaneous treatment of coronary artery disease. Histopathological examinations of thrombus material in patients presented with acute stent thrombosis have exposed the presence of eosinophils and mast cells [10]. The present case is consistent with type 1 Kounis syndrome since he had no known coronary artery disease or documented angiographic coronary artery stenosis or atheromatous plaque.\n\nThere is no specific pathognomonic test for the diagnosis of Kounis syndrome. The diagnosis is established based on symptoms and signs, ECG changes, laboratory findings, echocardiography, and angiography. Symptoms and signs of acute coronary syndrome and acute allergic reaction should suggest the diagnosis of Kounis syndrome. Patient with coronary syndrome may have angina-like chest pain. On the other hand, symptoms of allergic reaction may be encountered. Symptoms and signs of allergic reaction may include hypotension, pruritus, urticaria, dyspnea, wheezing, nausea, vomiting, and, in severe cases, angioedema after contacting with allergen.\n\nElectrocardiographic findings in Kounis syndrome may be either in the form of nonspecific ST segment and T-wave alterations or normal or in the form of extensive ST segment depression and ST elevation. ST segment alteration is related to coronary vasospasm and most commonly involved derivations are those that reflect the inferior region. Angiographically, right coronary artery is involved most frequently.\n\nLaboratory findings that indicate cardiac injury and allergic reaction are the other important analyses used in the diagnosis of Kounis syndrome. Troponin I/T, CK, CK-MB, and d-dimer are used for differential diagnosis among other causes of cardiac injury and chest pain. Analysis of tryptase concentration, histamine, arachidonic acid derivatives, interleukins, tumor necrosis factor, complement, eosinophil, and total and specific immunoglobulin E levels is recommended to specify the status of allergic reaction [11]. In the present case, the lack of analysis of immunological laboratory markers after pseudoephedrine use is the most significant limitation.\n\nEchocardiography is the other diagnostic tool used in the differential diagnosis of chest pain in a patient with Kounis syndrome. Echocardiography may allow evaluation of left ventricular functions, aortic dissection, pericardial effusion, and acute pulmonary embolus. Regional contraction defects, which are usually reversible, may be encountered in patients with Kounis syndrome.\n\nIn Kounis syndrome, coronary angiography is performed both for diagnostic purpose and for percutaneous treatment, if necessary. In addition, subtype classification could be performed based on coronary angiographic findings.\n\nTreatment of Kounis syndrome focuses on accompanying pathology and has no specific algorithm for treatment. Management of treatment of acute coronary syndrome is also valid for Kounis syndrome. Antiaggregant and anticoagulant treatments should be commenced in all cases with Kounis syndrome accompanied by acute coronary syndrome. Percutaneous intervention should be considered in cases having an underlying coronary lesion responsible for acute coronary syndrome. Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or beta-blockers can be used for long-term taking left ventricular functions into consideration [12].\n\nTreatment of allergic reaction can be performed in accordance with the recommendations of allergy, asthma, and immunology societies [13]. The main goal of treatment should focus on mast cells that play a role in the physiopathology of Kounis syndrome. Corticosteroids, H1 and H2 blockers, and adrenalin have been used for this purpose [14]. The present case was referred to the Immunology Polyclinic for the investigation of sensitivity to pseudoephedrine or other agents and the decision of long-term antiallergic therapy.\n\nRecurrent Kounis syndrome due to same agent is a quite rare condition. There are two cases in the literature. In the first case, it was observed that the patient, in whom clopidogrel treatment was commenced due to the diagnosis of acute coronary syndrome, developed chest pain and ST-T changes after clopidogrel. Similar findings were observed after the second clopidogrel given a day later [15]. In the second case, who was planned to undergo noncardiac surgical procedure under general anesthesia, the surgery was cancelled due to hypotension and ECG alterations developed after remifentanil. Similar clinical picture was observed when the patient again received remifentanil 1 month later for general anesthesia for the same surgery [16]. In the present case, pseudoephedrine use for two times at 8-month interval due to upper respiratory tract infection is in question. Chest pain and ECG changes were observed after pseudoephedrine use. Coronary arteries were normal on coronary angiography. Whilst there was a significant stenosis in coronary arteries in the aforementioned first case, coronary arteries were found to be normal in the second case.\n\nIn conclusion, allergic angina (Kounis syndrome) should be kept in mind in patients who present with acute coronary syndrome in case angiographic findings are inconsistent with clinical manifestation. Attention should be paid that recurrent use of or exposure to the agent that causes Kounis syndrome may lead to recurrent clinical pictures.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 One mm ST depression in the leads D2, D3, aVF, V4, V5, and V612 on electrocardiography of the patient performed at the Emergency Service.\n\nFigure 2 Normal appearance of coronary arteries: (a) left coronary artery system: left anterior descending artery and circumflex, (b) right coronary artery.\n==== Refs\n1 Kounis N. G. Zavras G. M. Histamine-induced coronary artery spasm: the concept of allergic angina British Journal of Clinical Practice 1991 45 2 121 128 2-s2.0-0025740848 1793697 \n2 Braunwald E. Unstable angina: an etiologic approach to management Circulation 1998 98 21 2219 2222 10.1161/01.CIR.98.21.2219 2-s2.0-0032564381 9826306 \n3 Tavil Y. Turfan M. Türkoǧlu S. Abaci A. Kounis syndrome secondary to amoxicillin/clavulanic acid use International Journal of Cardiology 2008 124 1 e4 e7 10.1016/j.ijcard.2006.11.165 2-s2.0-38149142306 17360053 \n4 Mazarakis A. Koutsojannis C. M. Kounis N. G. Alexopoulos D. Cefuroxime-induced coronary artery spasm manifesting as Kounis syndrome Acta Cardiologica 2005 60 3 341 345 10.2143/AC.60.3.2005015 2-s2.0-20444450896 15999477 \n5 Almpanis G. Siahos S. Karogiannis N. C. Kounis syndrome: two extraordinary cases International Journal of Cardiology 2011 147 2 e35 e38 10.1016/j.ijcard.2009.01.031 2-s2.0-79951942073 19203807 \n6 Akoz A. Bayramoglu A. Uzkeser M. Kantarci M. Aksakal E. Emet M. Two questions for Kounis syndrome: can we use magnetic resonance imaging in the diagnosis and does ST elevation correlates with troponin levels? The American Journal of Emergency Medicine 2012 30 9 2086.e5 2086.e7 2-s2.0-84874815877 10.1016/j.ajem.2011.12.016 \n7 Vivas D. Rubira J. C. G. Ortiz A. F. Macaya C. Coronary spasm and hypersensitivity to amoxicillin: kounis or not Kounis syndrome? International Journal of Cardiology 2008 128 2 279 281 10.1016/j.ijcard.2007.06.029 2-s2.0-47749109851 17707099 \n8 Kounis G. N. Kounis S. A. Hahalis G. Kounis N. G. Coronary artery spasm associated with eosinophilia: another manifestation of Kounis syndrome? Heart Lung and Circulation 2009 18 2 163 164 10.1016/j.hlc.2008.09.008 2-s2.0-63249137011 \n9 Kounis N. G. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? International Journal of Cardiology 2006 110 1 7 14 10.1016/j.ijcard.2005.08.007 2-s2.0-33646554451 16249041 \n10 Chen J. P. Hou D. Pendyala L. Goudevenos J. A. Kounis N. G. Drug-eluting stent thrombosis: the Kounis hypersensitivity-associated acute coronary syndrome revisited JACC: Cardiovascular Interventions 2009 2 7 583 593 10.1016/j.jcin.2009.04.017 2-s2.0-67650673809 19628178 \n11 Rico Cepeda P. Palencia Herrejón E. Rodríguez Aguirregabiria M. M. Kounis syndrome Medicina Intensiva 2012 36 5 358 364 10.1016/j.medin.2011.10.008 2-s2.0-84861675393 22154226 \n12 Kushner F. G. Hand M. Smith S. C. Jr. King S. B. III Anderson J. L. Antman E. M. Bailey S. R. Bates E. R. Blankenship J. C. Casey D. E. Jr. Green L. A. Hochman J. S. Jacobs A. K. Krumholz H. M. Morrison D. A. Ornato J. P. Pearle D. L. Peterson E. D. Sloan M. A. Whitlow P. L. Williams D. O. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Journal of the American College of Cardiology 2009 54 23 2205 2241 10.1016/j.jacc.2009.10.015 2-s2.0-70450199115 19942100 \n13 Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, Joint Council of Allergy, Asthma and Immunology The diagnosis and management of anaphylaxis: an updated practice parameter Journal of Allergy and Clinical Immunology 2005 115 S483 S523 10.1016/j.jaci.2005.01.010 15753926 \n14 Ridella M. Bagdure S. Nugent K. Cevik C. Kounis syndrome following beta-lactam antibiotic use: review of literature Inflammation and Allergy-Drug Targets 2009 8 1 11 16 10.2174/187152809787582462 2-s2.0-70349498715 19275688 \n15 Patanè S. Marte F. Currò A. Cimino C. Recurrent acute myocardial infarction and Kounis syndrome International Journal of Cardiology 2010 142 2 e20 e22 10.1016/j.ijcard.2008.11.167 2-s2.0-77953287400 19144425 \n16 Imanishi H. Kitamura A. Maruyama K. Ariyama J. Nakagawa H. Nishibe S. Hayashida M. Usuda Y. Suspected recurrent anaphylaxis in different forms during general anesthesia Journal of Anesthesia 2010 24 1 143 145 10.1007/s00540-009-0839-z 2-s2.0-76649092950 20052499\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2014()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "742905",
"pmc": null,
"pmid": "25435880",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "17360053;19144425;19081300;1793697;15999477;20052499;19942100;19203807;15753926;19275688;22386343;17707099;22154226;9826306;19628178;16249041",
"title": "A Case with Repeated Recurrent Acute Coronary Syndrome due to Pseudoephedrine Use: Kounis Syndrome.",
"title_normalized": "a case with repeated recurrent acute coronary syndrome due to pseudoephedrine use kounis syndrome"
} | [
{
"companynumb": "TR-RANBAXY-2014R1-90398",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PSEUDOEPHEDRINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nLevetiracetam (LEV) is effective in Idiopathic Generalized Epilepsy (IGE) and seems to be a good alternative to valproic acid in women of childbearing age. However, there is lack of approval for this indication as monotherapy. The aim of this study is to assess the efficacy of LEV as a first-line therapy in this population.\n\n\nMETHODS\nThe study is a descriptive analysis of women aged between 16 and 45 years old diagnosed with IGE and treated with LEV as first-line monotherapy. Minimum follow-up was 24 months.\n\n\nRESULTS\n26 women. Mean age: 25.4 years (17-43). 14 Juvenile Myoclonic Epilepsy; 8 Tonic-Clonic Seizures Alone; 4 Juvenile Absence. Mean follow-up: 68.3 months (24-120). 11 patients (40.7%) continued to take LEV as monotherapy, of which 10 were seizure-free, and three (11.5%) continue to be seizure-free after withdrawing LEV. 12 patients (46.2%) required a change of treatment: 25% (3/12) due to lack of efficacy, 42% (5/12) due to adverse effects and 33% (4/12) due to both. Irritability was the most frequent adverse effect. At the last assessment, three patients (11.5%) continued to have seizures despite polytherapy. Estimated retention rates were 78.1% at one year (SE 7.3%) and 51% at 5 years (SE 9.8%). Estimated median retention time is 72 months (CI 95%: 50.9-93.1).\n\n\nCONCLUSIONS\nLEV could be an effective drug as first-line treatment for IGE in women of childbearing potential. The adverse effects are its main limitation. Comparative studies are needed in order to establish it for this indication.",
"affiliations": "Epilepsy Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain.;Epilepsy Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain.;Epilepsy Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain.;Epilepsy Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain.;Epilepsy Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain.;Epilepsy Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain.;Epilepsy Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain.;Epilepsy Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain.;Epilepsy Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain.;Epilepsy Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain.",
"authors": "Ballvé|Alejandro|A|https://orcid.org/0000-0001-7587-2768;Salas-Puig|Javier|J|;Quintana|Manuel|M|https://orcid.org/0000-0003-0288-9088;Campos|Daniel|D|;Llauradó|Arnau|A|;Raspall|Miquel|M|;Fonseca|Elena|E|;Abraira|Laura|L|;Santamarina|Estevo|E|;Toledo|Manuel|M|https://orcid.org/0000-0003-1550-3316",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D014635:Valproic Acid; D010889:Piracetam",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ane.13389",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-6314",
"issue": "143(4)",
"journal": "Acta neurologica Scandinavica",
"keywords": "childbearing; epilepsy; genetic generalized epilepsy; idiopathic generalized; levetiracetam; women",
"medline_ta": "Acta Neurol Scand",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D004829:Epilepsy, Generalized; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077287:Levetiracetam; D010889:Piracetam; D012189:Retrospective Studies; D016896:Treatment Outcome; D014635:Valproic Acid; D055815:Young Adult",
"nlm_unique_id": "0370336",
"other_id": null,
"pages": "407-412",
"pmc": null,
"pmid": "33452703",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Levetiracetam as first-line monotherapy for Idiopathic Generalized Epilepsy in women.",
"title_normalized": "levetiracetam as first line monotherapy for idiopathic generalized epilepsy in women"
} | [
{
"companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-300847",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"d... |
{
"abstract": "We report a case of breast cancer with multiple liver metastases successfully treated with capecitabine monotherapy after failure of combination therapy comprising bevacizumab (Bev) and paclitaxel (PTX). In March 2012, a 67-year-old woman was diagnosed with Stage IV breast cancer with massive pleural effusion. Histological examination showed invasive ductal carcinoma (scirrhous carcinoma) that was positive for hormonal receptor but negative for HER2 expression, and the nuclear grade was 1. She first received chemotherapy to decrease the tumor volume followed by hormonal therapy. After progression, imaging studies showed increased multiple lung and liver metastases and pleural effusion. Subsequently, treatment with combination of Bev and PTX was started from July 2014. After 4 courses of the combination therapy, multiple liver metastases were unchanged, but her liver function was impaired. Hence, she received capecitabine monotherapy (1,800 mg bis in die [BID]; 2-week administration followed by a week of rest). Her liver function improved early, and a partial response (PR) in the multiple liver metastases was achieved 3 months after initiation of therapy. Furthermore, the metastatic lesions were well controlled 4 months later. These findings suggest that the sensitivity to an anticancer agent greatly varies among patients.",
"affiliations": "Dept. of Surgery (Breast Surgery), JCHO Kyoto Kuramaguchi Medical Center.",
"authors": "Ooe|Asako|A|;Suganuma|Yasushi|Y|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000068258:Bevacizumab; D000069287:Capecitabine; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(3)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001943:Breast Neoplasms; D000069287:Capecitabine; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D017239:Paclitaxel; D016879:Salvage Therapy",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "349-51",
"pmc": null,
"pmid": "27067853",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Breast Cancer with Multiple Liver Metastases Successfully Treated with Capecitabine Monotherapy after Failure of Combination Therapy Comprising Bevacizumab and Paclitaxel.",
"title_normalized": "breast cancer with multiple liver metastases successfully treated with capecitabine monotherapy after failure of combination therapy comprising bevacizumab and paclitaxel"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2016RR-119822",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drug... |
{
"abstract": "Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 micrograms/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 micrograms/kg on days -3, -1, and 1, or 0.6 micrograms/kg on days -1 and 1. G-CSF, 5 micrograms/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34(+) cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 x 10(6)/kg (range, 1.3 to 17.6) versus 0.8 x 10(6)/ kg (range, 0.3 to 4.2), P =.0003. The targeted minimum yield of 3 x 10(6) CD34(+) cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF-mobilized group versus 10% of G-CSF-mobilized patients (P =.001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P =.0001) and platelet recovery (day 9 v 10, P =.07) were accelerated, and fewer erythrocyte (3 v 4, P =.02) and platelet (4 v 5, P =.02) transfusions were needed compared with G-CSF-mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P <.0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 microgram/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF-mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.",
"affiliations": "Departments of Medical Oncology and Therapeutics Research, Transfusion Medicine, and Biostatistics, City of Hope National Medical Center, Duarte, CA, USA.",
"authors": "Somlo|G|G|;Sniecinski|I|I|;ter Veer|A|A|;Longmate|J|J|;Knutson|G|G|;Vuk-Pavlovic|S|S|;Bhatia|R|R|;Chow|W|W|;Leong|L|L|;Morgan|R|R|;Margolin|K|K|;Raschko|J|J|;Shibata|S|S|;Tetef|M|M|;Yen|Y|Y|;Forman|S|S|;Jones|D|D|;Ashby|M|M|;Fyfe|G|G|;Hellmann|S|S|;Doroshow|J H|JH|",
"chemical_list": "D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D003520:Cyclophosphamide; D013926:Thrombopoietin; D000069585:Filgrastim; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "93(9)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001781:Blood Component Removal; D001792:Blood Platelets; D001943:Breast Neoplasms; D002945:Cisplatin; D003520:Cyclophosphamide; D005047:Etoposide; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010976:Platelet Count; D011994:Recombinant Proteins; D013926:Thrombopoietin",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "2798-806",
"pmc": null,
"pmid": "10216073",
"pubdate": "1999-05-01",
"publication_types": "D016430:Clinical Trial; D018848:Controlled Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Recombinant human thrombopoietin in combination with granulocyte colony-stimulating factor enhances mobilization of peripheral blood progenitor cells, increases peripheral blood platelet concentration, and accelerates hematopoietic recovery following high-dose chemotherapy.",
"title_normalized": "recombinant human thrombopoietin in combination with granulocyte colony stimulating factor enhances mobilization of peripheral blood progenitor cells increases peripheral blood platelet concentration and accelerates hematopoietic recovery following high dose chemotherapy"
} | [
{
"companynumb": "US-AMGEN-USASP2021031646",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "Background: The current treatment for patients with aspirin-exacerbated respiratory disease (AERD) who have uncontrolled asthma or chronic rhinosinusitis is aspirin desensitization. For patients who are unable to undergo or do not benefit from aspirin desensitization, treatment with biologics is an option, although efficacy data for AERD is scarce. Objective: We reported a series of patients with AERD who were started on omalizumab and measured the outcomes to assess improvement. Methods: Adult patients with AERD who were initiated on omalizumab from January 2007 to January 2018 were included. We compared outcomes 6-12 months before initiating biologic therapy and during the last 6-12 months while they were on biologic therapy. Our study investigated the number of oral steroid courses, short-acting beta-agonists (SABA), antibiotics for sinusitis or pneumonia, emergency department visits, hospitalizations, pulmonary function tests, and changes in controller medications. Results: Twenty-nine patients were placed on omalizumab. Sixty-two percent demonstrated a reduction in the number of steroid courses (p = 0.0014) and number of SABA canisters used (p = 0.0005) during their last 12 months while on omalizumab. Eighty-six percent of the patients with AERD and on omalizumab demonstrated either a decrease in the number of steroid courses or number of SABA canisters used in the last year of the study. The patients with AERD and with concomitant immunoglobulin E (IgE) mediated respiratory disease showed a statistically significant reduction in the number of steroid courses and number of SABA canisters used while on omalizumab for 1 year (p = 0.002 and p = 0.005, respectively), whereas those without concomitant IgE-mediated respiratory disease did not have a substantial reduction in steroids or SABA canisters used. Conclusion: Our case series reported that omalizumab could effectively be used as an adjunct treatment for AERD, but additional larger and longitudinal studies are needed to corroborate these findings.",
"affiliations": "From the Department of Allergy and Immunology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California.;From the Department of Allergy and Immunology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California.;From the Department of Allergy and Immunology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California.;From the Department of Allergy and Immunology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California.;From the Department of Allergy and Immunology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California.;Department of Research and Evaluation, Kaiser Permanente, Pasadena, California.;From the Department of Allergy and Immunology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California.",
"authors": "Jean|Tiffany|T|;Eng|Victoria|V|;Sheikh|Javed|J|;Kaplan|Michael S|MS|;Goldberg|Bruce|B|;Jau Yang|Su|S|;Samant|Shefali|S|",
"chemical_list": "D018926:Anti-Allergic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D013256:Steroids; D000069444:Omalizumab; D007073:Immunoglobulin E; D001241:Aspirin",
"country": "United States",
"delete": false,
"doi": "10.2500/aap.2019.40.4241",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1088-5412",
"issue": "40(5)",
"journal": "Allergy and asthma proceedings",
"keywords": null,
"medline_ta": "Allergy Asthma Proc",
"mesh_terms": "D000328:Adult; D018926:Anti-Allergic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D055963:Asthma, Aspirin-Induced; D005260:Female; D006760:Hospitalization; D006801:Humans; D007073:Immunoglobulin E; D008297:Male; D008875:Middle Aged; D000069444:Omalizumab; D012120:Respiration Disorders; D013256:Steroids; D016896:Treatment Outcome",
"nlm_unique_id": "9603640",
"other_id": null,
"pages": "316-320",
"pmc": null,
"pmid": "31514790",
"pubdate": "2019-09-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effect of omalizumab on outcomes in patients with aspirin-exacerbated respiratory disease.",
"title_normalized": "effect of omalizumab on outcomes in patients with aspirin exacerbated respiratory disease"
} | [
{
"companynumb": "US-BAYER-2019-182759",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "BACKGROUND\nThe role of antitumour necrosis factor agents, in particular infliximab in ulcerative colitis (UC) has been well established. More recently adalimumab, a fully humanized antitumour necrosis factor α monoclonal antibody, was licensed for refractory moderately active UC in 2012. Available outcome data for adalimumab from routine clinical practice is limited.\n\n\nOBJECTIVE\nTo evaluate the clinical response and remission to adalimumab in a cohort of UC patients.\n\n\nMETHODS\nPatients with UC treated with adalimumab were identified from our inflammatory bowel disease database from 2007. A retrospective chart review was undertaken. Demographic and clinical data were recorded including a Mayo score and C-reactive protein (CRP) where available. All patients received standard induction subcutaneous therapy (160/80/40 mg) followed by a maintenance dose of 40 mg fortnightly. Clinical and biochemical response was assessed at 6 and 12 months. Clinical response was defined by a reduction in Mayo score more than or equal to 3, whereas clinical remission was defined by a total score of 2 or less. Dose adjustments and adverse events were also noted.\n\n\nRESULTS\nIn all, 52 patients were identified. Of these, 65% (n=34) were male and the mean age was 45 years (range 23-72 years). A total of 65% (n=34) had left sided disease, 31% (n=16) pancolitis and 4% (n=2) proctitis. The majority commenced adalimumab due to a loss of response to immunomodulator therapy (n=45, 87%), whereas the remaining 13% (n=7) had loss of response or been intolerant to infliximab. The mean disease duration was 8 years (1-29 years). At baseline 85% (n=44) had moderate disease and 15% (n=8) had mild disease. The baseline mean CRP was 13.5 mg/l (range 1-82 mg/l) and the mean Mayo score was 6 (range 4-10). The mean duration of treatment was 18.5 months (range 4-95 months). Follow-up data was available in 46 (88%) and 37 (71%) patients at 6 and 12 months. Overall there was a statistically significant improvement in mean partial Mayo score on follow-up; 6 months=2 [P=0.0001, 95% confidence interval (CI) 2.99-4.55], 12 months=2 (P=0.0001, 95% CI 2.74-4.46). While 65% (n=34) and 52% (n=27) had a clinical response at 6 and 12 months, respectively, 52% (n=27) and 42% (n=22) were in remission. Overall mean CRP normalized at 6 months (P=0.002, 95% CI 3.31-15.1). Of note 25% (n=13) required dose escalation during follow-up, while treatment was discontinued by seven patients, five (71%) due to a loss of response, the remaining two (29%) due to an adverse event.\n\n\nCONCLUSIONS\nOur study shows adalimumab is an effective and safe long-term therapy for moderately active UC refractory to other treatments. While this data is encouraging, further work is required on patient selection and to determine the impact of treatment on both natural history and quality of life.",
"affiliations": "aDepartment of Gastroenterology, Adelaide and Meath Hospital bDepartment of Gastroenterology, St James' Hospital, Trinity College Dublin cTrinity Academic Gastroenterology Group, Dublin, Republic of Ireland.",
"authors": "Hussey|Mary|M|;Mc Garrigle|Robert|R|;Kennedy|Una|U|;Holleran|Grainne|G|;Kevans|David|D|;Ryan|Barbara|B|;Breslin|Niall|N|;Mahmud|Nasir|N|;McNamara|Deirdre|D|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000000515",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "28(2)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents; D003093:Colitis, Ulcerative; D003430:Cross-Sectional Studies; D016208:Databases, Factual; D004334:Drug Administration Schedule; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D007494:Ireland; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "217-21",
"pmc": null,
"pmid": "26587866",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Long-term assessment of clinical response to adalimumab therapy in refractory ulcerative colitis.",
"title_normalized": "long term assessment of clinical response to adalimumab therapy in refractory ulcerative colitis"
} | [
{
"companynumb": "US-JNJFOC-20150603439",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Bell's palsy is one of the most common neurologic disorders affecting the seventh cranial nerve. Several disease states have been associated with facial paralysis. Drugs, however, have been rarely implicated as an etiology. We describe a 49-year-old man who developed peripheral facial paralysis after 3 weeks of linezolid therapy, along with recurrence of symptoms on rechallenge. He had insulin-dependent diabetes mellitus and a longstanding history of bilateral diabetes-related foot problems. After hospitalization, debridement, and vancomycin therapy for methicillin-resistant Staphylococcus aureus osteomyelitis, the patient was discharged to home with oral linezolid therapy. On day 23 of linezolid therapy, he developed signs and symptoms that were consistent with Bell's palsy. Linezolid was discontinued; the Bell's palsy gradually improved, with complete resolution occurring at month 3. On rechallenge with linezolid for recurrent osteomyelitis, the patient developed a second episode of Bell's palsy within a similar time frame as in the first episode. Assessment of causality using the Naranjo adverse drug reaction probability scale revealed a probable relationship between this adverse drug event and linezolid therapy. Clinicians should be aware that Bell's palsy may be another neuropathic adverse effect associated with linezolid.",
"affiliations": "Department of Pharmacy, Cambridge Health Alliance, Somerville, Massachusetts 02143, USA.",
"authors": "Thai|Xia C|XC|;Bruno-Murtha|Lou Ann|LA|",
"chemical_list": "D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": "10.1592/phco.26.8.1183",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "26(8)",
"journal": "Pharmacotherapy",
"keywords": null,
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000081:Acetamides; D000890:Anti-Infective Agents; D020330:Bell Palsy; D003922:Diabetes Mellitus, Type 1; D016903:Drug Monitoring; D006801:Humans; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D010019:Osteomyelitis; D023303:Oxazolidinones",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "1183-9",
"pmc": null,
"pmid": "16863496",
"pubdate": "2006-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Bell's palsy associated with linezolid therapy: case report and review of neuropathic adverse events.",
"title_normalized": "bell s palsy associated with linezolid therapy case report and review of neuropathic adverse events"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-08534",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "5",
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"activesubstancename": "LINEZOLID"
},
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{
"abstract": "Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder with clinical features consisting of poikiloderma, skeletal abnormalities, sparse hair, absent or scanty eyelashes and eyebrows and short stature. Patients with RTS due to genetic mutations of RECQL4 genes carry a high risk of developing osteosarcoma during childhood. Because of this, early genetic diagnosis is important. Here, we describe a 14-year-old white boy who developed an erythematous rash on both cheeks before the age of 3 months and was noted to have absent eyelashes and scanty eyebrows. He was found to have compound heterozygous mutations of the RECQL4 gene alleles at the age of 6 months and was diagnosed to have RTS type II. He subsequently developed osteosarcoma at age 10 which was successfully treated, and currently he has been tumour free for over 3 years.",
"affiliations": "Department of Combined Medicine-Pediatrics Residency Program, Hurley Medical Center, Flint, Michigan, USA.;Department of Pediatics, Hurley Medical Center, Flint, Michigan, USA.;Department of Combined Medicine-Pediatrics Residency Program, Hurley Medical Center, Flint, Michigan, USA.",
"authors": "Salih|Anas|A|;Inoue|Susumu|S|;Onwuzurike|Nkechi|N|",
"chemical_list": "C506731:RECQL4 protein, human; D053484:RecQ Helicases",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-222384",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "congenital disorders; dermatology; genetics; paediatric oncology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000293:Adolescent; D006801:Humans; D008297:Male; D009154:Mutation; D012516:Osteosarcoma; D053484:RecQ Helicases; D011038:Rothmund-Thomson Syndrome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29367366",
"pubdate": "2018-01-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18346259;12734318;9787328;18716613;20503338;28572264;20113479;18647888;17264332;24518840;9727245",
"title": "Rothmund-Thomson syndrome (RTS) with osteosarcoma due to RECQL4 mutation.",
"title_normalized": "rothmund thomson syndrome rts with osteosarcoma due to recql4 mutation"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/18/0096511",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
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{
"abstract": "Crystals are particles of endogenous inorganic or organic composition that can trigger kidney injury when deposited or formed inside the kidney. The most common forms of crystalline nephropathies (CNs) are nephrocalcinosis and oxalate nephropathy. The causes of early allograft dysfunction are changing constantly, and recently calcium oxalate (CaOx) crystal deposition has been added to this list. CaOx deposition in renal allograft is important and probably under-recognized cause of delayed graft function that requires adequate awareness with early intervention to improve the allograft outcome. Here, we describe four cases of irreversible renal graft injury due to CNs.",
"affiliations": "Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia.;Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia.;Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia.;Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia.;Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia.;Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia.;Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia.;Department of Pathology Laboratory, Habib Bourguiba Hospital, Sfax, Tunisia.;Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia.",
"authors": "Mnif|K|K|;Yaich|S|S|;Mars|M|M|;Kammoun|K|K|;Fendri|F|F|;Charfeddine|K|K|;Jarraya|F|F|;Boudawara|T|T|;Hachicha|J|J|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijn.IJN_76_17",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-28-47210.4103/ijn.IJN_76_17Case ReportCrystalline Nephropathy in Renal Transplant: A Series of 4 Cases Mnif K. Yaich S. Mars M. Kammoun K. Fendri F. Charfeddine K. Jarraya F. Boudawara T. 1Hachicha J. Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia1 Department of Pathology Laboratory, Habib Bourguiba Hospital, Sfax, TunisiaAddress for correspondence: Dr. K. Mnif, Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia. E-mail: kamour85@yahoo.frNov-Dec 2018 28 6 472 476 Copyright: © 2018 Indian Journal of Nephrology2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Crystals are particles of endogenous inorganic or organic composition that can trigger kidney injury when deposited or formed inside the kidney. The most common forms of crystalline nephropathies (CNs) are nephrocalcinosis and oxalate nephropathy. The causes of early allograft dysfunction are changing constantly, and recently calcium oxalate (CaOx) crystal deposition has been added to this list. CaOx deposition in renal allograft is important and probably under-recognized cause of delayed graft function that requires adequate awareness with early intervention to improve the allograft outcome. Here, we describe four cases of irreversible renal graft injury due to CNs.\n\nCrystalline nephropathyhyperoxaluriarenal allograft dysfunction\n==== Body\nIntroduction\nCrystalline nephropathies (CNs) refer to renal parenchymal deposition of crystals leading to kidney damage. The most common forms of CN encountered in renal pathology are nephrocalcinosis and oxalate nephropathy. Less frequent types include urate nephropathy, cystinosis, dihydroxyadeninuria, and drug-induced CN (e.g., caused by indinavir or triamterene). Monoclonal proteins can also deposit in the kidney as crystals and cause tissue damage.[1] Oxalate is the ionic form of oxalic acid and is derived from various animal and plant sources. Oxalate is excreted mainly through the kidneys. Hyperoxaluria is a state of disordered metabolism characterized by an increased urinary excretion of oxalate. The normal daily oxalate excretion in healthy individuals ranges between 10 and 40 mg per 24 h. Concentrations exceeding 40–45 mg per 24 h are considered as clinical hyperoxaluria.[2] This may result from increased endogenous production of oxalate in primary hyperoxaluria (PH), from increased in dietary and intestinal absorption (enteric hyperoxaluria), increased intake of oxalate precursors or alteration in intestinal microflora in secondary hyperoxaluria (SH).[2] The causes of early allograft dysfunction are changing constantly, and recently calcium oxalate (CaOx) crystal deposition has been added to this list.[3] Deposition of CaOx crystal in renal tubules can be seen in >50% of allograft biopsies performed <3 months post-transplant.[4] Although the presence of CaOx crystal in allografts can be benign, when present in moderate intensity, it contributes to increased incidence of acute tubular necrosis and poor allograft survival.[34] Systemic oxalosis should be prevented, but the diagnosis is often delayed in more than 40% of patients. In a survey by Hoppe and Langman, 30% of the patients were diagnosed only when they had already reached end-stage kidney disease (ESKD).[5] In some cases, the diagnosis is made after the disease recurs following renal transplant. Hyperoxaluria continues to be a challenging disease, and appropriate treatment requires a high index of suspicion and timely diagnosis. The aim of this presentation is to underline the causes of crystal nephropathy in allografts kidney and the related pathophysiologic mechanisms, which are involved, along with the description of four cases of irreversible renal graft injury due to CNs.\n\nCase Reports\nCase 1\nA 33-year-old female was on maintenance hemodialysis (HD) for ESKD of unknown etiology. She had first presented 10 years earlier with renal failure when she was found to have bilateral small kidneys on ultrasound examination. Serum and urinary oxalate were not tested because no obvious indication existed then. She received a renal allograft from a living related donor (mother) with a human leukocyte antigen (HLA) mismatch of two. The patient and the donor did not have personal or family history of urolithiasis and their abdominal radiographs were normal. Post-transplant immunosuppressive (IS) treatment included anti-thymocyte globulin (ATG) antibodies as induction agent and corticosteroids, mycophenolate mofetil (MMF), and tacrolimus as maintenance therapy. After surgery, diuresis occurred immediately and her serum creatinine (SCr) levels fell to 300 μmol/L by the 3rd day. However, on day 6 post transplantation, SCr levels went up to 587 μmol/L with reduced urine output. The blood tacrolimus level at this stage was 12 ng/mL. Doppler ultrasound of the graft was normal and there were no features of ureteric obstruction or vascular thrombosis. She underwent an allograft biopsy, which revealed wide-spread tubular degenerative changes typical of acute tubular necrosis and intratubular oxalate crystals. When viewed under polarized light, the tubular oxalate deposits appeared birefringent [Figure 1]. After the biopsy, the patient admitted to have taken at least 2 g/day of Vitamin C daily for several years. There was no specific indication for Vitamin C, but it was prescribed systematically for all patients in her dialysis unit, probably to optimize iron therapy. A 24-h urinary oxalate measurement performed in the donor was 117 μmol/L (normal values: 100–700 μmol/24 h). Bone marrow aspiration was performed, which showed extensive CaOx deposits. After reviewing the biopsy reports, besides advising to avoid high-oxalate foods, we prescribed diuretics (furosemide 1000 mg/day to augment urine output hoping to decrease supersaturation of CaOx and crystal formation) and pyridoxine 300 mg/d to try and eliminate the excess oxalate load. She also received daily HD sessions; however, there was no improvement in her graft function, and the patient returned to maintenance dialysis.\n\nFigure 1 Proximal tubules with diffuse degenerative changes typical of acute necrosis and tubular calcium oxalate crystals (H and E, ×200)\n\nCase 2\nA 50-year-old man was diagnosed as ESKD due to unknown etiology since 2007. He had a strong family history of urolithiasis in his father and sister. However, they were not evaluated. He received a preemptive living-related kidney transplant in 2010. The donor was his mother with 3 HLA mismatches. She did not have a history of urolithiasis, and her abdominal radiograph was normal. Posttransplant immunosuppression treatment included induction with anti-thymoglobulin antibodies, and he was maintained on corticosteroids, MMF, and cyclosporin. Posttransplant, the patient developed delayed graft function (DGF) and slow recovery of allograft function with reduction of SCr to 400 μmol/L over 9 days. The cyclosporine trough level was 150 ng/ml. Doppler ultrasound of the graft was normal, and there were no features of obstruction or vascular thrombosis. He underwent an allograft biopsy, which revealed medullary tissues without tubulitis. Twenty-eight days after transplantation, evolution was marked by spontaneous decrease in SCr to 155 μmol/L. However, the patient developed four episodes of septicemia (Escherichia coli) due to a vesicoureteral reflux Stage IV requiring ureteric reimplantation. He was treated with imipenem and ciprofloxacin. At 18 months posttransplant, the patient was hospitalized due to increasing SCr at 250 μmol/L. Ultrasound examination of the graft and venous duplex of renal vessels were normal. The second allograft biopsy showed tubular atrophy with the presence of CaOx crystals deposition (multicolored birefringence polygonal crystals under polarized light) [Figure 2]. Re-examination of the first graft biopsy confirmed the absence of birefringent deposits in polarized light. In the donor, 24-h urine examination for oxaluria was negative. In view of CaOx deposition, clinical evaluation performed for secondary hyperoxaluria (enteric hyperoxalosis, MMF-induced diarrhea, excessive oral intake of oxalate-containing foods including Vitamin C, ethylene glycol intoxication, or use of methoxyflurane), which was found to be negative. When SCr was 400 μmol/L, urinary pH was 7.2.\n\nFigure 2 Tubular calcium oxalate deposits appear birefringent under polarized light (H and E, ×200)\n\nCase 3\nThe patient was a 28-year-old man treated with maintenance hemodialysis since 1998 because of ESKD of an unknown etiology discovered in 1997. Renal biopsy was not performed as both kidneys were small at presentation. Neither self nor family history of urolithiasis or renal disease was reported. In 1999, the patient received a living-related kidney transplant. The donor was his 51-year-old mother, who had a good health with no medical history or physical abnormality at the pretransplantation check-up. Immunosuppression treatment composed of ATG for 10 days, cyclosporin, corticosteroids, and azathioprine. Because of persistent anuria after surgery, duplex ultrasound examination was performed and showed no blood flow in the graft vein. Surgical exploration 6 h after graft found a pleated graft vein and it was corrected. Graft biopsies were performed at the same time. It showed a normal histological appearance with no features of rejection. Twenty-five days after transplantation, urine output improved despite persistent graft dysfunction with a SCr of 700 μmol/l. A second allograft biopsy, performed at day 33, failed to show any features consistent with acute or chronic rejection. Subsequently, graft magnetic resonance imaging examination suggested partial cortical necrosis. However, graft function improved (SCr decreased to 500 μmol/L) and he was free of dialysis. Five months later, the patient was hospitalized because of increment of SCr to 950 μmol/L, while urine flow was maintained at about 1.5 l/24 h. Ultrasound examination of the graft and duplex ultrasound examination of renal vessels were normal. Cyclosporin monitoring was at the therapeutic range. Acute rejection was suspected and treatment with 3 methyl-prednisolone pulses was instituted empirically without a satisfactory response. A third allograft biopsy was performed and showed mild chronic tubule-interstitial changes with CaOx crystal deposits within the interstitium and lumena of the renal tubules. Re-examination of the first graft biopsy identified few CaOx crystal deposits. IS treatment was withdrawn and HD was restarted. Blood and urine oxalic acid in the patient and donor were slightly increased. Serum oxalic acid was 0.073 mmol/L and 0.068 mmol/L, respectively (normal <0.01 mmol/L). In the donor's urine, oxaluria was detected at a level of 0.77 mmol/L (normal <0.4 mmol/L).\n\nBone marrow examination failed to show oxalate deposits in either the patient or his mother. Native kidney, graft kidney, and mother's kidney showed no nephrocalcinosis or urolithiasis on radiological evaluation. Neither genetic studies nor liver enzyme activity measures were performed.\n\nCase 4\nA 34-year-old man was diagnosed with ESKD secondary to chronic interstitial nephropathy. History did not reveal personal or family history of urolithiasis or parental consanguinity. He received a renal allograft from a living-related donor (father) with a three HLA mismatches. Immunosuppression was induced with ATG, and he was maintained on corticosteroids, MMF, and cyclosporin. Despite having good diuresis postoperatively, serum creatinine remained at 350 μmol/L. Duplex ultrasound examination was normal. Since SCr further rose to 573 μmol/L by post-transplant day 21, an allograft biopsy was performed. It revealed the presence of CaOx crystal deposits within the renal tubules [Figure 3]. Biochemical analysis of blade biopsy revealed the presence of CaOx monohydrate crystals. Hemodialysis was restarted.\n\nFigure 3 Calcium oxalate crystal deposition in the renal tubules under polarized light microscopy\n\nDiscussion\nOxalate is a metabolic end product that is excreted essentially unchanged in the urine after absorption in the gastrointestinal tract.[6] Hyperoxaluria is a rare metabolic disorder characterized by CaOx deposition in different tissues. The kidney primarily excretes the excess oxalate. Increased urinary excretion of oxalate results in urinary CaOx supersaturation leading to crystal formation, urolithiasis, and/or nephrocalcinosis. CaOx crystals are typically deposited within the renal interstitium and renal tubular cells. When glomerular filtration rate falls below 30–40 ml/min per 1.73 m2, plasma oxalate levels increase because of reduced urinary oxalate excretion.[7] Urinary oxalate is largely derived from the endogenous metabolism of glycine, glycolate, hydroxyproline, and Vitamin C. Hyperoxalosis from any cause converges on a common final pathophysiological pathway of supersaturation of the renal tubular fluid leading to the precipitation of oxalate crystals in the renal interstitium creating an interstitial nephritis, macrophage recruitment and surge in inflammatory mediators ultimately leading to tubular atrophy and acute kidney injury (AKI).[6]\n\nHyperoxaluria is divided into two categories: primary (PH) and secondary (SH). PH includes a group of rare autosomal recessive disorders. Its estimated prevalence is <3 in one million and an incidence of 0.15 × 106/year.[8] Disease is characterized by overproduction of oxalate. There are three existing forms of the disease (Type I, II, and III) in which the underlying defects have been specifically identified. Type I PH is caused by the mutation of the liver-specific peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), whereas type II is caused by the mutation of glyoxylate reductase-hydroxypyruvate reductase. Type III PH results from defects in the liver-specific mitochondrial enzyme 4-hydroxy-2oxo-glutarate aldose. The mechanism that causes an increase in oxalate levels remains unclear. In this frame, potentially other forms of PH could be expected to be reported in the future.[8]\n\nMetabolic history and prevalence of secondary oxalosis are less well studied than that of PH.[9] SH is usually the result of conditions, which are characterized by increased intestinal oxalate absorption, including a high-oxalate diet or fat malabsorption (enteric hyperoxaluria) or alterations of the intestinal oxalate degrading microorganisms and genetic variations of the intestinal oxalate transporter.[7] It may also be secondary to vitamin deficiency (thiamine and pyridoxine) or decreased renal excretion of oxalate.[9] Crystal nephropathy may occur also during the administration of medications excreted by the kidney for which urine solubility depends on urine pH. Several drugs, notably acyclovir, methotrexate, indinavir, and sulfonamide are associated with crystalluria and crystal nephropathy. Sulfadiazine and methotrexate tend to precipitate in tubule when urine pH is low.[10]\n\nThe differential diagnosis between PH and SH represents the cornerstone for the treatment. SH should be ruled out before investigating for PH. Urinary oxalate excretion rates, combined with clinical findings, are the first steps for diagnosis. Urine testing for oxalate (normal <0.5), glycolate, and glycerate (L-glyceric acid) can help to distinguish PH from SH. In PH, the oxalate urinary excretion rate is much more (>1 mmol/1.73 m2 BSA/day), whereas in the SH, a lower increase is noted (<1.0 mmol/1.73 m2 BSA/day).[7] In patients with renal insufficiency, urinary oxalate will be falsely low. Oxalate will retain in the systemic circulation and plasma oxalate measurements could be helpful in this situation.[7]\n\nThe CaOx crystal appears as a colorless crystal predominantly present in the distal tubules and shows bright white polarization characteristics. The presence of oxalate crystals can be overlooked as these are colorless and are visible only on the hematoxylin and eosin stained slides. In addition, they are dissolved away and not readily visible with the other special stains routinely used for kidney biopsy such as periodic acid–Schiff, trichrome, and silver stains. Polarization microscopy does make them visible in a spectacular fashion and readily demonstrates the true extent.[6]\n\nThese 4 cases illustrate the importance of recognizing the presence of oxalate crystals as a distinct etiology of renal allograft dysfunction. In case 1, our patient had no personal or family history of lithiasis, and the donor urinary oxalate was normal. These findings are not consistent with a diagnosis of PH. It is very likely that Vitamin C was involved in the development of oxalosis in this patient because she was taking supranormal doses of this drug for more than 10 years. Vitamin C has been increasingly prescribed for a number of indications ranging from the common cold to anemia management in dialysis patients. Clinicians often underestimate the role of Vitamin C in hyperoxalosis. Vitamin C, being a water-soluble vitamin, offers a false sense of safety and although in the vast majority of cases, daily Vitamin C supplementation may not be of concern. However, it should be given with caution in patients with established risk factors for kidney disease. In addition, patients may receive Vitamin C as part of total parenteral nutrition. Previously reported cases series of liver transplant patients suggest that even normal doses of Vitamin C supplementation (≤500–1000 mg/day) may contribute to oxalosis with the presence of additional risk factors such as a diarrheal illness.[6] A dose not exceeding 100 mg after each HD session (300 mg/week) is safe in these patients.[9]\n\nThe cause for AKI in the second case could be attributed to CNs secondary to ciprofloxacin. About 30%–60% of the active drug (ciprofloxacin) is excreted in the urine during 24 h. The drug will be eliminated by glomerular filtration and active tubular secretion. The presence of crystal deposits was first reported in experimental studies in animals known to have alkaline urine. Clinical studies have demonstrated that crystalluria after ciprofloxacin treatment are uncommon and occur in alkaline urine (pH > 7.3).[10] In our patient, urine was alkaline (pH = 7.2). As urine acidification may potentially constitute a specific treatment. As urine acidification may potentially constitute a specific treatment, despite in literature crystal nephropathy might occur with acidic urine,[10] medical practitioners should be aware of this rare complication of a commonly prescribed antibiotic.[11]\n\nThe two other cases illustrate a fortuitous discovery of interstitial and tubular oxalate deposits in the renal allografts with no history of urolithiasis in either the donor or the recipient. They may be classified as type 3 PH since they did not experience any CaOx calculi. Enzymatic activities of AGT and GR/HPR should have been measured on liver biopsy specimen and genetic analyses have to be performed to support this hypothesis. It is known that CaOx recurs immediately after transplantation.[12] However, this fact cannot explain CaOx deposits in the third case because of the slight increase of oxalemia. In fact, in PH, the increase of serum oxalate is very important because of the association of an over-production with reduction of urinary excretion as a result of poor renal function. Probably, a moderate AGT defect in the mother and her son with the DGF that explain CaOx deposits seen in our patients, apparently these were enhanced following the surgical complications. In the literature, several cases of delayed diagnosis of PH has been reported, even after renal graft failure.[13] We believe that history of renal calculi with chronic interstitial nephropathy justifies the search for oxalosis before kidney transplantation; however, it is not justifiable to investigate each patient with unknown nephropathy for oxalosis.\n\nConclusions\nCaOx deposition in renal allograft is probably under-recognized cause of DGF that requires adequate awareness with early intervention to improve the allograft outcome. The differential diagnosis between PH and SH is the cornerstone for the management of such patients. Early identification and treatment of SH is important to prevent renal allograft dysfunction or graft loss.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Gupta V El Ters M Kashani K Leung N Nasr SH Crystalglobulin-induced nephropathy J Am Soc Nephrol 2015 26 525 9 25190731 \n2 Bhasin B Ürekli HM Atta MG Primary and secondary hyperoxaluria: Understanding the enigma World J Nephrol 2015 4 235 44 25949937 \n3 Parasuraman R L Zhang P Samarapungavan D Pothugunta K Reddy G Rocher L Primary nonfunction of renal allograft secondary to acute oxalate nephropathy Case Rep Transplant 2011 2011 876906 \n4 Pinheiro HS Câmara NO Osaki KS De Moura LA Pacheco-Silva A Early presence of calcium oxalate deposition in kidney graft biopsies is associated with poor long-term graft survival Am J Transplant 2005 5 323 9 15643992 \n5 Hoppe B Langman CB A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria Pediatr Nephrol 2003 18 986 91 12920626 \n6 Suneja M Kumar AB Secondary oxalosis induced acute kidney injury in allograft kidneys Clin Kidney J 2013 6 84 6 27818757 \n7 Karaolanis G Lionaki S Moris D Palla VV Vernadakis S Secondary hyperoxaluria: A risk factor for kidney stone formation and renal failure in native kidneys and renal grafts Transplant Rev (Orlando) 2014 28 182 7 24999029 \n8 Lorenz EC Michet CJ Milliner DS Lieske JC Update on oxalate crystal disease Curr Rheumatol Rep 2013 15 340 23666469 \n9 Yaich S Chaabouni Y Charfeddine K Zaghdane S Kharrat M Kammoun K Secondary oxalosis due to excess Vitamin C intake: A cause of graft loss in a renal transplant recipient Saudi J Kidney Dis Transpl 2014 25 113 6 24434393 \n10 Kammoun K Jarraya F Makni S Ben Mahmoud L Kharrat M Ben Hmida M Ciprofloxacin-induced crystal nephropathy Iran J Kidney Dis 2014 8 240 2 24878949 \n11 Thorsteinsson SB Bergan T Oddsdottir S Rohwedder R Holm R Crystalluria and ciprofloxacin, influence of urinary pH and hydration Chemotherapy 1986 32 408 17 3019613 \n12 Bilgin N Tirnaksiz MB Moray G Karakayali H Yildirim S Demirhan B Early recurrence of oxalate deposition after renal transplantation in a patient with primary hyperoxaluria type I Transplant Proc 1999 31 3219 20 10616450 \n13 Riksen NP Timmers HJ Assmann KJ Huysmans FT Renal graft failure due to type 1 primary hyperoxaluria Neth J Med 2002 60 407 10 12607592\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "28(6)",
"journal": "Indian journal of nephrology",
"keywords": "Crystalline nephropathy; hyperoxaluria; renal allograft dysfunction",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "472-476",
"pmc": null,
"pmid": "30647504",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "10616450;12607592;12920626;15643992;23213607;23666469;24434393;24878949;24999029;25190731;25949937;27818757;3019613",
"title": "Crystalline Nephropathy in Renal Transplant: A Series of 4 Cases.",
"title_normalized": "crystalline nephropathy in renal transplant a series of 4 cases"
} | [
{
"companynumb": "TN-ASTELLAS-2019US000090",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASCORBIC ACID"
},
"drugadditional": "3",
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{
"abstract": "The use of antithrombotic therapy may increase morbidity and mortality in patients with infective endocarditis (IE). This study evaluated the use of oral anticoagulant and antiplatelet agents on the development of embolic complications and bleeding episodes within 30 days of IE diagnosis.\n\n\n\nThis pilot study was a retrospective medical record review of patients receiving treatment for IE between July 1, 2012, and July 31, 2017. The 2 study arms were patients receiving long-term anticoagulant/antiplatelet therapy versus patients not receiving therapy at the time of IE. Patients were eligible for inclusion if they had definite IE per modified Duke criteria and received at least 48 h of antibiotic therapy. The primary and secondary outcomes evaluated the incidence of embolic phenomenon and bleeding events in each group, respectively.\n\n\n\nOf 129 patients with IE, 34 met the eligibility criteria, with 20 patients on receiving anticoagulant/antiplatelet therapy and 14 patients not receiving anticoagulant/antiplatelet therapy. The median age was 63 years, with 50% male patients. Staphylococcus aureus was the infecting pathogen in 41% of patients. Embolic events occurred in 30% of patients receiving anticoagulant/antiplatelet therapy versus 7.1% of those not receiving therapy. No patients in the anticoagulant/antiplatelet therapy arm experienced a bleeding event, whereas 7.1% of those in the comparator arm did.\n\n\n\nThis retrospective pilot study indicates that patients with IE receiving anticoagulant/antiplatelet agents may be at an increased risk for embolic episodes versus those who are not. Larger, prospective studies are necessary to find a definitive correlation.",
"affiliations": "Wyckoff Heights Medical Center, Brooklyn, NY, USA.;BronxCare Health System, Bronx, NY, USA.;Touro College of Pharmacy, New York, NY, USA; State University of New York Downstate Medical Center, Brooklyn, NY, USA.",
"authors": "Pathickal|Sherin M|SM|;Park|Tae Eun|TE|;Sharma|Roopali|R|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clinthera.2020.07.007",
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"issn_linking": "0149-2918",
"issue": "42(9)",
"journal": "Clinical therapeutics",
"keywords": "anticoagulants; antiplatelets; antithrombotics; bleeding; embolic phenomenon; infective endocarditis",
"medline_ta": "Clin Ther",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D004617:Embolism; D004696:Endocarditis; D005260:Female; D006470:Hemorrhage; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010975:Platelet Aggregation Inhibitors; D012189:Retrospective Studies; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus",
"nlm_unique_id": "7706726",
"other_id": null,
"pages": "1828-1838",
"pmc": null,
"pmid": "32758375",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Outcomes Associated With the Use of Anticoagulant and Antiplatelet Agents in Patients Undergoing Treatment for Infective Endocarditis: A Pilot Study.",
"title_normalized": "clinical outcomes associated with the use of anticoagulant and antiplatelet agents in patients undergoing treatment for infective endocarditis a pilot study"
} | [
{
"companynumb": "US-MYLANLABS-2020M1104340",
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"activesubstancename": "GENTAMICIN"
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"drugadditional": "3",
... |
{
"abstract": "Appendiceal malignancies are rare clinic entities. The clinical presentation of appendiceal malignancies is often atypical. Acute abdominal pain and acute appendicitis, which requires early surgical intervention, are the most common clinical presentations of appendiceal malignancies. In this case report, an adenocarcinoma of the appendix in a 64-year-old male from a nursing home has been presented. He had right lower quadrant pain for the last 5 days. On physical examination, he had significant guarding. Intravenous contrast-enhanced abdominopelvic tomography revealed no pathological features. Laparotomy under general anesthesia was scheduled. During exploration, a perforated appendicitis was observed. Formal appendectomy was performed. The patient was lost due to pneumonia and septic shock 5 days after surgical intervention. In addition, the natural history of the disease and its basic diagnostic and therapeutic aspects are discussed. Preoperative or intraoperative diagnosis may not be available for some patients. Thus, routine histopathological examination is essential for adequate diagnosis and treatment.",
"affiliations": "Clinic of General Surgery, Ministry Health Dumlupınar University Evliya Çelebi Training and Research Hospital, Kütahya, Turkey.;Department of General Surgery, Dumlupınar University School of Medicine, Kütahya, Turkey.;Department of General Surgery, Dumlupınar University School of Medicine, Kütahya, Turkey.;Clinic of General Surgery, Ministry Health Dumlupınar University Evliya Çelebi Training and Research Hospital, Kütahya, Turkey.;Department of Pathology, Dumlupınar University School of Medicine, Kütahya, Turkey.",
"authors": "Sönmez|Yalçın|Y|;Bayhan|Zülfü|Z|;Yaylak|Faik|F|;Ekici|Mehmet Fatih|MF|;Değer|Ayşe Nur|AN|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5152/UCD.2014.2335",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1300-0705",
"issue": "32(2)",
"journal": "Ulusal cerrahi dergisi",
"keywords": "Appendix vermiformis; acute abdomen; adenocarcinoma; geriatric patient",
"medline_ta": "Ulus Cerrahi Derg",
"mesh_terms": null,
"nlm_unique_id": "9425625",
"other_id": null,
"pages": "149-51",
"pmc": null,
"pmid": "27436927",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "17447078;10569505;1590322;17692116;7634979;15114326;2926741;16775823;10521058;17662117",
"title": "Appendix adenocarcinoma in an elderly patient from a nursing home.",
"title_normalized": "appendix adenocarcinoma in an elderly patient from a nursing home"
} | [
{
"companynumb": "TR-BAYER-2016-090100",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
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"drugadditional": null,
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{
"abstract": "OBJECTIVE\nWhen positioning patients with meningocele and meningomyelocele, it is standard practice to avoid direct pressure on the lesions. That caution is intended to prevent injury to neural elements within the lesion and violation of the cerebrospinal fluid space. We herein report an additional hazard of direct intraoperative pressure on such lesions. An adult patient with a lumbosacral pseudomeningocele sustained a cerebral ischemic injury as a consequence of direct pressure on the lesion during general anesthesia.\n\n\nMETHODS\nA 32-yr-old male with spina bifida and a pseudomeningocele related to recent lumbar surgery underwent a urologic procedure in the lithotomy position. Because the lesion was recognized to lie to the left of the midline, cushioning was placed under the patient's left hip and buttock. The patient was slow to awaken and has sustained significant long-term cognitive deficits. Imaging is consistent with a diffuse cerebral ischemic insult.\n\n\nCONCLUSIONS\nIn retrospect, the size and leftward extent of the pseudomeningocele were not appreciated preoperatively, and in spite of the care taken, intraoperative pressure was placed on the lesion. This report cautions that intraoperative pressure related to positioning patients with extra-axial lesions containing cerebrospinal fluid (CSF), e.g., meningoceles and pseudomeningoceles, can result in increases in CSF pressure and thereby a reduction in cerebral perfusion pressure sufficient to result in cerebral ischemia.",
"affiliations": "VA Medical Center, Anesthesia Service - 125, University of California, 3350 La Jolla Village Drive, San Diego, CA, 92161, USA, jdrummond@ucsd.edu.",
"authors": "Drummond|John C|JC|;Ciacci|Joseph D|JD|;Lee|Roland R|RR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12630-014-0164-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0832-610X",
"issue": "61(7)",
"journal": "Canadian journal of anaesthesia = Journal canadien d'anesthesie",
"keywords": null,
"medline_ta": "Can J Anaesth",
"mesh_terms": "D000328:Adult; D000768:Anesthesia, General; D002545:Brain Ischemia; D006801:Humans; D007431:Intraoperative Complications; D008161:Lumbosacral Region; D008297:Male; D008588:Meningocele; D056888:Patient Positioning; D016135:Spinal Dysraphism",
"nlm_unique_id": "8701709",
"other_id": null,
"pages": "656-9",
"pmc": null,
"pmid": "24744102",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Direct pressure on a pseudomeningocele resulting in intraoperative cerebral ischemia.",
"title_normalized": "direct pressure on a pseudomeningocele resulting in intraoperative cerebral ischemia"
} | [
{
"companynumb": "US-BAXTER-2015BAX011375",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FENTANYL"
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"drugadditional": null,
... |
{
"abstract": "We describe a case study of comorbid obsessive-compulsive disorder (OCD) in a nine-year-old boy with Duchenne muscular dystrophy (DMD). Patient history included persistent deficits in social communication and restrictive and repetitive patterns of behavior: a diagnosis of autism spectrum was formalized. Due to serious disruption on social functioning and negative development of the obsessive behavior we decided to start pharmacotherapy. Fluoxetine 5 mg/day was started and gradually increased to 20 mg/day. A significant positive effect was observed by both parents and teacher in daily functioning. Although parents reported a positive change in mood, formal behavior rating by them did not reveal a significant effect, reflecting the insensitivity of general behavior rating scales. However, neuropsychological testing revealed a significant effect. This case report highlights the diagnostic and therapeutic challenges of complex neuropsychiatric comorbidities in DMD. It is the first scientific report on fluoxetine effectiveness in this patient group. Further research is needed.",
"affiliations": "Center of Neurological Learning Disabilities, Kempenhaeghe, Heeze, The Netherlands; Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands. Electronic address: hendriksenj@kempenhaeghe.nl.;Center of Neurological Learning Disabilities, Kempenhaeghe, Heeze, The Netherlands; Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.;Center of Neurological Learning Disabilities, Kempenhaeghe, Heeze, The Netherlands; Koraalgroep, Gastenhof, Maasbracht, The Netherlands.;Division of Pediatric Neurology, Cincinnati Children's Hospital Medical Center, USA.;Department of Neurology, Leiden University Medical Center, The Netherlands.;Center of Neurological Learning Disabilities, Kempenhaeghe, Heeze, The Netherlands; Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.",
"authors": "Hendriksen|Jos G M|JG|;Klinkenberg|Sylvia|S|;Collin|Phillipe|P|;Wong|Brenda|B|;Niks|Erik H|EH|;Vles|Johan S|JS|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D005473:Fluoxetine",
"country": "England",
"delete": false,
"doi": "10.1016/j.nmd.2016.08.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8966",
"issue": "26(10)",
"journal": "Neuromuscular disorders : NMD",
"keywords": null,
"medline_ta": "Neuromuscul Disord",
"mesh_terms": "D000067877:Autism Spectrum Disorder; D002648:Child; D015897:Comorbidity; D005473:Fluoxetine; D006801:Humans; D008297:Male; D020388:Muscular Dystrophy, Duchenne; D009771:Obsessive-Compulsive Disorder; D017367:Serotonin Uptake Inhibitors",
"nlm_unique_id": "9111470",
"other_id": null,
"pages": "659-661",
"pmc": null,
"pmid": "27612598",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diagnosis and treatment of obsessive compulsive behavior in a boy with Duchenne muscular dystrophy and autism spectrum disorder: A case report.",
"title_normalized": "diagnosis and treatment of obsessive compulsive behavior in a boy with duchenne muscular dystrophy and autism spectrum disorder a case report"
} | [
{
"companynumb": "PHHY2016NL156220",
"fulfillexpeditecriteria": "1",
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"actiondrug": "5",
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"activesubstancename": "PREDNISOLONE"
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"drugadditional": "3",
"dru... |
{
"abstract": "Idiopathic acquired aplastic anemia (AA) is a rare lymphocyte-mediated bone marrow aplasia. No specific mechanisms or triggers of AA have been identified. We recently observed several patients who developed AA after Hodgkin lymphoma (HL). We hypothesized that the co-occurrence of HL and AA is not random and may be etiologically significant. To test this hypothesis, we determined the incidence of AA in HL patients at our institution. We identified four patients with co-occurring HL and AA, with the incidence of AA in HL patients >20-fold higher compared to the general population. We identified 12 additional patients with AA and HL through a systematic literature review. Of the 16 total patients,15 (93.8%) developed AA after or concurrent with a HL diagnosis. None of the patients had marrow involvement by HL. Five of 15 patients were in complete remission from HL at the time of AA diagnosis, and six had a concurrent presentation with no prior cytotoxic therapy, with diagnostic timeframe information unavailable for four patients. The median interval between HL diagnosis and AA onset was 16 months, ranging from concurrent to 14 years after a HL diagnosis. The median survival after AA diagnosis was 14 months (range: 1 month to 20 years). Our results show that patients with HL have a higher incidence of AA compared to the general population and suggest that HL-related immune dysregulation may be a risk factor for AA. Better recognition and management of AA in HL patients is needed to improve outcomes in this population.",
"affiliations": "Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.;Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Philadelphia, PA, United States of America.;Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, United States of America.;Division of Hematology-Oncology, Milton S. Hershey Medical Center, Penn State Cancer Institute, Hershey, PA, United States of America.;Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, United States of America.;Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, United States of America.;Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, United States of America.;Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America.;Penn Medicine Corporate Information Services, University of Pennsylvania Health System, Philadelphia, PA, United States of America.;Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.;Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Philadelphia, PA, United States of America.;Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, United States of America.;Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, United States of America.",
"authors": "Linaburg|Taylor|T|;Davis|Adam R|AR|;Frey|Noelle V|NV|;Khawaja|Muhammad R|MR|;Landsburg|Daniel J|DJ|;Schuster|Stephen J|SJ|;Svoboda|Jakub|J|;Li|Yimei|Y|;Borovskiy|Yuliya|Y|;Olson|Timothy S|TS|;Bagg|Adam|A|;Hexner|Elizabeth O|EO|;Babushok|Daria V|DV|0000-0002-1745-0353",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0215021",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0215021PONE-D-18-32790Research ArticleMedicine and Health SciencesDiagnostic MedicineCancer Detection and DiagnosisMedicine and Health SciencesOncologyCancer Detection and DiagnosisMedicine and Health SciencesDiagnostic MedicineMedicine and Health SciencesHematologyAnemiaAplastic AnemiaMedicine and Health SciencesHematologyBone Marrow FailureAplastic AnemiaMedicine and Health SciencesHematologyBone Marrow FailureMedicine and Health SciencesOncologyCancers and NeoplasmsHematologic Cancers and Related DisordersLymphomasHodgkin LymphomaMedicine and Health SciencesHematologyHematologic Cancers and Related DisordersLymphomasHodgkin LymphomaBiology and Life SciencesImmunologyImmune SuppressionMedicine and Health SciencesImmunologyImmune SuppressionMedicine and Health SciencesDiagnostic MedicineSigns and SymptomsImmune SuppressionMedicine and Health SciencesPathology and Laboratory MedicineSigns and SymptomsImmune SuppressionMedicine and Health SciencesOncologyCancers and NeoplasmsNeoplasmsBiology and Life SciencesPhysiologyImmune PhysiologyBone MarrowMedicine and Health SciencesPhysiologyImmune PhysiologyBone MarrowBiology and Life SciencesImmunologyImmune SystemBone MarrowMedicine and Health SciencesImmunologyImmune SystemBone MarrowHodgkin lymphoma patients have an increased incidence of idiopathic acquired aplastic anemia Aplastic anemia in Hodgkin lymphoma patientsLinaburg Taylor ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationWriting – original draftWriting – review & editing1Davis Adam R. Data curationMethodologyVisualizationWriting – review & editing2Frey Noelle V. MethodologyResourcesWriting – review & editing3Khawaja Muhammad R. MethodologyResourcesWriting – review & editing4Landsburg Daniel J. MethodologyResourcesWriting – review & editing3Schuster Stephen J. Formal analysisMethodologyResourcesWriting – review & editing3Svoboda Jakub MethodologyResourcesWriting – review & editing3Li Yimei Data curationFormal analysisMethodologyValidationWriting – review & editing5Borovskiy Yuliya Data curationMethodologyWriting – review & editing6Olson Timothy S. Data curationFormal analysisWriting – review & editing7Bagg Adam Data curationFormal analysisMethodologySupervisionWriting – review & editing2Hexner Elizabeth O. Funding acquisitionSupervisionWriting – review & editing3http://orcid.org/0000-0002-1745-0353Babushok Daria V. ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationSupervisionValidationWriting – review & editing3*1 \nPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America2 \nDepartment of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Philadelphia, PA, United States of America3 \nDivision of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, United States of America4 \nDivision of Hematology-Oncology, Milton S. Hershey Medical Center, Penn State Cancer Institute, Hershey, PA, United States of America5 \nDepartment of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America6 \nPenn Medicine Corporate Information Services, University of Pennsylvania Health System, Philadelphia, PA, United States of America7 \nDivision of Oncology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of AmericaBertolini Francesco EditorEuropean Institute of Oncology, ITALYCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: daria.babushok@uphs.upenn.edu5 4 2019 2019 14 4 e021502114 11 2018 25 3 2019 © 2019 Linaburg et al2019Linaburg et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Idiopathic acquired aplastic anemia (AA) is a rare lymphocyte-mediated bone marrow aplasia. No specific mechanisms or triggers of AA have been identified. We recently observed several patients who developed AA after Hodgkin lymphoma (HL). We hypothesized that the co-occurrence of HL and AA is not random and may be etiologically significant. To test this hypothesis, we determined the incidence of AA in HL patients at our institution. We identified four patients with co-occurring HL and AA, with the incidence of AA in HL patients >20-fold higher compared to the general population. We identified 12 additional patients with AA and HL through a systematic literature review. Of the 16 total patients,15 (93.8%) developed AA after or concurrent with a HL diagnosis. None of the patients had marrow involvement by HL. Five of 15 patients were in complete remission from HL at the time of AA diagnosis, and six had a concurrent presentation with no prior cytotoxic therapy, with diagnostic timeframe information unavailable for four patients. The median interval between HL diagnosis and AA onset was 16 months, ranging from concurrent to 14 years after a HL diagnosis. The median survival after AA diagnosis was 14 months (range: 1 month to 20 years). Our results show that patients with HL have a higher incidence of AA compared to the general population and suggest that HL-related immune dysregulation may be a risk factor for AA. Better recognition and management of AA in HL patients is needed to improve outcomes in this population.\n\nhttp://dx.doi.org/10.13039/100000050National Heart, Lung, and Blood InstituteHL132101http://orcid.org/0000-0002-1745-0353Babushok Daria V. http://dx.doi.org/10.13039/100002618Aplastic Anemia and MDS International Foundationhttp://orcid.org/0000-0002-1745-0353Babushok Daria V. American Society of HematologyHONORS AwardLinaburg Taylor This study was supported by the 2018 American Society of Hematology HONORS award to T.L. and E.H. (http://www.hematology.org/Awards/Medical-Student/378.aspx), and by the AA & MDS International Foundation Research Grant (https://www.aamds.org/) and NHLBI K08 HL132101 to D.B. (https://www.nhlbi.nih.gov/). Sponsors and funders did not play any role in study design, data collection or analysis, decision to publish, or manuscript preparation. Data AvailabilityAll relevant data are within the manuscript and its Supporting Information files.Data Availability\nAll relevant data are within the manuscript and its Supporting Information files.\n==== Body\nIntroduction\nIdiopathic acquired aplastic anemia (AA) is a rare, life-threatening disease characterized by pancytopenia and a hypocellular marrow that is caused by lymphocyte-mediated destruction of hematopoietic stem and progenitor cells [1]. Treatment of AA relies on lymphocyte-directed immunosuppression, administered either as anti-thymocyte globulin (ATG) and cyclosporine A (CsA) or as part of a bone marrow transplant (BMT) conditioning regimen [2]. Despite recent progress in outcomes of AA patients, the understanding of the autoimmune mechanism in AA remains limited; no triggers of autoimmunity in AA have been identified, and there are no known prevention strategies for this condition. The diagnosis of AA is established clinically through the systematic exclusion of mimicking entities, with T-cell immunosuppressive treatments continuing to be largely empiric.\n\nSeveral clinical observations have established a link between AA and other conditions that suggest a shared pathogenesis, most notably seronegative hepatitis [3] which precedes AA in ~10–15% of patients, and a less frequent association with eosinophilic faciitis [4, 5]. Epidemiologic and genetic association studies have identified several factors associated with a modest increase in the risk of AA, such as exposures to benzene, pesticides and waterfowl [6, 7], and genetic polymorphisms in cytokine genes, metabolic enzymes, and human leukocyte antigen (HLA) alleles [8–15]. More recently, a link between AA and lymphoid neoplasms, including T-cell large granular lymphocyte leukemia [15] and B-cell leukemias and lymphomas [16, 17] has also been proposed. However, there are no studies of the incidence of AA in B-cell or T-cell neoplasms and no specific connection to B-cell neoplasms has been established.\n\nInterestingly, we recently observed several patients who developed AA following a diagnosis of HL, a distinctive B-cell neoplasm associated with an abnormal immune response [18]. Because AA and HL are both very rare—the incidence of AA in Western countries is 2.2 cases per million per year and up to 7 cases per million per year in Asia [6, 19], while the incidence of HL is ~2.6 cases per 100,000 per year [20]—we hypothesized that their co-occurrence is etiologically linked and that HL patients are more likely to develop AA compared to the general population.\n\nTo test for an association between AA and HL, we determined the incidence of AA in patients with HL seen at our institution between 2005 and 2018 and compared it to the incidence of AA in the general population. Strikingly, patients with HL had at least a 20-fold higher incidence of AA than the general population. To comprehensively evaluate the characteristics of AA in patients with HL, we expanded our institutional cohort by including published cases identified through a systematic literature review. In the following analysis, we present the clinical and pathologic characteristics of AA when presenting in patients with HL, as well as treatment strategies and patient outcomes seen with this rare and difficult-to-treat population.\n\nMethods\nPatients and study oversight\nData collection and analysis were performed with the approval of the Institutional Review Board of the University of Pennsylvania. Cases of co-occurring HL and AA were identified by the search of electronic medical records of patients treated at the Hospital of the University of Pennsylvania between 2005 and 2018 using ICD-9 and ICD-10 diagnosis codes (Tables A-C in S1 Appendix). 2801 patients with a diagnosis of HL and 6842 patients with a diagnosis of AA or pancytopenia were identified, with 125 patients carrying both AA or pancytopenia and HL diagnoses. This 125 patient cohort was then used to identify patients who met the full diagnostic criteria for both HL and AA through the comprehensive manual review of medical charts. After completion of the diagnostic review, bone marrow histology was assessed in a blinded manner by a hematopathologist for patients who were entered into the study. The diagnosis of HL was established according to the 2016 World Health Organization (WHO) classification [21, 22]. The diagnosis of AA was established according to the International Study of Agranulocytosis and Aplastic Anemia criteria and required systematic exclusion of mimicking entities [2, 19, 23]. After the manual record review, 91 of the 125 patients were confirmed to have a diagnosis of HL (72.8% true positive rate of HL based on ICD-9 and ICD-10 code search for HL) and 4 of 125 patients were confirmed to have a diagnosis of AA (3.2% true positive rate of AA based on ICD-9 and ICD-10 code search for AA or pancytopenia).\n\nCase presentations\nPatient 1 is a South Asian Indian male who, at the age of 34 years, was diagnosed with HL and achieved a complete remission after receiving ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) followed by ASHAP (doxorubicin, methylprednisone, high dose cytarabine, cisplatin). Fourteen years after the diagnosis of HL, the patient developed severe pancytopenia and was found to have a markedly hypocellular bone marrow (Table 1, Fig 1A). There was no evidence of HL recurrence. Cytogenetics were normal, and there was no dysplasia. Work-up did not reveal any infectious or nutritional causes of pancytopenia. Epstein-Barr Virus (EBV) serologies were consistent with a prior but not current infection. Paroxysmal Nocturnal Hemoglobinuria (PNH) flow cytometry was negative. Past medical history was notable for testicular carcinoma in the remote past treated by orchiectomy as well as etoposide and cisplatin-based chemotherapy, with complete blood count recovery after therapy. Based on AA diagnostic and severity criteria, a diagnosis of severe AA was made. The patient received immunosuppressive therapy with horse ATG (hATG) and cyclosporine A (CsA) with no response at six months, followed by the addition of eltrombopag with no response. Eleven months after the initial diagnosis, the patient received a 9/10-matched unrelated donor bone marrow transplant (MUD-BMT) for severe AA with Fludarabine (Flu)/Cyclophosphamide(Cy)/rabbit ATG (rATG) conditioning and total-body irradiation of 200 cGy. Graft versus host disease (GVHD) prophylaxis was methotrexate and tacrolimus. The patient’s post-transplant course was complicated by primary graft failure, with the patient ultimately dying from infectious complications after transplant.\n\n10.1371/journal.pone.0215021.g001Fig 1 Bone marrow histology at the time of aplastic anemia diagnosis in patients with previous history of Hodgkin Lymphoma.\nThe hematoxylin and eosin (H&E) stained bone marrow histology sections at 25x, 50x, and 100x magnification reveal severely reduced cellularity and reduced trilineage hematopoiesis of Patient 1 (A), Patient 2 (B), and Patient 3 (C).\n\n10.1371/journal.pone.0215021.t001Table 1 Clinical and pathologic characteristics of patients with AA and HL.\nPatient #\tHL subtype\tBone marrow histology at AA diagnosis\tCytogenetics\tT-cell receptor rearrangement\tNGS for myeloid malignancy-associated mutations\tPNH flow cytometry\tHLA alleles\tInherited marrow failure testing, if available\t\nPatient 1\tn/a\tMarkedly hypocellular (5% cellularity) with markedly decreased trilineage hematopoiesis.\t46,XY[20] (diagnosis); evolved to 46,XY,der(21)t(3;21)(q11.2;p13)[12] after immunosuppression\tPolyclonal\tNegative\tNegative\tA*01:01, A*24:07, B*35:02, C*04:01, DR*11:04\tn/a\t\nPatient 2\tnodular sclerosis\tMarkedly hypocellular marrow (<5% cellularity) with markedly decreased trilineage hematopoiesis.\t46,XY [20]\tPolyclonal\tNegative\tNegative\tA* 68:02, A*02:01; B* 14:02, B*18:01, C*08:02, C*07:01, DR* 13:03, 08:01\tChromosome breakage: normal; Lymphocyte telomere length: very high\t\nPatient 3\tnodular sclerosis\tMarkedly hypocellular marrow (<5% cellularity) with markedly decreased trilineage hematopoiesis.\t46,XY[1]; poor growth\tn/a\tn/a\tNegative\tA*2, 24; B*39, 51; Cw*7, 15, DR*4, 13, DQ*6, 8\tn/a\t\nPatient 4\tnodular sclerosis\tHypocellular marrow (20%), with foci of erythropoiesis and myelopoiesis.\tNormala\tn/a\tn/a\tn/a\tA*1, 3; B*35, 57; Cw*02:02; Cw*06:02\tn/a\t\nHL, Hodgkin Lymphoma; AA, Idiopathic Acquired Aplastic Anemia; NGS, Next-Generation Sequencing; HLA, Human Leukocyte Antigen; PNH, Paroxysmal Nocturnal Hemoglobinuria.\n\naFor patient 4, results of metaphase cytogenetics from the time of AA diagnosis are not available, however, karyotype after immunosuppression was normal (46,XY,inv(9)(p11q13)c[20]).\n\nPatient 2 is a Caucasian male who, at the age of 28, was diagnosed with a gastric mucosa-associated lymphoid tissue (MALT) lymphoma and achieved a complete remission with four cycles of rituximab. Two years later, the patient developed progressive pancytopenia, supraclavicular and mediastinal adenopathy, and drenching night sweats. Initial lymph node biopsies revealed no malignancy. The patient’s bone marrow was hypocellular with normal cytogenetics and no lymphomatous involvement. The patient was initially treated with empiric steroids, intravenous immunoglobulin (IVIG) and eltrombopag without response. Subsequent positron emission tomography-computed tomography (PET-CT) demonstrated increasing Fluorodeoxyglucose (FDG)-avid lymphadenopathy in the mediastinum and supraclavicular areas, and a femoral lesion. An excisional biopsy of a cervical lymph node was diagnostic for HL, nodular sclerosis type. The patient developed progressive neutropenia and continued to be red cell and platelet-transfusion dependent, with a bone marrow biopsy showing a hypocellular bone marrow with 5% cellularity, no dysplasia and no evidence of involvement by HL (Fig 1B, Table 1). No infectious or nutritional causes of pancytopenia were identified. EBV polymerase chain reaction (PCR) was negative. PNH flow cytometry was negative. T-cell receptor gamma gene rearrangement showed no clonal T-cell process. Lymphocyte telomere length and chromosome breakage studies showed no evidence of a short telomere syndrome or Fanconi Anemia. Because of the concomitant HL and AA presentation, he was not able to receive standard therapy for either condition. After progressing on brentuximab vedotin, MUD-BMT was recommended. However, he died of neutropenic sepsis with fungal pneumonia 17 months after initial presentation, following one cycle of salvage ICE (ifosfamide, carboplatin, etoposide) chemotherapy in an attempt to control his HL prior to BMT.\n\nPatient 3 is a South Asian Indian male who, at the age of 35 years, was diagnosed with stage IVB nodular sclerosis HL. He achieved a complete remission after receiving six cycles of ABVD. Ten years after his initial diagnosis of HL, he developed severe thrombocytopenia and was initially empirically treated with prednisone and IVIG without significant improvement. Subsequent bone marrow biopsy showed a markedly hypocellular marrow with essentially absent trilineage hematopoiesis and without evidence of malignancy (Fig 1C, Table 1). Work-up for infectious etiologies was unrevealing. A presumptive diagnosis of severe AA was made. The patient was treated with immunosuppressive therapy with hATG and CsA. Four months after his AA presentation, the patient developed a rising white count with immunophenotypically aberrant cells indicative of a therapy-related myeloid neoplasm (TRMN) in the setting of prior cytotoxic therapy. The patient died shortly afterwards from infectious complications.\n\nPatient 4 is a Caucasian male diagnosed with severe AA at the age of 32 years who achieved remission after immunosuppressive therapy with ATG and CsA. Seven years after initial therapy, he developed falling blood counts and splenic enlargement. Splenectomy revealed splenic MALT lymphoma. Six years later, the patient developed adenopathy and night sweats. PET-CT showed extensive cervical lymphadenopathy and numerous foci of intense FDG activity within the skeleton; lymph node biopsy demonstrated HL, nodular sclerosis subtype. He was treated with six cycles of ABVD, achieving a complete remission and remains well without cytopenias 80 months after completion of chemotherapy.\n\nCalculation of incidence and prevalence of AA in HL patients and statistical analysis\nThe incidence of AA in HL patients was determined as the number of HL patients diagnosed with AA divided by the AA-free person-years of HL patients treated at the Hospital of the University of Pennsylvania between 2005 and 2018. The AA-free person-years in HL patients were conservatively estimated as follows. 2801 total HL patients (determined from HL ICD-9/-10 electronic medical record review) x 72.8% (true positive rate of HL determined by manual review of patients identified by ICD-9/-10 codes) resulted in ~2040 patients with HL. Of these patients, 2036 patients did not have a diagnosis of AA, and their disease-free person-years were calculated as the 13 years of the study period x 2036 patients. For the four patients who had HL and AA, the disease-free person-years were manually calculated based on the number of years within the study period prior to AA diagnosis (11, 12, 6, 0, for a total of 29). The prevalence of AA in HL patients was calculated as the number of AA diagnoses in HL patients divided by the total number of HL patients evaluated during the study period.\n\nWe found the estimated incidence of AA in HL patients to be ~151 cases per million HL patients per year (4 in 26,497 person-years, 95% confidence interval (CI) [41 per million, 385 per million]). We compared this estimated incidence to the published incidence of AA in the general population of 2.2 cases per million per year in Western countries to ~7 cases per million per year in Asia [6],[19] [6, 19] using the two-tailed Exact test based on Poisson distribution using the Stata 15 software (StataCorp LLC, College Station, TX) with a significance level of p<0.05. We found the prevalence of AA in our institutional cohort to be 0.2% (4 of 2040 patients, 95% CI of [0.05%, 0.51%]), and compared this value to the prevalence of AA in patients with HL from published studies [24, 25] using the two-tailed Fisher’s exact test with a significance level of p<0.05.\n\nSystematic literature review\nThis systematic review was performed according to the Preferred Reporting Items for the Systematic Review and Meta-Analyses (PRISMA) Statement [26] (Figure A in S1 Appendix). The inclusion criteria for article selection were that the abstracts must mention a patient or a patient population with HL or Hodgkin disease (HD) as well as AA or pancytopenia. Full-text articles were then reviewed and excluded if the article included: a) patients with AA with no evidence of a HL or HD diagnosis, b) patients with HL or HD with no evidence of an AA or unexplained pancytopenia diagnosis (e.g., we excluded HL complications where an alternative etiology of pancytopenia was likely, such as post-chemotherapy myelosuppression, infections, myelodysplastic syndrome, acute leukemia, and hemophagocytic syndrome), c) relevant cases already described in previously identified research articles. This search strategy was used to identify appropriate abstracts and subsequent articles from Pubmed and was supplemented by a manual search of Google Scholar. Candidate abstracts were identified using keywords “Hodgkin lymphoma,” “Hodgkin disease,” “Aplastic anemia,” and “pancytopenia,” excluding the term “Non-Hodgkin.” No date or language limits were applied to the database search. Non-English language articles were translated and reviewed. Two authors (T.L. and D.B.) performed the search and evaluated abstracts independently.\n\nAnalysis of clinical characteristics of AA in patients with HL\nTo the extent available within published reports and medical records, we collected the following variables for all patients with diagnoses of AA and HL: patient’s sex, age at HL and AA diagnosis respectively, interval between HL and AA diagnoses and order of diagnoses, HL subtype and Ann Arbor stage, HL treatment prior to AA diagnosis, HL outcome, HL status at AA diagnosis, severity of AA, treatment offered for AA, AA outcome, other pertinent neoplasms, cytogenetics, family history, duration of follow-up and overall survival.\n\nResults\nPatients with HL have an increased incidence of AA compared to the general population\nOf the 2040 patients with a diagnosis of HL evaluated at the Hospital of the University of Pennsylvania between 2005 and 2018, four patients were also diagnosed with AA (Figs 1 and 2, Tables 1 and 2). All four patients were male, and three of the four presented with AA after or concurrent with a HL diagnosis. The median age at AA presentation was 39 years (range: 31 to 49 years). All patients had severe or very severe AA, and none had evidence of active EBV infection, myelodysplasia, or features consistent with an occult inherited bone marrow failure syndrome (see methods for detailed case descriptions).\n\n10.1371/journal.pone.0215021.g002Fig 2 Clinical Course of patients with Hodgkin Lymphoma and Aplastic Anemia.\nA schematic diagram demonstrating the clinical course of 15 patients with diagnoses of HL and AA. Patient reported by Brusamolino et al. is not shown because of incomplete clinical information. Blue triangle, HL diagnosis; red circle, AA diagnosis; black triangle, death; green cross, last follow-up. Treatments for HL and AA are denoted by black vertical lines, with treatment and response listed above the respective line. HL, Hodgkin Lymphoma; AA, Idiopathic Acquired Aplastic Anemia; ABVD, Doxorubicin, Bleomycin, Vinblastine, Dacarbazine; ASHAP, Doxorubicin, Solumedrol, Cytarabine, Cisplatin; MOPP, Mechlorethamine, Vincristine, Procarbazine, Prednisone; MTNI, Modified Total Nodal Irradiation; C-MOPP, Cyclophosphamide, Vincristine, Procarbazine, Prednisone; CHOP, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone; Allo BMT, Allogenic Bone Marrow Transplant; hATG, Horse Antithymocyte Globulin; ATG, Antithymocyte Globulin; ALG, Antilymphocyte Globulin, CsA, Cyclosporine A; Tac, Tacrolimus; G-CSF, Granulocyte Colony Stimulating Factor; CR, Complete Response; PR, Partial Response; NR, No Response.\n\n10.1371/journal.pone.0215021.t002Table 2 Clinical characteristics of patients with hodgkin lymphoma and aplastic anemia.\nPatient\tHL type Stage (if available)\tHL Treatment pre-AA diagnosis\tHL Status at AA diagnosis\tAge at AA diagnosis/Sex\tInterval between HL and AA diagnoses\tAA treatment\tSurvival after AA diagnosis\tStatus of AA at last follow-up\t\nPatients reported in this study\t\nUPENN 1\tN/A;\nStage IIa\tABVD, ASHAP\tCR\t49/M\t14 years\thATG/CsA; Eltrombopag/Tac; Allo BMT\t12 months\tRefractory; died of primary graft failure after Allo BMT\t\nUPENN 2\tnodular sclerosis;Stage IV\tNone\tProgression s/p 8 cycles Brentuximab\t31/M\t≤ 2 months; concurrent\tEltrombopag\t17 months\tRefractory; died of AA complications\t\nUPENN 3\tnodular sclerosis;Stage IVB\tABVD\tCR\t46/M\t10 years\tCsA/Solumedrol; hATG/G-CSF\t4 months\tRefractory; transformed to TRMN\t\nUPENN 4\tnodular sclerosis; Stage IVB\tNoneb\tCR s/p 6 cycles ABVD\t32/M\tAA preceded HL\nby 13 years\tCsA/ATG\tNot reached (>20 years)\tCR s/p CsA\t\nPatients from the Systematic Literature Review\t\nBrusamolino et al., 1994\tN/A\tMOPP/ABVD\tPresumed CR\tN/A\tN/A\tSupportive\tN/A\tDied of hemorrhage\t\nJohnston et al., 1991\tlymphocyte depleted; Stage IIIB\tMOPP\tCR\t31/F\t0 months; concurrent\tSupportive\tNot reached (34 months as of publication)\tActive AA\t\nJuliusson et al., 1991\tnodular sclerosis; Stage IIA\tNone\tCR s/p Allo BMT\t46/M\t0 months; concurrent\tCorticosteroids/ALG; Allo BMT\tNot reached (16 months as of publication)\tCR s/p Allo BMT\t\nLouwagie et al., 1978\tlymphocyte predominant; Stage I\tNone\tConcurrent\t24/M\t≤ 2 months; concurrent\tCorticosteroids\t8 months\tDied of cerebral hemorrhage\t\nMendenhall et al., 1989\tN/A; Stage IIIB\tMOPP, MTNI\tCR\t14/M\t2 years\tSupportive\t1 months\tDied within 1 month of AA diagnosis\t\nRovo et al., 2017 (5 cases)\t1 nodular sclerosis; 2 lymphocyte predominant; 1 mixed cellularity; 1 unspecified\tUnknown\tUnknown\tUnknown\tConcurrent; 12 months; 20 months; 8 years; 10 years\tUnknown\tUnknown\tUnknown\t\nSaitoh et al., 2007\tnodular sclerosis; Stage IVA\tC-MOPP\tCR\t39/F\t12 years\tPrednisolone/CsA\t14 months\tRefractory; died of GI hemorrhage\t\nZamar et al., 1956\tN/A\tNone\tConcurrent\t12/M\t0 months; concurrent\tSupportive\t3 months\tDied 3 months after AA diagnosis\t\nN/A, Not Available; HL, Hodgkin Lymphoma; AA, Idiopathic Acquired Aplastic Anemia; ABVD, Doxorubicin, Bleomycin, Vinblastine, Dacarbazine; ASHAP, Doxorubicin, Solumedrol, Cytarabine, Cisplatin; MOPP, Mechlorethamine, Vincristine, Procarbazine, Prednisone; C-MOPP, Cyclophosphamide, Vincristine, Procarbazine, Prednisone; MTNI, Modified Total Nodal Irradiation; CR, Complete Remission; PR, Partial Response; Allo BMT, Allogenic Bone Marrow Transplant; ATG, Antithymocyte Globulin; hATG, Horse Antithymocyte Globulin; CsA, Cyclosporine A; Tac, Tacrolimus; G-CSF, Granulocyte Colony Stimulating Factor; ALG, Antilymphocyte Globulin; TRMN, Therapy-Related Myeloid Neoplasm; GI, Gastrointestinal.\n\naIncomplete staging information.\n\nbAA diagnosed and treated before onset of HL.\n\nUsing a conservative assumption that all HL patients who were seen at the Hospital of the University of Pennsylvania between 2005 and 2018 had their AA diagnosis captured within the University of Pennsylvania medical record, the estimated incidence of AA in HL patients was ~151 cases per million HL patients per year (4 in 26,497 person-years, 95% CI [41 per million, 385 per million]). Compared to the published epidemiologic data for AA incidence in the general population of 2.2 cases per million per year in Western countries to ~7 cases per million per year in Asia [6],[19], we estimate that patients with HL have at least a 20-fold higher incidence of AA compared to the general population (range: 21 to 68-fold higher; p = 0.0001). Because of the strikingly high incidence of AA in our HL patient cohort, we wondered whether the increased AA incidence could be explained by atypical referral patterns to our tertiary care center. To address this question, we compared the observed prevalence of AA in our institutional cohort to that reported in prospective studies of long-term outcomes in HL patients; a prevalence comparison was performed because the incidence data for AA in published HL cohorts was not available. We found that the prevalence of AA in our institutional cohort (0.2%, 4 of 2040, 95% CI [0.05%, 0.51%]) was not different from the prevalence of AA in prospective HL cohorts, where AA was reported at frequencies of 0.7% (1 of 138) [24] and 0.5% (1 of 200) [25] (p = 0.205). Because no published data on the prevalence of AA in B cell neoplasms are available, we compared the prevalence of AA in patients with HL to the AA prevalence in patients with chronic lymphocytic leukemia (CLL) also seen at our institution. The prevalence of AA in HL patients was higher than in patients with CLL (0.2% (4 of 2040) compared to 0.04% (1 of 2802)), although the small number of patients limited the strength of this comparison (p = 0.169).\n\nTwelve additional cases of AA in HL patients were identified through a systematic literature review\nTo more comprehensively evaluate the characteristics of AA when presenting in patients with HL, we performed a systematic literature review. Using a literature search strategy in accordance PRISMA best practices for systematic reviews and meta-analyses, we identified 172 unique abstracts of which 25 full-text articles fulfilled the eligibility criteria (Figure A in S1 Appendix). After a detailed review, we identified eight articles that included a total of 12 cases where HL patients were also diagnosed with AA (Fig 2, Table 2). In all cases, AA was diagnosed either concurrently with HL or when the patient was in remission from a previous HL diagnosis.\n\nClinical and pathologic characteristics of AA occurring in HL patients\nOf the 16 patients with AA and HL (four from our institution and 12 identified through the systematic literature review), the median age at AA diagnosis was 31.5 years (range: 12 to 49 years) with eight of the ten patients who had evaluable demographic information being male (80%). Fifteen of the 16 patients (93.8%) developed AA after or concurrent with a HL diagnosis (Table 2). From the 15 cases for which the interval between the two diagnoses was available, six patients (40.0%) developed AA concurrently with HL (i.e. identified simultaneously or recognized in short succession within two months of diagnosis of HL), three patients (20.0%) developed AA within two years of HL diagnosis, five patients (33.3%) developed AA over five years after HL diagnosis, and one patient (6.7%) had an AA diagnosis that preceded HL by 13 years. The median interval between HL diagnosis and AA onset was 16 months, ranging from concurrent presentation to a maximum of 14 years after HL.\n\nOf the 11 patients with available HL pathologic subtype, six had nodular sclerosis (54.6%), one had lymphocyte depleted HL (9.1%), one had mixed cellularity HL (9.1%), and three patients presented with lymphocyte predominant HL (27.3%) (Table 2). HL subtype was not available for five patients. Six patients were diagnosed with advanced stage (stage III-IV), and three patients had early-stage HL; staging information was not available for seven patients (Table 2). None of the patients had HL involvement of their bone marrow at the time of AA diagnosis.\n\nAt the time of AA diagnosis, AA was graded as severe or very severe in all patients for whom severity grading information was available (eight of eight patients). Cytogenetic analysis at the time of AA diagnosis was normal in all evaluable patients (five of five patients). Among the four cases from our institution, two had remote diagnoses of MALT lymphoma (one treated by splenectomy, one by rituximab monotherapy), and one had a prior history of testicular carcinoma treated by orchiectomy and chemotherapy. There was no family history suggestive of inherited bone marrow failure syndromes in any of the cases.\n\nTreatment and outcomes\nPatients presenting with HL and AA sequentially received therapy that generally followed standard practices for each condition. One patient presented with AA before HL and was treated with ATG-based immunosuppression, achieving a complete remission; he subsequently developed HL 13 years after his AA diagnosis and achieved a complete remission with ABVD. Nine patients presented with HL before AA: all patients for whom HL treatment and outcome information was available (five of the five evaluable patients) received standard HL-directed chemotherapy, achieving a complete remission from HL (Table 2). All five patients subsequently died of AA-related complications: two patients received ATG/CsA without response (one subsequently evolved to TRMN, and one died of AA-related complications after salvage allogeneic BMT and graft failure), one patient was treated with CsA and steroids without response and died of hemorrhage, and two patients received supportive care only (Table 2).\n\nIn contrast, there was no consensus approach for therapy among the six patients who presented with AA and HL concurrently. Of the five patients with available treatment and outcome information, only one patient achieved a complete remission at 16 months of follow-up: he was treated with immunosuppression with anti-lymphocyte globulin and steroids with persistent cytopenias, followed by MUD-BMT with Cy and total lymphoid irradiation conditioning; his HL was reported to have been in radiographic remission as assessed by thoracic chest computed tomography at the time of transplant. One patient was treated with brentuximab vedotin for HL with progression after eight cycles and with eltrombopag monotherapy for AA without response; he died of neutropenic sepsis after one cycle of salvage ICE chemotherapy. One patient was treated with MOPP (mechlorethamine, vincristine, procarbazine, prednisone) therapy for HL with a complete response of HL and a transient improvement of bone marrow aplasia, followed by a recurrence of AA four months after the patient achieved a complete remission from HL; no additional clinical follow-up is presented in the publication. Two patients were treated with supportive care only.\n\nOverall, of the ten patients who developed AA concurrent with or after HL with available outcome information, eight patients (80%) died of AA-related complications at a median of eight months (range: 1 to 84 months) from the time of AA diagnosis, one patient continued to have AA at the time of the report, and only one patient achieved a complete remission from both AA and HL after Allo BMT (Fig 2, Table 2).\n\nDiscussion\nOur data demonstrate that patients with HL have at least a 20-fold higher incidence of AA compared to the general population. We show that in HL patients, AA is significantly more likely to arise concurrently with or after a diagnosis of HL, and thus is probably not linked to previous exposure to cytotoxic chemotherapy. Our results indicate that AA occurs without marrow involvement by HL and in 25% of patients, AA emerges multiple years after achieving a complete remission from HL. We show that outcomes of HL patients who develop AA are extremely poor with current management strategies for AA, with 80% of patients in our study for whom outcome information was available dying from AA-related complications. Taken together, our findings suggest that the occurrence of HL increases the risk of developing AA and underscore the need for improved recognition and treatment of this patient population.\n\nProspective epidemiologic studies of rare disorders can be logistically prohibitive, particularly for studies of co-occurrence of two very rare diseases such as HL and AA. We acknowledge that it is not possible to estimate with precision the incidence of AA in HL patients based on a retrospective analysis, which can be affected by referral and ascertainment biases. Importantly, despite this limitation, our results provide multiple lines of evidence for a significantly increased incidence of AA in HL patients. First, our results likely underestimate the true incidence of AA in our institutional cohort because not all HL patients continued to receive follow-up at our institution for the full duration of the study period. Second, the prevalence of AA in our institution’s cohort is in agreement with several prospective studies of HL outcomes, where single cases of AA were noted in cohorts of only 130–200 patients [24, 25]. It is likely that some prospective HL studies did not include AA or non-malignant hematologic conditions as a reportable outcome; additionally, clinical trials of HL may not have included HL patients with concurrent AA. Finally, the link between the occurrence of HL and risk of AA is further supported by the striking temporal association between the HL and AA diagnoses, where HL precedes or occurs concurrently with AA in nearly all cases. Only one patient in our study developed AA prior to HL, and to the best of our knowledge there have been no additional reports of HL in patients previously treated for AA neither in individual case reports nor in clinical trials of AA patients. Because of the different order of ocurrence, we speculate that the relationship between AA and HL emergence in Patient 4 is distinct from other cases. Importantly, even after excluding that case, the estimated incidence of AA in HL patients in our study (113 per million per year with 95% CI of [23 per million, 331 per million]) is still significantly higher than the population-based incidence of 2.2 cases per million per year in Western countries to ~7 cases per million per year in Asia (p<0.05) [6],[19].\n\nThe mechanism through which HL can predispose to the development of AA is not known. Because immune dysregulation is a feature of both AA and HL, we hypothesize that the link may be due to a HL-related break in immune tolerance, e.g., through cross-reacting immune responses directed against HL or by altering immune regulatory pathways. Importantly, our results argue against several alternative explanations. AA is unlikely to represent a late toxicity related to HL therapy because in 37.5% of HL patients who also developed AA, AA was found concurrently with HL without prior HL-directed treatment. Similarly, AA is unlikely to be a paraneoplastic manifestation of HL because ~25% of patients developed AA after two years or more of complete remission from HL. The strict temporal relationship with HL preceding AA argues against a common infectious trigger or an occult inherited bone marrow failure syndrome, situations in which a predilection for one diagnosis occurring temporally before the other would not be expected. Notably, none of the patients in our cohort received checkpoint inhibitor immunotherapy for HL, the introduction of which could theoretically further increase the incidence of HL-associated AA.\n\nImportantly, our analysis indicates that in contrast to AA in the general population, where five-year overall survival is >80% in pediatric and >60% in adult patients [27], the outcomes of AA in patients with HL diagnosed concurrently or those with a prior history of HL are markedly inferior. Eighty percent of patients in our study for whom survival information is available died from AA-related complications at a median survival of eight months from the time of AA diagnosis. We cannot make definitive conclusions as to the reasons for such poor outcomes, because this would require larger, prospective studies. However, our study raises several potential possibilities. Because AA is rare and remains a diagnosis of exclusion, patients with a history of HL or concurrent HL may have a delay in diagnosis of AA and thus a delay in starting AA-directed therapy; 40% of evaluable patients in our study received supportive care only. Our cohort includes three patients who presented with AA at least a decade after achieving a complete remission with standard cytotoxic therapy for HL and were treated with immunosuppression for AA (two with ATG/CsA and one with CsA/steroids). All three patients were refractory to immunosuppression and died of AA-related complications, including one patient who evolved to TRMN after immunosuppression. We speculate that patients with a prior history of intensive chemotherapy could have a compromised stem cell pool and may have impaired hematopoietic recovery and be predisposed to clonal complications. In fact, both patients from our institution experienced clonal evolution after immunosuppression—one patient developed a new cytogenetic abnormality while the other transformed to a myeloid neoplasm. An alternative explanation for poor response to immunosuppression may be that the etiology of AA, at least in some HL patients, may instead be due to an overlap between AA and hypoplastic MDS [28] or may not be immune-mediated. Finally, the treatment of patients presenting with AA and HL concurrently is particularly challenging. Our results indicate that the majority of this population did not receive standard therapy for either condition and that outcomes for this group are mostly driven by AA-related complications. Novel approaches, perhaps incorporating upfront allogeneic BMT, are needed to improve overall survival in this population.\n\nIn conclusion, we have shown that patients with HL have a significantly higher incidence of AA compared to the general population. Our results underscore that HL-associated AA carries a poor prognosis with conventional approaches to therapy. Recognition of this association, both when presenting as a new diagnosis of AA in a patient with a remote history of HL or as a new diagnosis of HL concurrent with severe pancytopenia and bone marrow aplasia, is essential for the institution of optimal therapy and the improvement of outcomes in this population. Future studies are needed to determine the pathogenic mechanisms underlying the development of AA in HL patients, as well as to develop more effective treatment approaches for this rare and difficult-to-treat population.\n\nSupporting information\nS1 Appendix Supporting appendix containing Tables A- C, and Figure A.\n(DOCX)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Young NS . Current concepts in the pathophysiology and treatment of aplastic anemia . 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International Journal of Laboratory Hematology . 2014 :382 –7 .\n17 Rovo A , Kulasekararaj A , Medinger M , Chevallier P , Ribera JM , Peffault de Latour R , et al\nAssociation of aplastic anaemia and lymphoma: a report from the severe aplastic anaemia working party of the European Society of Blood and Bone Marrow Transplantation . Br J Haematol . 2017 .\n18 Skinnider BF , Mak TW . The role of cytokines in classical Hodgkin lymphoma . Blood . 2002 ;99 (12 ):4283 –97 . 10.1182/blood-2002-01-0099 \n12036854 \n19 International Agranulocytosis and Aplastic Anemia Study . Incidence of aplastic anemia: the relevance of diagnostic criteria . Blood . 1987 ;70 (6 ):1718 –21 . 3676511 \n20 SEER*Explorer: An interactive website for SEER cancer statistics. [Available from: https://seer.cancer.gov/explorer/.\n21 Swerdlow SH , Campo E , Pileri SA , Harris NL , Stein H , Siebert R , et al\nThe 2016 revision of the World Health Organization classification of lymphoid neoplasms . Blood . 2016 ;127 (20 ):2375 –90 . 10.1182/blood-2016-01-643569 \n26980727 \n22 Swerdlow SH , Campo E , Harris NL , Jaffe ES , Pileri SA , Stein H . WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues . Lyon, France : IARC Press ; 2008 .\n23 Scheinberg P , Young NS . How I treat acquired aplastic anemia . Blood . 2012 ;120 (6 ):1185 –96 . 10.1182/blood-2011-12-274019 \n22517900 \n24 Brusamolino E , Orlandi E , Morra E , Castelli G , Pagnucco G , Livraghi A , et al\nAnalysis of long-term results and prognostic factors among 138 patients with advanced Hodgkin's disease treated with the alternating MOPP/ABVD chemotherapy . Ann Oncol . 1994 ;5 \nSuppl 2 :53 –7 .7515648 \n25 Mendenhall NP , Shuster JJ , Million RR . The impact of stage and treatment modality on the likelihood of second malignancies and hematopoietic disorders in Hodgkin's disease . Radiother Oncol . 1989 ;14 (3 ):219 –29 . 2710953 \n26 Moher D , Liberati A , Tetzlaff J , Altman DG , Group P . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement . J Clin Epidemiol . 2009 ;62 (10 ):1006 –12 . 10.1016/j.jclinepi.2009.06.005 \n19631508 \n27 Locasciulli A , Oneto R , Bacigalupo A , Socie G , Korthof E , Bekassy A , et al\nOutcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade: a report from the European Group for Blood and Marrow Transplantation (EBMT) . Haematologica . 2007 ;92 (1 ):11 –8 . 17229630 \n28 Babushok DV , Stanley N , Xie HM , Huang H , Bagg A , Olson TS , et al\nClonal Replacement Underlies Spontaneous Remission in Paroxysmal Nocturnal Haemoglobinuria . Br J Haematol . 2017 ;176 (3 ):487 –90 . 10.1111/bjh.13963 \n26913981\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "14(4)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D000741:Anemia, Aplastic; D000970:Antineoplastic Agents; D006689:Hodgkin Disease; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012196:Review Literature as Topic; D012307:Risk Factors; D014481:United States",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0215021",
"pmc": null,
"pmid": "30951562",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "23926297;22517900;16079101;12941546;15327519;29265360;16254144;3676511;7994040;17229630;12036854;23798465;2710953;18379007;24319166;28232583;26913981;7144530;28971166;24750685;7515648;9283913;26980727;9091802;29143887;19631508",
"title": "Hodgkin lymphoma patients have an increased incidence of idiopathic acquired aplastic anemia.",
"title_normalized": "hodgkin lymphoma patients have an increased incidence of idiopathic acquired aplastic anemia"
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"abstract": "We describe the neuraxial anesthetic management of a 28-year-old primigravid patient with severe, treatment-refractory anti-N-methyl-D-aspartate receptor encephalitis undergoing cesarean delivery. The presence of an ovarian teratoma was suspected although not confirmed by imaging. The severity of symptoms, ineffective immunotherapy and the need for chemotherapy necessitated cesarean delivery and resection of a suspected teratoma at 28weeks estimated gestational age. A combined spinal-epidural technique was used. Delivery was uneventful, and a right oophorectomy was performed for a visible lesion that was later confirmed to be a mature cystic teratoma.",
"affiliations": "Department of Anesthesiology, Bassett Healthcare, Cooperstown, NY, USA. Electronic address: ldemma@gmail.com.;Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA.;Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA.",
"authors": "Demma|L|L|;Norris|S|S|;Dolak|J|J|",
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"country": "Netherlands",
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"issue": "31()",
"journal": "International journal of obstetric anesthesia",
"keywords": "Anesthesia, combined spinal-epidural; Anti-N-methyl-D-aspartate receptor encephalitis; Cesarean delivery; Ovarian teratoma",
"medline_ta": "Int J Obstet Anesth",
"mesh_terms": "D000328:Adult; D000767:Anesthesia, Epidural; D000773:Anesthesia, Obstetrical; D000775:Anesthesia, Spinal; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D002585:Cesarean Section; D005260:Female; D006801:Humans; D009407:Nerve Block; D010051:Ovarian Neoplasms; D010052:Ovariectomy; D010347:Patient Care Planning; D011247:Pregnancy; D013724:Teratoma",
"nlm_unique_id": "9200430",
"other_id": null,
"pages": "104-107",
"pmc": null,
"pmid": "28684142",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neuraxial anesthesia in a patient with anti-N-methyl-D-aspartate receptor encephalitis in pregnancy: management for cesarean delivery and oophorectomy.",
"title_normalized": "neuraxial anesthesia in a patient with anti n methyl d aspartate receptor encephalitis in pregnancy management for cesarean delivery and oophorectomy"
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{
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"abstract": "Amphotericin B deoxycholate (AmBd) is rarely used due to its adverse effect profile, which includes nephrotoxicity, infusion-related reactions, and hepatotoxicity. The incidence of hepatotoxicity related to AmBd is 18-23%, but the reports of this adverse effect are mainly in immunocompromised patients receiving chemotherapy. We report a case of AmBd-related acute hepatic injury in an immunocompetent male with multiple medical problems. The patient initially had acute hepatic injury likely caused by poor nutritional status and a diagnosis of failure to thrive, but was recovering. He was also diagnosed with bilateral renal fungal mycetomas and received systemic treatment initially with micafungin and then fluconazole after urine cultures returned with the growth of Candida glabrata. Therapy was expanded to systemic AmBd when the fungal balls persisted. The patient subsequently developed hepatic re-injury with 1 dose of AmBd, and the therapy was discontinued. Caution should be exerted when utilizing AmBd in treating patients with previous hepatic injury.",
"affiliations": "Department of Pharmacy Practice, University of Mississippi School of Pharmacy, Jackson, Mississippi, USA.;Department of Pharmacy Practice, University of Mississippi School of Pharmacy, Jackson, Mississippi, USA.",
"authors": "Wagner|Jamie L|JL|;Bell|Allison M|AM|",
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"doi": "10.4103/0976-500X.184779",
"fulltext": "\n==== Front\nJ Pharmacol PharmacotherJ Pharmacol PharmacotherJPPJournal of Pharmacology & Pharmacotherapeutics0976-500X0976-5018Medknow Publications & Media Pvt Ltd India JPP-7-11210.4103/0976-500X.184779Case ReportAcute hepatic injury with amphotericin B deoxycholate in an immunocompetent patient Wagner Jamie L. Bell Allison M. Department of Pharmacy Practice, University of Mississippi School of Pharmacy, Jackson, Mississippi, USAAddress for correspondence: Jamie L. Wagner, Department of Pharmacy Practice, University of Mississippi School of Pharmacy, 2500 N State Street, Jackson, Mississippi 39216, USA. E-mail: jwagner@umc.eduApr-Jun 2016 7 2 112 114 16 12 2015 19 2 2016 30 5 2016 Copyright: © Journal of Pharmacology and Pharmacotherapeutics2016This 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.Amphotericin B deoxycholate (AmBd) is rarely used due to its adverse effect profile, which includes nephrotoxicity, infusion-related reactions, and hepatotoxicity. The incidence of hepatotoxicity related to AmBd is 18–23%, but the reports of this adverse effect are mainly in immunocompromised patients receiving chemotherapy. We report a case of AmBd-related acute hepatic injury in an immunocompetent male with multiple medical problems. The patient initially had acute hepatic injury likely caused by poor nutritional status and a diagnosis of failure to thrive, but was recovering. He was also diagnosed with bilateral renal fungal mycetomas and received systemic treatment initially with micafungin and then fluconazole after urine cultures returned with the growth of Candida glabrata. Therapy was expanded to systemic AmBd when the fungal balls persisted. The patient subsequently developed hepatic re-injury with 1 dose of AmBd, and the therapy was discontinued. Caution should be exerted when utilizing AmBd in treating patients with previous hepatic injury.\n\nKey words\nAntifungalCandida glabratafungemialiver dysfunction\n==== Body\nINTRODUCTION\nThe clinical use of amphotericin B deoxycholate (AmBd) is primarily limited due to its adverse effect profile, which includes nephrotoxicity, infusion-related reactions, and hepatotoxicity.[1] Around 18-23% of the patients who receive any formulation of amphotericin B will experience an increase in liver function tests (LFTs), but <1% will actually discontinue therapy due to this elevation.[2] However, most evidence of hepatotoxicity due to amphotericin B is described mainly in oncology patients,[23] with few case reports in immunocompetent patients.[4] We present a case of probable AmBd-induced acute hepatic injury in an immunocompetent patient resulting in drug discontinuation.\n\nCASE REPORT\nA 39-year-old African-American male was admitted (day 1) from a nursing home for a chief complaint of weakness and decreased appetite for several days. He was initially admitted to the medical Intensive Care Unit for suspected sepsis of unknown origin and was started empirically on vancomycin and meropenem. At that time, his urine cultures grew >100,000 colony-forming units (CFU)/mL of Candida glabrata (sensitivities not performed); however, no antifungal therapy was added to his antimicrobial regimen as this was thought to be colonization secondary to his chronic indwelling Foley catheter for urinary retention. He was stabilized and transferred to the general medical floor on day 6 for further management of his sepsis. Subsequent workup on days 10–13 revealed osteomyelitis due to a Stage IV sacral decubitus ulcer with exposed bone. The patient had negative blood cultures, but urine cultures continued to remain positive now yielding 15,000 CFU/mL of Candida albicans (sensitivities not performed) on day 28. This organism was thought to be a colonizer and no treatment was received. The patient was treated for a total of 45 days for his osteomyelitis with a combination of vancomycin and various Gram-negative therapies including meropenem, ertapenem, and ceftazidime.\n\nConcurrently to the patient's infectious workup, he received a workup for failure to thrive (body mass index 14.7 kg/m2) on day 2 and consequently received a percutaneous endoscopic gastrostomy tube placement on day 12. The patient experienced elevated alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase throughout his hospital course, primarily attributed to failure to thrive and poor nutritional status. The patient was also found to have extremely brittle diabetes with occurrences of multiple hypoglycemic episodes correctable with 50% dextrose boluses. The patient was started on insulin glargine 2 units every evening, but this produced large fluctuations in blood sugars ranging from 18 to 460 mg/dL, with an average of 233 mg/dL. The patient was switched to neutral protamine Hagedorn (NPH) insulin on day 51 at 2 units twice daily in an attempt to avoid hypoglycemia. It was also found that when the patient was not allowed to eat or drink, his blood sugars would drop to <50 mg/dL unless a 5% dextrose infusion was administered. Glycemic goals for this patient were to avoid hypoglycemia and diabetic ketoacidosis, which was extremely difficult despite switching from insulin glargine to NPH insulin.\n\nDespite broad-spectrum antimicrobial treatment for osteomyelitis, the patient continued to have leukocytosis. Subsequent blood and urine cultures were drawn on day 34. On day 36, an abdominal computed tomography (CT) scan was ordered to identify other potential sources of infection. The scan demonstrated right-sided pyelonephritis and left-sided hydronephrosis and hydroureter. The patient's antimicrobial therapy was expanded to include micafungin. Urology was consulted on day 37 for further management. A repeat abdominal CT scan on day 38 demonstrated pyelonephritis in both kidneys, as well as filling defects (left >right) and mild debris along the bladder base, indicative of fungus balls/mycetomas. On day 40, urine cultures returned growing 35,000 CFU/mL of C. glabrata (fluconazole with minimum inhibitory concentration [MIC] of 8 and caspofungin MIC of 0.5 mg/L) and C. albicans (fluconazole MIC of 4 mg/L and caspofungin MIC of ≤0.25 mg/L). Blood cultures also returned on day 40 and revealed C. glabrata with a fluconazole MIC of 2 mg/L. The patient was switched from micafungin to high-dose fluconazole based on susceptibilities. In addition, urology recommended drainage of the fungal balls and subsequent irrigation with AmBd via bilateral nephrostomy tubes. A nephrostomy tube was placed in his left kidney on day 45 in an attempt to drain the fungal ball and in preparation for AmBd irrigation. After 6 days of systemic antifungal therapy, the blood cultures cleared; however, a renal ultrasound performed on day 54 was still concerning for continued presence of fungal balls. A lack of improvement in renal impairment was observed, indicated by an estimated glomerular filtration rate of 10-30 mL/min/1.73 m2, which was comparable to prenephrostomy tube placement. The patient eventually required intermittent hemodialysis on day 56. On day 59, the patient was taken to interventional radiology for possible placement of the right nephrostomy tube; however, this placement failed. The decision was then made to discontinue fluconazole and initiate systemic AmBd at 0.7 mg/kg/day (29.3 mg) to treat the renal fungal balls. On day 61, the patient's LFTs significantly worsened [Table 1]. This was attributed to the AmBd (Naranjo adverse drug reaction probability scale score of 5). The patient's LFTs returned almost to near baseline, suggesting amphotericin B as the culprit of acute liver injury.\n\nTable 1 Kidney and liver function test trends leading up to and following amphotericin B deoxycholate administration in a 39-year-old male\n\nAfter it was discussed with the patient that all medical treatment options had been thoroughly exhausted, the patient decided to change his code status to do not resuscitate. The patient's condition continued to decline, and his daughter decided to stop the 5% dextrose infusion that was required to keep his blood glucose normal. The patient expired after 66 days of hospital admission.\n\nDISCUSSION\nThis patient is unique in that he developed renal fungal balls with C. glabrata. Development of renal fungal balls in an adult patient is extremely rare; however, risk factors for development include diabetes mellitus, prolonged antibiotic therapy, and malnutrition.[5] Our patient had all the three of these risk factors: Poor glycemic control with extremely brittle diabetes, an extended antibiotic course for osteomyelitis, and significant malnutrition. Primary therapy for fungus balls, especially with Candida, includes systemic therapy with amphotericin B +/− flucytosine or fluconazole, but almost always requires an invasive procedure to remove the bulk of the infection.[6] This patient was not stable enough to survive an invasive procedure and had already received 26 days of systemic therapy with micafungin and fluconazole, hence the decision was made to switch to AmBd. AmBd binds to sterols in the cell membranes of fungal and human cells due to its high affinity to biological membranes.[3] It achieves the highest concentrations in the liver, yet actual adverse effects on liver function are rare.[7] Unfortunately, this patient received one dose of AmBd and developed acute liver injury. While most patients do not require discontinuation of amphotericin due to acute rises in LFTs, caution should be applied to patients with recent liver injury.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgment\nThe corresponding author attests that all authors contributed significantly to this work. The authors would like to thank Dr. Christopher DeGroat, Dr. Stephen Anderson, Dr. Jarrett Morgan, and Dr. Kenneth Bennett in their management of this complicated patient.\n==== Refs\nREFERENCES\n1 Bristol-Myers Squibb Canada Prescribing Information for Fungizone 2009 Last accessed on 2015 Sep 10 Available from: http://www.bmscanada.ca/static/products/en/pm_pdf/Fungizone_EN_PM.pdf \n2 Wang JL Chang CH Young-Xu Y Chan KA Systematic review and meta-analysis of the tolerability and hepatotoxicity of antifungals in empirical and definitive therapy for invasive fungal infection Antimicrob Agents Chemother 2010 54 2409 19 20308378 \n3 Girois SB Chapuis F Decullier E Revol BG Adverse effects of antifungal therapies in invasive fungal infections: Review and meta-analysis Eur J Clin Microbiol Infect Dis 2006 25 138 49 16622909 \n4 Gill J Sprenger HR Ralph ED Sharpe MD Hepatotoxicity possibly caused by amphotericin B Ann Pharmacother 1999 33 683 5 10410179 \n5 Praz V Burruni R Meid F Wisard M Jichlinski P Tawadros T Fungus ball in the urinary tract: A rare entity Can Urol Assoc J 2014 8 E118 20 24554976 \n6 Fisher JF Sobel JD Kauffman CA Newman CA Candida urinary tract infections – Treatment Clin Infect Dis 2011 52 Suppl 6 S457 66 21498839 \n7 Inselmann G Inselmann U Heidemann HT Amphotericin B and liver function Eur J Intern Med 2002 13 288 92 12144907\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0976-500X",
"issue": "7(2)",
"journal": "Journal of pharmacology & pharmacotherapeutics",
"keywords": "Antifungal; Candida glabrata; fungemia; liver dysfunction",
"medline_ta": "J Pharmacol Pharmacother",
"mesh_terms": null,
"nlm_unique_id": "101552113",
"other_id": null,
"pages": "112-4",
"pmc": null,
"pmid": "27440960",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "16622909;10410179;21498839;12144907;24554976;20308378",
"title": "Acute hepatic injury with amphotericin B deoxycholate in an immunocompetent patient.",
"title_normalized": "acute hepatic injury with amphotericin b deoxycholate in an immunocompetent patient"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2016-03797",
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"activesubstance": {
"activesubstancename": "VANCOMYCIN"
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{
"abstract": "BACKGROUND\nA phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to (i) estimate the maximum tolerated doses (MTDs) or recommended phase II doses (RP2Ds) of veliparib and TMZ; (ii) describe the toxicities of this regimen; and (iii) evaluate the plasma pharmacokinetic parameters and extent of PARP inhibition in peripheral blood mononuclear cells (PBMCs) following veliparib.\n\n\nMETHODS\nTMZ was given once daily and veliparib twice daily for 5 days every 28 days. Veliparib concentrations and poly(ADP-ribose) (PAR) levels in PBMCs were measured on days 1 and 4. Analysis of pharmacokinetic and PBMC PAR levels were performed twice during study conduct to rationally guide dose modifications and to determine biologically optimal MTD/RP2D.\n\n\nRESULTS\nTwenty-nine evaluable patients were enrolled. Myelosuppression (grade 4 neutropenia and thrombocytopenia) were dose limiting. The RP2Ds are veliparib 25 mg/m(2) b.i.d. and TMZ 135 mg/m(2)/d. Only 2 out of 12 patients treated at RP2Ds experienced dose-limiting toxicities. Although no objective response was observed, 4 patients had stable disease >6 months in duration, including 1 with glioblastoma multiforme and 1 with ependymoma. At the RP2D of veliparib, pediatric pharmacokinetic parameters were similar to those in adults.\n\n\nCONCLUSIONS\nVeliparib and TMZ at the RP2D were well tolerated in children with recurrent brain tumors. A phase I/II trial to evaluate the tolerability and efficacy of veliparib, TMZ, and radiation in children with newly diagnosed brainstem gliomas is in progress.",
"affiliations": "Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).;Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).",
"authors": "Su|Jack M|JM|;Thompson|Patrick|P|;Adesina|Adekunle|A|;Li|Xiao-Nan|XN|;Kilburn|Lindsay|L|;Onar-Thomas|Arzu|A|;Kocak|Mehmet|M|;Chyla|Brenda|B|;McKeegan|Evelyn|E|;Warren|Katherine E|KE|;Goldman|Stewart|S|;Pollack|Ian F|IF|;Fouladi|Maryam|M|;Chen|Alice|A|;Giranda|Vincent|V|;Boyett|James|J|;Kun|Larry|L|;Blaney|Susan M|SM|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D003606:Dacarbazine; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide",
"country": "England",
"delete": false,
"doi": "10.1093/neuonc/nou103",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1522-8517",
"issue": "16(12)",
"journal": "Neuro-oncology",
"keywords": "ABT-888; CNS tumors; PARP inhibition; pediatric phase I study; veliparib",
"medline_ta": "Neuro Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D001932:Brain Neoplasms; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine; D005260:Female; D006801:Humans; D007223:Infant; D007963:Leukocytes, Mononuclear; D008297:Male; D020714:Maximum Tolerated Dose; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide; D055815:Young Adult",
"nlm_unique_id": "100887420",
"other_id": null,
"pages": "1661-8",
"pmc": null,
"pmid": "24908656",
"pubdate": "2014-12",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "20609467;12778123;21719137;22307137;21917757;20609468;19526240;17505006;22184287;18199854;16556909;20200537;21795476;14751510;19533660;19934293;16369571;21825264;17473206;16899365;9603959;20547991;20142589;9207086;18456354;21849329;18674509;19364967;21571912;23071597;22833573;20530668;17705175;22028822;12488414",
"title": "A phase I trial of veliparib (ABT-888) and temozolomide in children with recurrent CNS tumors: a pediatric brain tumor consortium report.",
"title_normalized": "a phase i trial of veliparib abt 888 and temozolomide in children with recurrent cns tumors a pediatric brain tumor consortium report"
} | [
{
"companynumb": "US-MYLANLABS-2019M1048628",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Estrogen, whether therapeutic or physiologic, can cause hypertriglyceridemia. Hypertriglyceridemia-induced pancreatitis is a rare complication.\n\n\n\nWe report 2 women who developed estrogen-associated severe hypertriglyceridemia with pancreatitis. The first patient developed pancreatitis secondary to hypertriglyceridemia associated with in vitro fertilization cycles. Marked reduction in her triglyceride was achieved with dietary restrictions and fibrate. The second patient developed pancreatitis secondary to hypertriglyceridemia during her pregnancies. She was noncompliant with the treatment; therefore, her triglyceride remained high after delivery. In both patients, no hypertriglyceridemia-associated genes mutations were identified, although the second patient had strong polygenic susceptibility to hypertriglyceridemia.\n\n\n\nEstrogen-induced severe hypertriglyceridemia with pancreatitis can be a life-threatening condition. Screening in high-risk patients is crucial to prevent subsequent complications.",
"affiliations": "Department of Cardiology and Research Institute, McGill University Health Center, Montreal, Quebec, Canada. Electronic address: sumayah.aljenedil@mail.mcgill.ca.;Department of Endocrinology and Metabolism, Robarts Research Institute, London, Ontario, Canada.;Department of Cardiology and Research Institute, McGill University Health Center, Montreal, Quebec, Canada.;Department of Cardiology and Research Institute, McGill University Health Center, Montreal, Quebec, Canada; Department of Biochemistry and Molecular Genetics, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.",
"authors": "Aljenedil|Sumayah|S|;Hegele|Robert A|RA|;Genest|Jacques|J|;Awan|Zuhier|Z|",
"chemical_list": "D004967:Estrogens",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jacl.2016.12.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-4789",
"issue": "11(1)",
"journal": "Journal of clinical lipidology",
"keywords": "Estrogen; Hypertriglyceridemia; In vitro fertilization; Pancreatitis; Pregnancy",
"medline_ta": "J Clin Lipidol",
"mesh_terms": "D000328:Adult; D036861:Delivery, Obstetric; D004967:Estrogens; D005260:Female; D006801:Humans; D015228:Hypertriglyceridemia; D009154:Mutation; D010195:Pancreatitis; D011247:Pregnancy",
"nlm_unique_id": "101300157",
"other_id": null,
"pages": "297-300",
"pmc": null,
"pmid": "28391900",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Estrogen-associated severe hypertriglyceridemia with pancreatitis.",
"title_normalized": "estrogen associated severe hypertriglyceridemia with pancreatitis"
} | [
{
"companynumb": "CA-009507513-1706LBN009652",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LUTROPIN ALFA"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nNorth American data are lacking on the effect of nucleos(t)ide analogues (NA) in preventing chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC).\n\n\nOBJECTIVE\nTo determine the incidence of HCC in NA-treated patients and compare this risk with that predicted without treatment based on the REACH-B model.\n\n\nMETHODS\nIn this retrospective study, the incidence of HCC was determined in CHB patients initiated on NA from 1999 to 2012. Pre-treatment data utilised in the REACH-B model were used to predict the annual HCC risk. The standardised incidence ratio (SIR) for HCC was calculated by comparing the observed to expected number of cases, and HCC risk factors determined by Cox proportional hazards regression.\n\n\nRESULTS\nFive hundred and forty nine initiated NA (14% lamivudine, 5% adefovir, 1.5% telbivudine, 39% entecavir, 41% tenofovir). Over a median follow-up of 3.2 years (IQR 1.9-4.6), 11 (3.2%) were diagnosed with HCC. Among 322 with data to calculate the REACH-B model, the median age at treatment initiation was 46 years (IQR 38-55), 65% were male, 32% HBeAg positive and 20% had cirrhosis. The median pre-treatment ALT was 71 U/L (IQR 41-127) and HBV DNA was 6.48 log10 copies/mL (4.95-8.04). The observed annual HCC incidence (0.9%; 95% CI 0.5-1.7) was significantly lower than predicted without treatment by the REACH-B model (SIR 0.46; 95% CI 0.23-0.82); this risk was reduced after 4 years of therapy (SIR 0.49; 95% CI 0.2-1.00).\n\n\nCONCLUSIONS\nIn this Canadian study of nucleos(t)ide analogues-treated patients with chronic hepatitis B, the incidence of HCC was lower than expected, suggesting that NA reduce the risk of chronic hepatitis B-related HCC.",
"affiliations": "Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.",
"authors": "Coffin|C S|CS|;Rezaeeaval|M|M|;Pang|J X|JX|;Alcantara|L|L|;Klein|P|P|;Burak|K W|KW|;Myers|R P|RP|",
"chemical_list": "D000998:Antiviral Agents; D006513:Hepatitis B e Antigens; D009705:Nucleosides; D063065:Organophosphonates; D000077712:Telbivudine; D019259:Lamivudine; C413685:entecavir; D006147:Guanine; C053001:adefovir; D000068698:Tenofovir; D000225:Adenine; D013936:Thymidine",
"country": "England",
"delete": false,
"doi": "10.1111/apt.12990",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2813",
"issue": "40(11-12)",
"journal": "Alimentary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Aliment Pharmacol Ther",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000998:Antiviral Agents; D002170:Canada; D006528:Carcinoma, Hepatocellular; D005260:Female; D006147:Guanine; D006513:Hepatitis B e Antigens; D019694:Hepatitis B, Chronic; D006801:Humans; D015994:Incidence; D019259:Lamivudine; D008103:Liver Cirrhosis; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009705:Nucleosides; D063065:Organophosphonates; D012189:Retrospective Studies; D012307:Risk Factors; D000077712:Telbivudine; D000068698:Tenofovir; D013936:Thymidine",
"nlm_unique_id": "8707234",
"other_id": null,
"pages": "1262-9",
"pmc": null,
"pmid": "25312649",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The incidence of hepatocellular carcinoma is reduced in patients with chronic hepatitis B on long-term nucleos(t)ide analogue therapy.",
"title_normalized": "the incidence of hepatocellular carcinoma is reduced in patients with chronic hepatitis b on long term nucleos t ide analogue therapy"
} | [
{
"companynumb": "CA-CIPLA LTD.-2014CA01581",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "Isolated iliac artery aneurysms are rare and commonly associated with aortic aneurysms. Hypogastric artery aneurysms (HAAs) are exceptionally rare. The general approach to HAAs has been exclusion and bypass, although when this is complicated by mycotic disease, endovascular techniques can provide unique approaches to management. We present the case of a patient with a mycotic HAA treated with endovascular coil and exclusion followed by aortic to external iliac artery bypass with cadaveric conduit.",
"affiliations": "Department of Surgery, Santa Barbara Cottage Hospital, Santa Barbara, Calif.;Department of Surgery, Santa Barbara Cottage Hospital, Santa Barbara, Calif.;Department of Internal Medicine, Santa Barbara Cottage Hospital, Santa Barbara, Calif.;Department of Surgery, Santa Barbara Cottage Hospital, Santa Barbara, Calif.",
"authors": "Paisley|Michael|M|;Faunce|Nick|N|;Hosea|Stephen|S|;Casey|Kevin|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jvscit.2018.09.001",
"fulltext": "\n==== Front\nJ Vasc Surg Cases Innov TechJ Vasc Surg Cases Innov TechJournal of Vascular Surgery Cases and Innovative Techniques2468-4287Elsevier S2468-4287(18)30119-910.1016/j.jvscit.2018.09.001Vascular infectionIsolated mycotic hypogastric artery aneurysm Paisley Michael MDmjpaisley@gmail.coma∗Faunce Nick MDaHosea Stephen MDbCasey Kevin MD, FACSaa Department of Surgery, Santa Barbara Cottage Hospital, Santa Barbara, Califb Department of Internal Medicine, Santa Barbara Cottage Hospital, Santa Barbara, Calif∗ Correspondence: Michael Paisley, MD, Department of Surgery, Santa Barbara Cottage Hospital, 400 W Pueblo St, Santa Barbara, CA 93105 mjpaisley@gmail.com31 12 2018 3 2019 31 12 2018 5 1 22 25 5 6 2018 1 9 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Isolated iliac artery aneurysms are rare and commonly associated with aortic aneurysms. Hypogastric artery aneurysms (HAAs) are exceptionally rare. The general approach to HAAs has been exclusion and bypass, although when this is complicated by mycotic disease, endovascular techniques can provide unique approaches to management. We present the case of a patient with a mycotic HAA treated with endovascular coil and exclusion followed by aortic to external iliac artery bypass with cadaveric conduit.\n\nKeywords\nAneurysmHypogastric artery aneurysmMycotic aneurysm\n==== Body\nIliac artery aneurysms are frequently found in conjunction with aortic aneurysms and isolated iliac aneurysms are uncommon. The incidence of hypogastric artery aneurysms (HAAs) is exceedingly low, occurring in <0.0001% of the population.1, 2 Mycotic HAAs have rarely been described in the literature.3, 4, 5 The best treatment of this rare entity may be different from and more challenging than that of a mycotic aortoiliac aneurysm. We present the case of a patient with an infected HAA and discuss a unique approach to treatment of this unusual entity. The patient consented to publication of this case.\n\nCase report\nA 78-year-old man was handling and eating rattlesnakes near his home when several days later he developed profound myalgias and arthralgias. He was seen by a medical provider, diagnosed with polymyalgia rheumatica, and treated with steroids. He was transferred to our medical facility with persistently high fevers and left-sided hip and testicular pain. Blood cultures identified Salmonella arizonae bacteremia, and cross-sectional imaging revealed a 3.8-cm left HAA with surrounding inflammation (Fig 1).Fig 1 A 3.8-cm left hypogastric artery aneurysm (HAA) with surrounding inflammation, marked by the white arrow.\n\n\n\nIntravenous antibiotics were administered, and after clearance of bacteremia and systemic illness, he underwent an endovascular repair. After diagnostic aortography from a percutaneous bilateral common femoral artery approach, the patient was heparinized in the standard fashion. The left HAA was first embolized from a contralateral approach with two Amplatzer (Abbott, St. Paul, Minn) vascular plugs (7 × 10 mm, 9 × 12 mm). Next, from an ipsilateral common femoral artery approach, a covered stent was placed extending from the common iliac artery to external iliac artery (EIA) using an Excluder (W. L. Gore & Associates, Flagstaff, Ariz) limb placed in a reversed configuration (Fig 2).6 There were no acute postoperative complications, and he was discharged home on intravenous ceftriaxone for 4 weeks. One-month computed tomography (CT) scan showed a patent stent with successful occlusion of the aneurysm and complete resolution of the associated inflammation (Fig 3). He was transitioned to trimethoprim-sulfamethoxazole for lifelong suppression. His antibiotic regimen was switched to azithromycin at 6 weeks because of gastrointestinal intolerance. Three months after the endovascular intervention, he presented with recurrence of fever, malaise, and left thigh and testicular pain. Blood cultures were negative, but erythrocyte sedimentation rate and C-reactive protein level were significantly elevated. A repeated CT scan demonstrated a dilated portion of the EIA where the graft was in place, with adjacent inflammatory changes noted throughout the psoas muscle and surrounding retroperitoneum. The patient's symptoms quickly resolved with intravenous antibiotics, and he was discharged with short-term follow-up.Fig 2 Covered stent placement with internal iliac exclusion.\n\nFig 3 Computed tomography (CT) follow-up at 1 month demonstrating resolution of inflammation and patency of stent.\n\n\n\nA subsequent CT scan demonstrated aggressive dilation of the EIA to 2.6 cm (Fig 4). Because of the concern of an infected endovascular stent and aggressive aneurysmal dilation, the patient underwent an aorto-EIA bypass. This was performed through lower midline laparotomy with standard retroperitoneal exposure. Proximal control was obtained at the aorta and right common iliac artery and distal control at the EIA. Explantation of the stent graft and native iliac arteries with débridement of all inflamed retroperitoneal tissue was performed. All intraoperative cultures, including those taken of the covered stent, retroperitoneum, and native iliac vessels, were negative. Vascular reconstruction was performed using cryopreserved artery (CryoLife Inc, Kennesaw, Ga). The patient had an uneventful postoperative course. He remained on oral antibiotics for a period of 6 months after surgery and has had no long-term evidence of infection at 18 months.Fig 4 Axial images with inflammatory changes around dilated portion of external iliac artery (EIA), marked by the white arrow.\n\n\n\nDiscussion\nIliac artery aneurysms are rare. Autopsy studies demonstrate that 0.2% of the population have isolated iliac vessel aneurysms. However, common iliac artery aneurysms can occur in up to 20% of patients with concomitant abdominal aortic aneurysms.7 Unlike abdominal aortic aneurysms, no screening criteria exist for these, which often are incidentally identified.\n\nIsolated HAAs represent an even rarer pathologic process, accounting for <0.4% of the population. Because no imaging had previously been performed, we presume the HAA was mycotic rather than a pseudoaneurysm, which would be even less likely. Although there is a paucity of literature on HAAs, most available reports focus on management of acute rupture.8, 9, 10 The traditional approach to treating HAAs is centered on exclusion and bypass with autogenous conduit in the setting of infection. Distal control has proved exceptionally difficult because of the vessels' retroperitoneal and pelvic location and adjacent venous structures. As endovascular techniques have become more prevalent, coil embolization and coverage of aneurysms are now commonly performed. Whereas buttock claudication has been noted in up to 30% of patients with unilateral hypogastric artery ligation, it usually resolves. Vascular impotence and ischemic complications (colonic ischemia, buttock necrosis) are reported but uncommon in patients with a patent contralateral hypogastric artery.11, 12\n\nMycotic aneurysms (MAs) represent <1% of all aneurysms. Historically associated with syphilis, they are now more commonly due to bacterial endocarditis. Staphylococcus aureus is a commonly identified pathogen, usually from septic emboli. Salmonella, the most common pathogen identified today, is thought to be related to dietary habits and transient bacteremia. This includes the handling and ingestion of rattlesnake meat.13, 14 MAs have been found to progress more rapidly than atherosclerotic aneurysms, possibly because of bacterial enzyme production (elastase, pancrease) and the lysosomal enzyme released by neutrophils as a part of the innate immune response.\n\nThe approach to MAs is both patient and case specific, with immediate repair indicated for rupture or symptomatic MAs. Repair can be performed by ligation and subsequent oversewing of outflow vessels or ligation with venous patch closure of the origin of the hypogastric artery. Extra-anatomic bypass or in-line reconstruction with autogenous vein, rifampin-soaked Dacron, or cadaveric tissue can be performed. An in-line bypass was chosen because of the higher patency rates compared with extra-anatomic bypass. In addition, a femoral-femoral crossover bypass adds incisions in the bilateral groins but could be reserved for the unlikely event of graft failure or development of aneurysm in the cadaveric tissue.15, 16 We contemplated using superficial femoral vein for this procedure but chose cadaveric artery. Although not prohibitive, his prior saphenous vein harvests made this option less attractive, as did the increased morbidity and extensive dissection.\n\nWhereas open repair has historically been standard of care for treatment of nonmycotic aneurysmal disease, the endovascular approach has become an equally acceptable and more frequently chosen option.17 It can be argued that graft placement in a ruptured MA contradicts general surgical principals. Yet one review of the literature found that an endovascular approach was successful in 76% of cases and that many of these patients did not require graft explantation after placement.18 Lifelong antibiotics were required for all patients.\n\nThe treatment of mycotic aortoiliac aneurysms has been adequately reviewed. There is very little in the literature regarding treatment of mycotic HAAs.5 As such, no true algorithm exists as to the best treatment plan. The treatment of a mycotic HAA presents several unique challenges. As previously stated, its location deep in the pelvis makes an initial open repair less appealing. As with all elective approaches, we were certain to ensure that the bacteremia was effectively treated and the patient had no clinical signs of infection. Our “coil and cover” approach was performed with two percutaneous access sites and minimal blood loss and ensured successful exclusion of the aneurysm. The patient initially responded well and appeared to have a successful outcome.\n\nHowever, several months later, the patient returned with concerns of recurrent infection. Although he never had evidence of recurrent Salmonella bacteremia, despite many preoperative and intraoperative cultures, the concern was high, given his symptoms. The main impetus for returning to the operating room was the aggressive dilation of the EIA after graft placement. Whereas this can occur from aggressive graft oversizing (>20%), this was not the case in our patient. We believe this was more likely secondary to significant inflammation at initial presentation (Fig 4) and possible sequelae of subclinical infection. The subsequent inflammatory extension to the psoas muscle and surrounding tissues may have led to a weakening of the vessel walls and predisposed the patient to future dilation. Although studies have demonstrated successful outcomes of covered stents placed for MAs, caution should be exercised in placing stents for the treatment of more virulent organisms as definitive therapy. Furthermore, close follow-up with the patient must be maintained because of the concern for future problems and aneurysmal degeneration.\n\nConclusions\nOur initial strategy of HAA exclusion and covered stent placement proved to be a bridge to open surgery. This approach allowed the aneurysm to thrombose, reduced immediate inflammation, and temporized disease progression in the setting of active infection, which likely assisted in the patient's overall outcome. Consideration should be given to this approach, especially in patients who are poor surgical candidates. Lifelong treatment with antibiotics should be considered, although it may not be necessary if a cadaveric bypass is used. The best treatment plan should be patient and pathogen guided.\n\nAuthor conflict of interest: none.\n\nThe editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest.\n==== Refs\nReferences\n1 Zimmer P.W. Raker E.J. Quigley T.M. Isolated hypogastric artery aneurysms Ann Vasc Surg 13 1999 545 549 10467000 \n2 Lucke B. Rea M.H. Studies on aneurysm. I. General statistical data on aneurysms JAMA 77 1921 935 940 \n3 Tatebe S. Kanazawa H. Yamazaki Y. Aoki E. Sakurai Y. Mycotic aneurysm of the internal iliac artery caused by Klebsiella pneumoniae Vasa 25 1996 184 187 8659223 \n4 Kretz B. Pages P.B. Loffroy R. Piroth L. Bastable P. Steinmetz E. Aneurysm of both internal iliac arteries due to Candida albicans Ann Vasc Surg 28 2014 e11 e14 \n5 Purnell R.A. Ruptured mycotic aneurysm of the internal iliac artery and septic arthritis complicating Salmonella infection Br J Clin Pract 44 1990 497 499 2282306 \n6 van der Steenhoven T.J. Heyligers J.M. Tielliu I.F. Zeebregts C.J. The upside down Gore Excluder contralateral leg without extracorporeal predeployment for aortic or iliac aneurysm exclusion J Vasc Surg 53 2011 1738 1741 21296541 \n7 Armon M.P. Wenham P.W. Whitaker S.C. Gregson R.H. Hopkinson B.R. Common iliac artery aneurysms in patients with abdominal aortic aneurysms Eur J Vasc Endovasc Surg 15 1998 255 257 9587341 \n8 Yu S.Y. Shieh H.C. Ko P.J. Huang Y.K. Chu J.J. Lee C.H. Surgical outcomes for mycotic aortic and iliac aneurysm World J Surg 35 2011 1671 1678 21541801 \n9 Sugimoto M. Banno H. Idetsu A. Matsushita M. Ikezawa T. Komori K. Surgical experience of 13 infected infrarenal aortoiliac aneurysms: preoperative control of septic condition determines early outcome Surgery 149 2011 699 704 21429546 \n10 Laohapensang K. Aworn S. Orrapi S. Rutherford R. Management of the infected aortoiliac aneurysms Ann Vasc Dis 5 2012 334 341 23555533 \n11 Farahmand P. Becquemin J.P. Desgranges P. Allaire E. Marzelle J. Roudot-Thoraval F. Is hypogastric artery embolization during endovascular aortoiliac aneurysm repair (EVAR) innocuous and useful? Eur J Vasc Endovasc Surg 35 2008 429 435 18276173 \n12 Mehta M. Veith F.J. Ohki T. Cynamon J. Goldstein K. Suggs W.D. Unilateral and bilateral hypogastric artery interruption during aortoiliac aneurysm repair in 154 patients: a relatively innocuous procedure J Vasc Surg 33 Suppl 2001 S27 S32 11174809 \n13 Benenson S. Raveh D. Schlesinger Y. Alberton J. Rudensky B. Hadas-Halpem I. The risk of vascular infection in adult patients with nontyphi Salmonella bacteremia Am J Med 110 2001 60 63 11152867 \n14 Lukac M. Pedersen K. Prukner-Radovcic E. Prevalence of Salmonella in captive reptiles from Croatia J Zoo Wildl Med 46 2015 234 240 26056873 \n15 Leidenbaum M. Verdam F. Spelt D. de Groot H. van der Wall J. van der Lann L. The outcome of the axillofemoral bypass: a retrospective analysis of 45 patients World J Surg 33 2009 2490 2496 19697078 \n16 Lee G.C. Yang S.S. Park K.M. Park Y. Kim Y.W. Park K.B. Ten year outcomes after bypass surgery in aortoiliac occlusive disease J Korean Surg Soc 82 2012 365 369 22708098 \n17 Mehta M. Byrne J. Darling R.C. Paty P.S. Roddy S.P. Kreienberg P.B. Endovascular repair of ruptured infrarenal aortic aneurysm is associated with lower 30-day mortality and better 5-year survival rates than open surgical repair J Vasc Surg 57 2013 368 375 23265582 \n18 Shahi N. Kwon J.J. Arosemena M. Salvatore D.M. DiMuzio D.J. Abai B. Endovascular repair of ruptured infected arteries as a temporizing measure versus destination therapy Vasc Endovasc Surg 50 2016 373 379\n\n",
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"issue": "5(1)",
"journal": "Journal of vascular surgery cases and innovative techniques",
"keywords": "Aneurysm; Hypogastric artery aneurysm; Mycotic aneurysm",
"medline_ta": "J Vasc Surg Cases Innov Tech",
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"title": "Isolated mycotic hypogastric artery aneurysm.",
"title_normalized": "isolated mycotic hypogastric artery aneurysm"
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"abstract": "BACKGROUND\nWith advances in minimally invasive approaches, laparoscopically placed abdominal cerclages are becoming more common. Although not meant to replace vaginally placed cerclages, one potential advantage is reuse in subsequent pregnancies. Their lifespan, potential remote complications, and long-term management remain unexplored.\n\n\nMETHODS\nReported is a patient with a laparoscopic abdominal cerclage who carried two pregnancies to term. Seven years after initial placement, 3 years after her last delivery, an abscess developed at the cerclage site. Erosion and subsequent expulsion of the cerclage followed.\n\n\nCONCLUSIONS\nThe longevity of abdominally placed cerclages is unknown. Placement in the peritoneal cavity reduces suture migration risk, yet tissue degradation may limit the lifespan. Patients with retained abdominal cerclages after completion of childbearing are at risk for remote complications. Closer long-term surveillance on an individual level and a collective level is warranted.",
"affiliations": "North Shore-Long Island Jewish Health System, Manhasset, New York.",
"authors": "Hawkins|Eleanor|E|;Nimaroff|Michael|M|",
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"mesh_terms": "D000328:Adult; D023802:Cerclage, Cervical; D005260:Female; D006801:Humans; D010535:Laparoscopy; D011247:Pregnancy; D014623:Vaginal Diseases",
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"title": "Vaginal erosion of an abdominal cerclage 7 years after laparoscopic placement.",
"title_normalized": "vaginal erosion of an abdominal cerclage 7 years after laparoscopic placement"
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"abstract": "Avapritinib is a tyrosine kinase inhibitor currently being investigated on clinical trials for the treatment of unresectable or metastatic gastrointestinal stromal tumour (GIST). It has been recently approved by the Food and Drug Administration and the European Medicines Agency for the treatment of unresectable or metastatic GIST harbouring PDGFRa Exon 18 mutation and by the European Medicines Agency for the treatments of unresectable or metastatic GIST harbouring the PDGFRa D842V mutation. We report a clinical case of a 76-year-old female, diagnosed with a stage IV GIST, treated with avapritinib 300 mg once daily. through compassionate use who experienced an intraocular side effect not previously reported avapritinib. She developed preseptal cellulitis on her right eye following 2 months of treatment with avapritinib and, subsequently evolved to an intraocular inflammatory reaction and persistent corneal epithelial defect. The treatment with avapritinib was stopped and the patient received corticosteroid and corneal regenerating agents. The symptoms resolved within 1 month and the patient has remained on stable disease at two subsequent adjusted avapritinib doses (100 mg once daily) for over 1 year.",
"affiliations": "Ophtalmology Department.;Medical Oncology Department, Hospital Clinico san Carlos, Madrid, Spain.;Ophtalmology Department.",
"authors": "García Caride|Sara|S|;Marquina|Gloria|G|;Díaz Valle|David|D|",
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"title": "Preseptal cellulitis, intraocular inflammatory reaction and corneal persistent epithelial defect as side effects of avapritinib.",
"title_normalized": "preseptal cellulitis intraocular inflammatory reaction and corneal persistent epithelial defect as side effects of avapritinib"
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"abstract": "Thyroid cancer metastasizes in 4% of cases. Approximately two-thirds of these patients are refractory to radioactive iodine-131 (RAI) therapy and have a poor 10-year survival prognosis. Treatment with tyrosine kinase inhibitors (TKIs) may be administered in selected RAI-refractory patients. However, these agents are often associated with adverse events, including vomiting. We report the case of a patient affected by RAI-refractory thyroid cancer with lung and intracranial metastases undergoing treatment with the antiangiogenic TKI lenvatinib, and with teriparatide replacement therapy for postsurgical hypoparathyroidism. Due to lenvatinib-related vomiting, which did not respond to therapy, conventional oral calcium supplementation failed to maintain normal serum calcium levels and the patient had repeated episodes of hypocalcemia. Subcutaneous teriparatide injections restored serum calcium levels, and thus lenvatinib therapy could be continued. This experience indicates that hormone replacement with teriparatide is a feasible option for cancer patients affected by hypoparathyroidism not treatable with oral calcium supplementation.",
"affiliations": "Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.;Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.;Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.;Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.;Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.",
"authors": "Porcelli|Tommaso|T|;Sessa|Francesca|F|;Caputo|Angela|A|;Catalini|Christian|C|;Salvatore|Domenico|D|",
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"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)Front Endocrinol (Lausanne)Front. Endocrinol.Frontiers in Endocrinology1664-2392Frontiers Media S.A. 10.3389/fendo.2018.00244EndocrinologyCase ReportTeriparatide Replacement Therapy for Hypoparathyroidism During Treatment With Lenvatinib for Advanced Thyroid Cancer: A Case Report Porcelli Tommaso *Sessa Francesca Caputo Angela Catalini Christian Salvatore Domenico *Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, ItalyEdited by: Gabriella Pellegriti, Università degli Studi di Catania, Italy\n\nReviewed by: Marialuisa Appetecchia, Istituti Fisioterapici Ospitalieri (IRCCS), Italy; Dario Giuffrida, Istituto Oncologico del Mediterraneo, Italy\n\n*Correspondence: Tommaso Porcelli, tommasoporcelli@gmail.com; Domenico Salvatore, domsalva@unina.itSpecialty section: This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology\n\n17 5 2018 2018 9 24422 2 2018 30 4 2018 Copyright © 2018 Porcelli, Sessa, Caputo, Catalini and Salvatore.2018Porcelli, Sessa, Caputo, Catalini and SalvatoreThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Thyroid cancer metastasizes in 4% of cases. Approximately two-thirds of these patients are refractory to radioactive iodine-131 (RAI) therapy and have a poor 10-year survival prognosis. Treatment with tyrosine kinase inhibitors (TKIs) may be administered in selected RAI-refractory patients. However, these agents are often associated with adverse events, including vomiting. We report the case of a patient affected by RAI-refractory thyroid cancer with lung and intracranial metastases undergoing treatment with the antiangiogenic TKI lenvatinib, and with teriparatide replacement therapy for postsurgical hypoparathyroidism. Due to lenvatinib-related vomiting, which did not respond to therapy, conventional oral calcium supplementation failed to maintain normal serum calcium levels and the patient had repeated episodes of hypocalcemia. Subcutaneous teriparatide injections restored serum calcium levels, and thus lenvatinib therapy could be continued. This experience indicates that hormone replacement with teriparatide is a feasible option for cancer patients affected by hypoparathyroidism not treatable with oral calcium supplementation.\n\nmetastatic thyroid cancertyrosine kinase inhibitorstargeted therapylenvatinibpostsurgical hypoparathyroidismrecombinant human parathyroid hormone (1–34)teriparatide\n==== Body\nBackground\nPatients affected by thyroid cancer have a 5-year survival rate of 98.2%. Distant metastases occur in approximately 4% of cases (1). Two-thirds of follicular cell-derived metastatic thyroid cancers do not respond adequately to radioactive iodine-131 (RAI) ablation therapy. In fact, they either fail to uptake iodine at the first ablation or become refractory to treatment. The prognosis for RAI-refractory (RAI-R) patients is poor, the 10-year overall survival rate being <10% (2, 3). The recommended treatment for patients with metastatic, rapidly progressive, symptomatic, and/or imminently threatening RAI-R cancer who do not respond to locoregional treatments is systemic therapy with tyrosine kinase inhibitors (TKIs) (4). Lenvatinib is a multitargeting antiangiogenic agent approved for progressive advanced RAI-R thyroid cancer (5). TKIs have class-related adverse events and vomiting is a common event in patients treated with antiangiogenic agents (6).\n\nHere we report the first case of a patient affected by progressive metastatic thyroid cancer and postsurgical hypoparathyroidism, in whom TKI-induced vomiting impaired oral calcium intake thereby causing severe hypocalcemia. Teriparatide (recombinant human parathyroid hormone, rhPTH (1–34)) replacement therapy allowed restoration of circulating calcemic levels without discontinuation of oncological therapy.\n\nCase Report\nA 66-year-old woman presented with a recent history of diplopia and right palpebral ptosis. She had undergone total thyroidectomy in another Institute in June 2015 due to the enlargement of a nodule in the right thyroid lobe within a longstanding goiter. Pathology showed a Hürthle cell carcinoma, 7 cm maximum diameter, with extensive vascular invasion that involved the perithyroidal soft tissue. Due to postsurgical hypoparathyroidism, the patient started substitutive therapy with oral calcium and activated vitamin D. In November 2015, she received a dose of 142.4 mCi RAI. Her stimulated thyroglobulin (Tg) level at that time was 8.9 ng/ml with undetectable thyroglobulin antibodies (Tg-Ab). Therapeutic whole body scan (RxWBS) revealed non-specific uptake in the left paratracheal region. Neck recurrence appeared a few months later and, in July 2016, the patient received a 214.6 mCi dose of RAI. RxWBS was negative, whereas SPECT/CT fusion images revealed RAI-refractory tumor tissue in the right supraclavicular region. Consequently, the patient underwent surgery in August 2016 and an infiltrative TTF1 and Tg-positive lesion, 3 cm maximum diameter, was removed. However, in November 2016, basal Tg increased to 126 ng/ml and an 18FDG PET/CT revealed disease persistence in the right neck and multiple bilateral lung micrometastases.\n\nAt our first observation in May 2017, basal Tg was 500 ng/ml, Tg-Ab <20 U/ml, TSH 0.015 mU/l, and daily levothyroxine intake was 137.5 mcg. Diplopia and right palpebral ptosis had started about 1-month earlier. A subsequent 18FDG PET/CT scan showed intense glucose metabolism in the basisphenoid region (Figure 1) and a gadolinium-enhanced brain MRI scan revealed a mass in the right cavernous sinus measuring 2.5 cm × 2.0 cm × 1.8 cm, with a low signal in T2 and enhancement on post-contrast images, which was compatible with a metastasis. The lesion encapsulated a 2-cm segment of the right internal carotid artery, without causing luminal narrowing (Figures 2A–C). Given the patient’s non response to RAI treatment and the locally advanced and progressively increasing metastatic burden, lenvatinib was initiated in June 2017. Because the intracranial lesion encapsulated a considerable portion of the right internal carotid artery, we started with a low dose (10 mg daily) to avoid the risk of artery damage consequent to rapid tumor shrinkage. An MRI performed about 30 days later showed that the metastasis in the right cavernous sinus was significantly smaller and that the integrity of the internal carotid was preserved (Figures 2D–F). Diplopia and palpebral ptosis progressively regressed with treatment and the patient did not complain of any cerebral symptom. Basal Tg declined to 338.4 ng/ml without Tg-Ab, in line with a reduction in neck lesions volume (Figure 3).\n\nFigure 1 18FDG PET/CT performed before lenvatinib administration. Besides the numerous bilateral lung metastases, note the intense uptake by two locally recurrent lesions in the neck and by the cavernous sinus metastasis.\n\nFigure 2 MRI brain scans performed before (A–C) and one month after (D–F) the administration of lenvatinib. The right cavernous sinus metastasis completely encapsulates a consistent portion of the intracranial tract of the right internal carotid artery.\n\nFigure 3 Ultrasound scan of a locally recurrent neck lesion in right supraclavicular region. (A) Imaging before lenvatinib start. (B) Ultrasound scan after 1 month of therapy at 10 mg daily. Tumor vascularization is significantly reduced. (C,D) Progressive tumor reduction after 2 (C) and 6 months (D) of treatment at the same dose.\n\nTwo weeks later, the patient had grade 2 vomiting and was treated with serotonin 5-HT3 receptor antagonists. However, vomiting worsened to grade 3, and lenvatinib was suspended for 1 week. Despite the transdermal administration of granisetron, grade 1 vomiting persisted and was exacerbated by the oral assumption of calcium that the patient needed to control the severe hypoparathyroidism. Notwithstanding the administration of high doses of calcitriol, the hypocalcemic episodes were frequent and the patient underwent intravenous calcium gluconate infusion in various hospital emergency departments. Because of vomiting after oral calcium intake, it was not possible to restore normal serum calcium levels and the patient became dependent on intravenous therapy.\n\nDue to the patient’s poor clinical condition, we decided to admit her to our department and administered 20 µg teriparatide in daily subcutaneous injections as replacement therapy for hypoparathyroidism. Intravenous calcium infusion was progressively reduced and was suspended after 1 week, when serum calcium levels became stable at a dose of 20 µg teriparatide twice daily. No adverse event occurred. Subsequent controls showed normal serum calcium and phosphorus levels; no clinical signs of hypocalcemia were reported. At the last control in March 2018, basal Tg was 82 ng/ml (without Tg-Ab), serum calcium was 8.8 mg/dl, and phosphorus was 3.3 mg/dl.\n\nDiscussion\nThis is the first report of the use of teriparatide as hormonal replacement therapy for hypoparathyroidism in a patient with metastatic thyroid cancer. Our patient was affected by rapidly progressive macroscopic refractory disease and was on systemic therapy with the antiangiogenic multikinase inhibitor lenvatinib. Patients affected by advanced thyroid cancer are prone to parathyroid damage and postsurgical hypothyroidism because they undergo aggressive neck surgery (7). Therapy with a systemic TKI is indicated in case of substantial disease progression not otherwise treatable (4). Vomiting is a common class-related adverse event of antiangiogenic TKIs (6). Since current treatment for hypoparathyroidism consists of activated vitamin D and calcium, both of which must be taken orally, intractable vomiting places patients at a high risk of hypocalcemia. Consequently, such patients require alternative therapeutic options.\n\nAfter a lenvatinib-associated G3 adverse event, it is common practice to suspend treatment and resume it at a lower dosage (8). In our case, the patient was already on a low dose, namely, 10 mg daily. Therefore, after a 1-week drug-free interval, we associated 10 mg lenvatinib daily with transdermal granisetron. Vomiting was controlled but oral calcium assumption triggered intolerable vomiting. Therefore, conventional supplementation for hypoparathyroidism could not be used to correct the patient’s hypocalcemia. Continuity of therapy is crucial for patients undergoing treatment with a TKI (9). Thus, to treat hypoparathyroidism without interrupting lenvatinib therapy, we administered replacement therapy with subcutaneous teriparatide. In Italy, rhPTH (1–34) as substitutive therapy for severe chronic hypoparathyroidism became reimbursable by the National Health Service in June 2013. Inclusion criteria for this treatment are non response to oral activated vitamin D and recurrent severe episodes of hypocalcemia. Contraindications for treatment are previous external beam radiation therapy to the skeleton and bone malignancies or bone metastases (10).\n\nConcerns about the carcinogenic potential of long-term rhPTH (1–34) treatment were raised consequent to evidence obtained in rats of increased osteosarcoma risk in relation to dose and treatment duration (11). However, clinical studies conducted over a period of 10 years did not find an increase in the incidence of osteosarcoma in patients taking teriparatide. Similarly, the risk of malignancies was not increased in patients on long-term replacement with rhPTH (1–34) (12–14). In our case, the benefit of normalization of serum calcium levels largely outweighed the potential risk related to treatment with teriparatide.\n\nConcluding Remarks\nDuring anticancer treatment, vomiting unresponsive to therapy can be a major issue for hypoparathyroidal patients who are dependent on oral calcium intake. This case shows that replacement therapy with teriparatide can be considered for the treatment of cancer patients who do not have bone metastases and are intractable to oral calcium supplementation for postsurgical hypoparathyroidism.\n\nEthics Statement\nThe patient provided written informed consent for research participation and for the publication of indirectly identifiable data.\n\nAuthor Contributions\nTP, FS, AC, CC, and DS managed the case. TP wrote the manuscript. All the authors revised and approved the final manuscript and agreed to be accountable for the content of the work.\n\nConflict of Interest Statement\nThe authors declare that this case report was carried out in the absence of any personal, professional, or financial relationships that could potentially be construed as a conflict of interest.\n\nWe thank Jean Ann Gilder (Scientific Communication Srl., Naples, Italy) for editing the text.\n==== Refs\nReferences\n1 National Cancer Institute . Surveillance Epidemiology and End Results Program: Seer Stat Facts: Thyroid Cancer . (2018 ). Available from: http://seer.cancer.gov/statfacts/html/thyro.html (Accessed: February 16, 2018).\n2 Durante C Haddy N Baudin E Leboulleux S Hartl D Travagli JP \nLong-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy . J Clin Endocrinol Metab (2006 ) 91 :2892 –9 .10.1210/jc.2005-2838 16684830 \n3 Wassermann J Bernier MO Spano JP Lepoutre-Lussey C Buffet C Simon JM \nOutcomes and prognostic factors in radioiodine refractory differentiated thyroid carcinomas . Oncologist (2016 ) 21 :50 –8 .10.1634/theoncologist.2015-0107 26675742 \n4 Haugen BR Alexander EK Bible KC Doherty GM Mandel SJ Nikiforov YE \n2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer . Thyroid (2016 ) 26 :1 –133 .10.1089/thy.2015.0020 26462967 \n5 Schlumberger M Tahara M Wirth LJ Robinson B Brose MS Elisei R \nLenvatinib versus placebo in radioiodine-refractory thyroid cancer . N Engl J Med (2015 ) 372 :621 –30 .10.1056/NEJMoa1406470 25671254 \n6 Cohen RB Oudard S . Antiangiogenic therapy for advanced renal cell carcinoma: management of treatment-related toxicities . Invest New Drugs (2012 ) 30 :2066 –79 .10.1007/s10637-012-9796-8 22327313 \n7 Shoback D \nClinical practice. Hypoparathyroidism . N Engl J Med (2008 ) 359 :391 –403 .10.1056/NEJMcp0803050 18650515 \n8 Haddad RI Schlumberger M Wirth LJ Sherman EJ Shah MH Robinson B \nIncidence and timing of common adverse events in lenvatinib-treated patients from the SELECT trial and their association with survival outcomes . Endocrine (2017 ) 56 :121 –8 .10.1007/s12020-017-1233-5 28155175 \n9 Tuttle RM Brose MS \nBest use of the tyrosine kinase inhibitors in progressive differentiated thyroid cancer: discussion . Clin Adv Hematol Oncol (2016 ) 14 (5 Suppl 9 ):12 –3 .\n10 Official Gazette of the Italian Republic-General Series . 154th Year, Number 141 of June 18, 2013. p.42 –4 . Available from: http://www.gazzettaufficiale.it/eli/id/2013/06/18/13A05201/sg (Accessed: February 16, 2018).\n11 Vahle JL Sato M Long GG Young JK Francis PC Engelhardt JA \nSkeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1–34) for 2 years and relevance to human safety . Toxicol Pathol (2002 ) 30 :312 –21 .10.1080/01926230252929882 12051548 \n12 Cusano NE Rubin MR Bilezikian JP . Parathyroid hormone therapy for hypoparathyroidism . Best Pract Res Clin Endocrinol Metab (2015 ) 29 :47 –55 .10.1016/j.beem.2014.09.001 25617172 \n13 Winer KK Ko CW Reynolds JC Dowdy K Keil M Peterson D \nLong-term treatment of hypoparathyroidism: a randomized controlled study comapring parathyroid hormone (1–34) versus calcitriol and calcium . J Clin Endocrinol Metab (2003 ) 88 :4214 –20 .10.1210/jc.2002-021736 12970289 \n14 Marcucci G Della Pepa G Brandi ML . Drug safety evaluation of parathyroid hormone for hypocalcemia in patients with hypoparathyroidism . Expert Opin Drug Saf (2017 ) 16 :617 –25 .10.1080/14740338.2017.1311322 28332412\n\n",
"fulltext_license": "CC BY",
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"issue": "9()",
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"keywords": "lenvatinib; metastatic thyroid cancer; postsurgical hypoparathyroidism; recombinant human parathyroid hormone (1–34); targeted therapy; teriparatide; tyrosine kinase inhibitors",
"medline_ta": "Front Endocrinol (Lausanne)",
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"title": "Teriparatide Replacement Therapy for Hypoparathyroidism During Treatment With Lenvatinib for Advanced Thyroid Cancer: A Case Report.",
"title_normalized": "teriparatide replacement therapy for hypoparathyroidism during treatment with lenvatinib for advanced thyroid cancer a case report"
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"abstract": "In patients with frequently relapsing nephrotic syndrome, immunosuppressive therapy such as cyclosporine are often required to maintain remission. Cyclosporine has been noted to have tumorgenesis effects. In this case report, we present a child with relapsing nephrotic syndrom developed a rhabdomyosarcoma on her tongue after adout 4 years of continual immunosuppressive therapy.\n\n\n\nA 2-year-old female child had nephrotic syndrome (urine protein-creatinine ratio 749.1 mg/mg; blood urea nitrogen 11 mg/dL; serum creatinine 0.3 mg/dL; and serum albumin 1.8 g/dL.) Proteinuria resolved on treatment with daily prednisolone for 4 weeks at the dose of 45 mg (2.5 mg/kg/day) but recurred with taper from 25 mg/day to 10 mg/day. At least five more episodes of relapse occurred within about a 3-year period. After the third relapse, she was treated with prednisolone and cyclosporine (at initial dose of 50 mg/day [1.7 mg/kg/day]) for immunosuppression. About 4 years after the diagnosis of nephrotic syndrome had been made, an embryonal rhabdomyosarcoma developed on her tongue. The cancer was treated with TPOG-RMS-LR protocol, with vincristine, actinomycin, and cyclophosphamide. Magnetic resonance imaging scan, performed about 3 years after the start of TPOG-RMS-LR therapy, revealed complete remission of the cancer.\n\n\n\nAlthough treatment with cyclosporine cannot be conclusively implicated as the cause the rhabdomyosarcoma in this patient, the association should prompt consideration of its use in the treatment of frequently relapsing nephrotic syndrome in children.",
"affiliations": "Eudcation Center, National Cheng Kung University Hospital, Tainan, Taiwan.;Division of Pediatric Hematology, Department of Pediatrics, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.;Division of Pediatric Hematology, Department of Pediatrics, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.;Division of Pediatric Nephrology, Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan. yuanyow@mail.ncku.edu.tw.",
"authors": "Wu|Huai-Chueh Gem|HG|;Cheng|Chao-Neng|CN|;Chen|Jiann-Shiuh|JS|;Chiou|Yuan-Yow|YY|0000-0002-5279-0660",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine",
"country": "England",
"delete": false,
"doi": "10.1186/s12882-020-02136-6",
"fulltext": "\n==== Front\nBMC Nephrol\nBMC Nephrol\nBMC Nephrology\n1471-2369 BioMed Central London \n\n2136\n10.1186/s12882-020-02136-6\nCase Report\nRhabdomyosarcoma in a child with nephrotic syndrome treated with cyclosporine: a case report with literature review\nWu Huai-Chueh Gem 1 Cheng Chao-Neng 2 Chen Jiann-Shiuh 2 http://orcid.org/0000-0002-5279-0660Chiou Yuan-Yow yuanyow@mail.ncku.edu.tw 34 1 grid.412040.30000 0004 0639 0054Eudcation Center, National Cheng Kung University Hospital, Tainan, Taiwan \n2 grid.412040.30000 0004 0639 0054Division of Pediatric Hematology, Department of Pediatrics, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan \n3 grid.412040.30000 0004 0639 0054Division of Pediatric Nephrology, Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan \n4 grid.64523.360000 0004 0532 3255Institute of Clinical Medicine, Medical College, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 704 Taiwan \n17 11 2020 \n17 11 2020 \n2020 \n21 49024 6 2020 29 10 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nIn patients with frequently relapsing nephrotic syndrome, immunosuppressive therapy such as cyclosporine are often required to maintain remission. Cyclosporine has been noted to have tumorgenesis effects. In this case report, we present a child with relapsing nephrotic syndrom developed a rhabdomyosarcoma on her tongue after adout 4 years of continual immunosuppressive therapy.\n\nCase presentation\nA 2-year-old female child had nephrotic syndrome (urine protein-creatinine ratio 749.1 mg/mg; blood urea nitrogen 11 mg/dL; serum creatinine 0.3 mg/dL; and serum albumin 1.8 g/dL.) Proteinuria resolved on treatment with daily prednisolone for 4 weeks at the dose of 45 mg (2.5 mg/kg/day) but recurred with taper from 25 mg/day to 10 mg/day. At least five more episodes of relapse occurred within about a 3-year period. After the third relapse, she was treated with prednisolone and cyclosporine (at initial dose of 50 mg/day [1.7 mg/kg/day]) for immunosuppression. About 4 years after the diagnosis of nephrotic syndrome had been made, an embryonal rhabdomyosarcoma developed on her tongue. The cancer was treated with TPOG-RMS-LR protocol, with vincristine, actinomycin, and cyclophosphamide. Magnetic resonance imaging scan, performed about 3 years after the start of TPOG-RMS-LR therapy, revealed complete remission of the cancer.\n\nConclusions\nAlthough treatment with cyclosporine cannot be conclusively implicated as the cause the rhabdomyosarcoma in this patient, the association should prompt consideration of its use in the treatment of frequently relapsing nephrotic syndrome in children.\n\nSupplementary Information\nThe online version contains supplementary material available at 10.1186/s12882-020-02136-6.\n\nKeywords\nChildhood nephrotic syndromeCyclosporineImmunosuppressive therapyRhabdomyosarcomaCase reportissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nNephrotic syndrome is defined by nephrotic-range proteinuria (≥40 mg/m2/h or urine protein/creatinine ratio ≥ 200 mg/mL or 3+ protein on urine dipstick), hypoalbuminemia (< 25 g/L) and edema [1]. The reported incidence of idiopathic nephrotic syndrome is 1.15–16.9 per 100,000 children, varying by ethnicity and region [2]. The cause remains unknown, but the pathogenesis is thought to involve immune dysregulation, systemic circulating factors, or inherited structural abnormalities of the podocyte. The disease most often resolves spontaneously, but corticosteroids often are required. About 1–3% of children with nephrotic syndrome have frequent relapses or steroid-dependent nephrotic syndrome. Resistance to steroids or steroid toxicity often prompts administration of other immunosuppressive drugs, such as cyclosporine (CsA), cyclophosphamide, rituximab [3]. and others. Rhabdomyosarcoma (RMS) is the kind of soft tissue sarcoma (STS) and most common occurs in children and adolescents [4]. RMS is accounting for 4.5% of all children cancer cases and the incidence is around 6 cases per million per year [5]. However, the aetiology of RMS is still need to be identified. Although tumorigenesis risks have not been found in children with nephrotic syndrome treated with CsA, one of the most feared adverse effects of the drug is de novo cancers [6, 7]. Herein we describe a patient with frequently relapsing nephrotic syndrome who received a long course of CsA and developed a rhabdomyosarcoma (RMS) of the tongue.\n\nCase presentation\nA 2-year-4-month-old girl was referred to our hospital about 1 month after the diagnosis of nephrotic syndrome with relapse had been made: urine protein-creatinine ratio markedly increased (749.1 mg/mg); blood urea nitrogen 11 mg/dL; serum creatinine 0.3 mg/dL; and serum albumin 1.8 g/dL. Proteinuria resolved on treatment with daily prednisolone for 4 weeks at the dose of 45 mg (2 mg/kg)/day) but recurred with taper from 25 mg/day to 10 mg/day (spot proteinuria ≥300 mg/dL protein).\n\nA second relapse occurred near 3 months after the first when the daily dose of prednisolone was decreased and proteinuria resolved with prednisolone at 45 mg/day for nearly a week.\n\nA third relapse occurred 3 months after the second when she had taken 30 mg prednisolone once every 2 days for 3 weeks (spot proteinuria > 500 mg/dL). CsA was added at a daily dose of 50 mg/day (1.7 mg/kg/day). Prednisolone was tapered over 3 months and discontinued after about 1 years of regular use. CsA was prescribed continuously, with the dose of 50 mg/day since no proteinuria was noted. After a year of CsA maintenance without steroid, she developed bilateral leg edema, massive proteinuria, and decreased urine output. The dose of CsA was increased to 75 mg/day (3 mg/kg/day) for 4 months. The proteinuria resolved within 2 weeks under the combination of prednisolone 45 mg/day and CsA 75 mg/day, tapered to 50 mg/day for another 3 months.\n\nThe fifth relapse, 9 months from the previous relapse, occurred (spot proteinuria 100 mg/dl) after she had been prednisolone free for nearly 20 days. Since the fifth replace, the prednisolone was held at dose 60 mg/day and cyclosporine was prescribed with dose 100 mg/day.\n\nBefore CsA was replaced with mycophenolic acid 720 mg/day (20 mg/kg). The sixth relapse has occurred since daily dose of steroid was discontinued, and the proteinuria was controled by undertake prednisolone 45 mg/day. She has had frequent urinary tract infections during the four-year use of steroids with other steroid-sparing immunosuppressive therapy.\n\nAt about 4 years after the diagnosis of nephrotic syndrome was made, reddish flat-topped masses appeared her tongue (Fig. 1). Curative wedge resection revealed an exophytic polypoid lesion that was histopathologically diagnosed embryonal RMS. After total excision of the tumor, she was treated according to TPOG-RMS-LR protocol, with vincristine, actinomycin, and cyclophosphamide (VAC). Mycophenolic acid and prednisolone were discontinued since the dose and duration of cyclophosphamide per TPOG protocol was more than the required amount for treatment of nephrotic syndrome. No proteinuria or nephrotic syndrome were noted during the 48-week VAC treatment and 10 months thereafter. The length and cumulative dosage of these immunosuppressive drugs are illustrated as supplemental figure 1.\nFig. 1 A reddish flat-topped mass on the tongue\n\n\n\nDiscussion and conclusions\nWe know of no other reports of RMS in children treated with CsA for nephrotic syndrome, although a case of embryonal RMS in pediatric nephrotic syndrome without evident immunosuppressive therapy has been described [8]. CsA has been widely accepted in the treatment of frequent relapsing nephrotic syndrome in children [9, 10]. It is reported effective and safe in treatment of that condition to avoid the toxicity of corticosteroids [10]. Nevertheless, because of cyclosporine’s risk in a wide variety of cancers, including RMS [6, 7, 11–13], even an isolated case of RMS in a child with nephrotic syndrome should prompt caution about its use in that population.\n\nCsA may promote tumor angiogenesis through VEGF and blockake T lymphocytes function under high-dose CsA (≥4–5 mg/kg/day) treatment [14]. The present study expanded this finding and further showed that CsA-related RMS has been described only in case reports (Table 1). Cescon et al. [11] reported a 23-year-old girl who received CsA for liver transplantation immunosuppression and later developed orbital embryonal RMS. A 47-year-old Japanese man, who received CsA for treatment of Behçet’s disease, developed a malignant rhabdoid tumor in his posterior femoral region 3 years later [12]. A 15-year-old boy, treated with CsA to prevent kidney transplant rejection, developed RMS of the nasopharynx [13]. The tumors of our patient and the patient of Cescon et al. [11] were of the embryonal histology, which is the most common subtype. Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is known as an FDA-approved immunosuppression agent and exists the function of anti-tumor activity, which mainly acts on inosine monophosphate dehydrogenase (IMDPH) to treat with immune-related adverse events effectively [15, 16]. Thus, utilizing CsA may exert the risk in promoting tumorigenesis during the treatment course of disease.\nTable 1 Case reports on cyclosporine associated rhabdomyosarcoma or rhabdoid tumor\n\nYear, Author\tPatient data\tIndication for CsA\tDosage (mg/kg/day)\tDuration of CsA\tExposure to Diagnosis\tTumor type, location\tRMS treatment\ttreatment response\t\nCurrent case\t8 y/o\n\nfemale\n\n\tnephrotic syndrome\t1.8–3.0\t3 years\t4 years 2 months\tembryonal, tongue\tResection\n\nVAC\n\n(48 weeks)\n\n\tComplete remission\n\n(27 months)\n\n\t\n2003, Cescon [11]\t23 y/o\n\nfemale\n\n\tliver transplant\t13.0\t16 months\t16 months\tembryonal, orbit\tRT▲\n\nVAC\n\n(24 weeks)\n\n\tStable Disease\n\n(38 months)\n\n\t\n1998, Muramatsu [12]\t47 y/o\n\nmale\n\n\tBehçet’s disease\t5.0\t9 months▽\t3 years\tmalignant rhabdoid tumor, femur\tResection\n\nRT\n\n\tComplete remission\n\n(36 months)\n\n\t\n1991, Piller [13]\t15 y/o\n\nmale\n\n\trenal transplant\tN/A\t23 months\t23 months\trhabdomyosarcoma, nasopharynx\tN/A\tN/A\t\n▲ 5000 cGy in 5 weeks\n\n▽ After 9 months of cyclosporine, the patient found a mass over his posterior thigh. However, he did not seek medical attention until 3 years later\n\nCSA Cyclosporine A, RMS Rhabdomyosarcoma, RT Radiation therapy, VAC Vincristine, actinomycin, and cyclophosphamide\n\n\n\nAlthough over 95% of RMSs arise de novo, the role of immunosuppressants in their causation-- especially in transplant patients, who require high dose and life-long administration -- is persuasive. Further evidence of cyclosporine’s oncogenic potential is that patients receiving reduced-dose of drug have had a lower risk of malignancies than did those receiving full-dose [17]. There is no solid evidence supporting an oncogenic effect of CsA in pediatric RMS, but other carcinogenic factors have not been identified. Molecular mechanisms of cyclosporine’s tumor- promoting activity are incompletely defined. However, in human studies, CsA induced cancer progression via increasing production of TGF-beta and inhibiting T-lymphocyte function, and, in a murine model, T-cell-based therapy was effective in treating RMS [18]. These results suggest that defective T-cell immunity contributes to rhabdomyosarcoma oncogenesis. CsA also has caused defective nucleotide excision repair in cells [19]. However, RMS has been thought as the dominant hereditary genetic diseases [20], but some risk factors may trigger the occurrence of RMS including, the familial syndromes (Li-Fraumeni syndrome), the sign with a lump or swelling and keep getting bigger, and bulging eyes or hematuria. Otherwise, lifestyle-related risk factors, for examples, body weight, diet and physical activity, may not play a role in the occurrence of RMS, which is commonly occurred in childhood (under 10 years old). Altogether, the present case report suggests that the risk, albeit low, of rhabdomyosarcoma with cyclosporine immunosuppression be considered in the selection of immunotherapeutic agents in the treatment of relapsing nephrotic syndrome in children.\n\nSupplementary Information\n\nAdditional file 1:\nFigure S1. Schematic the time line of different drugs utilized in treatment of nephrotic syndrome patient with RSM.\n\n \n\nAbbreviations\nRMSRhabdomyosarcoma\n\nCsACyclosporine\n\nTPOG-RMS-LRTaiwan Pediatric Oncology Group-RMS-Low risk group\n\nVACVincristine, actinomycin, and cyclophosphamide\n\nVEGFVascular endothelial growth factor\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNone.\n\nAuthors’ contributions\nYYC had made substantial contributions to the conception and study design; HGW and YYC collected the data; HGW and YYC analyzed the data; HGW, CNC, JSC, and YYC prepared the manuscript and critical revision of the manuscript; all authors read and approved the final version for submission.\n\nFunding\nNone.\n\nAvailability of data and materials\nThe data used to support the findings of this study are included within the article.\n\nEthics approval and consent to participate\nInstitutional review board of National Cheng Kung University Hospital approval to publish this information was obtained (No. A-EC-109-015). The written informed consent was provided by the patient’s parent for participation in this study at National Cheng Kung University Hospital.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Downie ML Gallibois C Parekh RS Noone DG Nephrotic syndrome in infants and children: pathophysiology and management Paediatr Int Child Health 2017 37 4 248 258 10.1080/20469047.2017.1374003 28914167 \n2. Noone DG Iijima K Parekh R Idiopathic nephrotic syndrome in children Lancet 2018 392 10141 61 74 10.1016/S0140-6736(18)30536-1 29910038 \n3. Kari JA Alhasan KA Albanna AS Safdar OY Shalaby MA Bockenhauer D El-Desoky SM Rituximab versus cyclophosphamide as first steroid-sparing agent in childhood frequently relapsing and steroid-dependent nephrotic syndrome Pediatr Nephrol 2020 35 1445 10.1007/s00467-020-04570-y 32337638 \n4. Malempati S Hawkins DS Rhabdomyosarcoma: review of the Children's oncology group (COG) soft-tissue sarcoma committee experience and rationale for current COG studies Pediatr Blood Cancer 2012 59 1 5 10 10.1002/pbc.24118 22378628 \n5. Chou SW Chang HH Lu MY Yang YL Lin DT Lin KH Jou ST Clinical outcomes of pediatric patients with newly diagnosed rhabdomyosarcoma treated by two consecutive protocols - a single institution report in Taiwan J Formos Med Assoc 2019 118 1 Pt 2 332 340 10.1016/j.jfma.2018.05.015 29903549 \n6. Andre N Roquelaure B Conrath J Molecular effects of cyclosporine and oncogenesis: a new model Med Hypotheses 2004 63 4 647 652 10.1016/j.mehy.2004.03.030 15325009 \n7. Walsh SB Xu J Xu H Kurundkar AR Maheshwari A Grizzle WE Timares L Huang CC Kopelovich L Elmets CA Cyclosporine a mediates pathogenesis of aggressive cutaneous squamous cell carcinoma by augmenting epithelial-mesenchymal transition: role of TGFbeta signaling pathway Mol Carcinog 2011 50 7 516 527 10.1002/mc.20744 21308804 \n8. Olowu WA Salako AA Adelusola KA Sowande OA Adetiloye VA Adefehinti O Osasan SA Focal segmental glomerulosclerosis and nephrotic syndrome in a child with embryonal rhabdomyosarcoma Clin Exp Nephrol 2008 12 2 144 148 10.1007/s10157-007-0015-4 18175060 \n9. Hamasaki Y Komaki F Ishikura K Hamada R Sakai T Hataya H Ogata K Ando T Honda M Nephrotoxicity in children with frequently relapsing nephrotic syndrome receiving long-term cyclosporine treatment Pediatr Nephrol 2017 32 8 1383 1390 10.1007/s00467-017-3641-4 28378029 \n10. Ishikura K Ikeda M Hattori S Yoshikawa N Sasaki S Iijima K Nakanishi K Yata N Honda M Effective and safe treatment with cyclosporine in nephrotic children: a prospective, randomized multicenter trial Kidney Int 2008 73 10 1167 1173 10.1038/ki.2008.24 18305467 \n11. Cescon M Grazi GL Assietti R Scanni A Frigerio F Sparacio F Ercolani G Cavallari A Embryonal rhabdomyosarcoma of the orbit in a liver transplant recipient Transpl Int 2003 16 6 437 440 10.1111/j.1432-2277.2003.tb00327.x 12819877 \n12. Muramatsu M Kotake S Yoshikawa K Sasamoto Y Matsuda H Yamawaki S The development of malignant rhabdoid tumor in a patient with Behcet's disease treated with ciclosporin Graefes Arch Clin Exp Ophthalmol 1998 236 10 798 799 10.1007/s004170050162 9801898 \n13. Piller P Herman D Stierle JL Conraux C Rhabdomyosarcoma of the nasopharynx occurring with immunosuppressive treatment with cyclosporin a. apropos of a case Ann Otolaryngol Chir Cervicofac 1991 108 1 38 40 2018275 \n14. Flores C Fouquet G Moura IC Maciel TT Hermine O Lessons to learn from low-dose Cyclosporin-a: a new approach for unexpected clinical applications Front Immunol 2019 10 588 10.3389/fimmu.2019.00588 30984176 \n15. Majd N, Sumita K, Yoshino H, Chen D, Terakawa J, Daikoku T, Kofuji S, Curry R, Wise-Draper TM, Warnick RE, et al. A review of the potential utility of mycophenolate mofetil as a cancer therapeutic. J Cancer Res. 2014:423401.\n16. Simsek M Tekin SB Bilici M Immunological agents used in Cancer treatment Eurasian J Med 2019 51 1 90 94 10.5152/eurasianjmed.2018.18194 30911265 \n17. Kahan BD Yakupoglu YK Schoenberg L Knight RJ Katz SM Lai D Van Buren CT Low incidence of malignancy among sirolimus/cyclosporine-treated renal transplant recipients Transplantation 2005 80 6 749 758 10.1097/01.TP.0000173770.42403.F7 16210961 \n18. Hojo M Morimoto T Maluccio M Asano T Morimoto K Lagman M Shimbo T Suthanthiran M Cyclosporine induces cancer progression by a cell-autonomous mechanism Nature 1999 397 6719 530 534 10.1038/17401 10028970 \n19. Kuschal C Thoms KM Boeckmann L Laspe P Apel A Schon MP Emmert S Cyclosporin a inhibits nucleotide excision repair via downregulation of the xeroderma pigmentosum group a and G proteins, which is mediated by calcineurin inhibition Exp Dermatol 2011 20 10 795 799 10.1111/j.1600-0625.2011.01320.x 21707758 \n20. Kerin U Wolohan C Cooke K Rhabdomyosarcoma: an overview and nursing considerations Br J Nurs 2018 27 6 328 332 10.12968/bjon.2018.27.6.328 29561665\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "21(1)",
"journal": "BMC nephrology",
"keywords": "Case report; Childhood nephrotic syndrome; Cyclosporine; Immunosuppressive therapy; Rhabdomyosarcoma",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D016572:Cyclosporine; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008279:Magnetic Resonance Imaging; D008297:Male; D009404:Nephrotic Syndrome; D012074:Remission Induction; D018233:Rhabdomyosarcoma, Embryonal; D014059:Tongue; D014062:Tongue Neoplasms",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "490",
"pmc": null,
"pmid": "33203378",
"pubdate": "2020-11-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "30911265;22378628;29903549;29910038;10028970;16210961;9801898;21707758;28378029;29561665;12819877;30984176;21308804;2018275;18175060;32337638;28914167;18305467;15325009",
"title": "Rhabdomyosarcoma in a child with nephrotic syndrome treated with cyclosporine: a case report with literature review.",
"title_normalized": "rhabdomyosarcoma in a child with nephrotic syndrome treated with cyclosporine a case report with literature review"
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"companynumb": "TW-TEVA-2020-TW-1860997",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
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{
"abstract": "BACKGROUND\nPheochromocytoma, a rare catecholamine-producing tumor, might provoke stress-induced Takotsubo-like cardiomyopathy and severe cardiogenic shock. Because venoarterial-extracorporeal membrane oxygenation (VA-ECMO) rescue of pheochromocytoma-induced refractory cardiogenic shock has rarely been reported, we reviewed our ICU patients' presentations and outcomes.\n\n\nMETHODS\nAll pheochromocytoma-induced refractory cardiogenic shock cases managed with VA-ECMO (January 2007-March 2015) were prospectively included and reviewed. We also performed a systematic review on this topic.\n\n\nRESULTS\nNine patients (7 women, 2 men; 31-51 [median, 43 (IQR 36-49) years old]) were included; none had a previously known pheochromocytoma. Six of them had medical histories suggestive of the diagnosis: palpitations and headaches for several months for four, multiple endocrine neoplasia syndrome type 1 for one and recurrent Takotsubo disease for one; at hospital admission, all were hypertensive despite cardiogenic shock. Three others had an identified surgical triggering factor. All nine patients rapidly developed refractory cardiogenic shock with very severe left ventricular (LV) impairment (LV ejection-fraction range 5-20%; LV outflow-tract velocity-time integral range 3-8 cm). Seven patients' abdominal computed tomography scans showed pheochromocytoma-suggestive adrenal gland tumors (no scan during ICU stay for 2). Despite VA-ECMO implantation, three patients died of refractory multiple organ failure. For the six others, myocardial function improved and ECMO was removed 3-7 days post-implantation; α- and β-blockers were progressively introduced. Five survivors underwent pheochromocytoma excision 3 weeks-4 months post-ICU discharge, with satisfactory outcomes. One patient, whose pheochromocytoma was diagnosed 1 year after the index event, underwent uneventful surgical adrenalectomy. Systematic review retrieved 40 cases of pheochromocytoma-induced cardiogenic shock requiring mechanical support (mostly ECMO), with a mortality rate of 7%. Pheochromocytoma was removed surgically after mechanical support weaning in 31 patients and during mechanical support in 5. Four were not operated.\n\n\nCONCLUSIONS\nPheochromocytoma is a rare but reversible cause of cardiogenic shock amenable to VA-ECMO rescue. Adrenal gland imaging should be obtained for all patients with unexplained cardiogenic shock. Lastly, it might be safer to perform adrenalectomy several weeks after the initial catastrophic presentation, once recovery of LV systolic function is complete.",
"affiliations": "Intensive Care Unit, Institute of Cardiology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France. guillaume.hekimian@aphp.fr.;Institute of Endocrinology, Pierre et Marie Curie Sorbonne Université, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;Intensive Care Unit, Institute of Cardiology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.;Intensive Care Unit, Institute of Cardiology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.;Institute of Endocrinology, Pierre et Marie Curie Sorbonne Université, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;Department of Cardiac and Thoracic Surgery, Pierre et Marie Curie Sorbonne Université, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;Institute of Endocrinology, Pierre et Marie Curie Sorbonne Université, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;Department of General and Endocrine Surgery, Pierre et Marie Curie Sorbonne Université, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;Intensive Care Unit, Institute of Cardiology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.;Department of Cardiac and Thoracic Surgery, Pierre et Marie Curie Sorbonne Université, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;Intensive Care Unit, Institute of Cardiology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.;Intensive Care Unit, Institute of Cardiology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.;Intensive Care Unit, Institute of Cardiology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.",
"authors": "Hekimian|Guillaume|G|;Kharcha|Fatima|F|;Bréchot|Nicolas|N|;Schmidt|Matthieu|M|;Ghander|Cécile|C|;Lebreton|Guillaume|G|;Girerd|Xavier|X|;Tresallet|Christophe|C|;Trouillet|Jean-Louis|JL|;Leprince|Pascal|P|;Chastre|Jean|J|;Combes|Alain|A|;Luyt|Charles-Edouard|CE|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1186/s13613-016-0219-4",
"fulltext": "\n==== Front\nAnn Intensive CareAnn Intensive CareAnnals of Intensive Care2110-5820Springer Paris Paris 21910.1186/s13613-016-0219-4ResearchExtracorporeal membrane oxygenation for pheochromocytoma-induced cardiogenic shock Hekimian Guillaume guillaume.hekimian@aphp.fr 12Kharcha Fatima fatima.kharcha@aphp.fr 3Bréchot Nicolas nicolas.brechot@aphp.fr 12Schmidt Matthieu matthieu.schmidt@aphp.fr 12Ghander Cécile cecile.ghander@aphp.fr 3Lebreton Guillaume guillaume.lebreton@aphp.fr 4Girerd Xavier xavier.girerd@aphp.fr 3Tresallet Christophe christophe.tresallet@aphp.fr 5Trouillet Jean-Louis jean-louis.trouillet@aphp.fr 12Leprince Pascal pascal.leprince@aphp.fr 4Chastre Jean jean.chastre@aphp.fr 12Combes Alain alain.combes@aphp.fr 12Luyt Charles-Edouard charles-edouard.luyt@aphp.fr 121 Intensive Care Unit, Institute of Cardiology, Groupe Hospitalier Pitié–Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France 2 UPMC Université Paris 06, INSERM, UMRS_1166-ICAN Institute of Cardiometabolism and Nutrition, Paris, France 3 Institute of Endocrinology, Pierre et Marie Curie Sorbonne Université, APHP, Groupe Hospitalier Pitié–Salpêtrière, Paris, France 4 Department of Cardiac and Thoracic Surgery, Pierre et Marie Curie Sorbonne Université, APHP, Groupe Hospitalier Pitié–Salpêtrière, Paris, France 5 Department of General and Endocrine Surgery, Pierre et Marie Curie Sorbonne Université, APHP, Groupe Hospitalier Pitié–Salpêtrière, Paris, France 28 11 2016 28 11 2016 2016 6 11717 8 2016 21 11 2016 © The Author(s) 2016\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.Background\nPheochromocytoma, a rare catecholamine-producing tumor, might provoke stress-induced Takotsubo-like cardiomyopathy and severe cardiogenic shock. Because venoarterial-extracorporeal membrane oxygenation (VA-ECMO) rescue of pheochromocytoma-induced refractory cardiogenic shock has rarely been reported, we reviewed our ICU patients’ presentations and outcomes.\n\nMethods\nAll pheochromocytoma-induced refractory cardiogenic shock cases managed with VA-ECMO (January 2007–March 2015) were prospectively included and reviewed. We also performed a systematic review on this topic.\n\nResults\nNine patients (7 women, 2 men; 31–51 [median, 43 (IQR 36–49) years old]) were included; none had a previously known pheochromocytoma. Six of them had medical histories suggestive of the diagnosis: palpitations and headaches for several months for four, multiple endocrine neoplasia syndrome type 1 for one and recurrent Takotsubo disease for one; at hospital admission, all were hypertensive despite cardiogenic shock. Three others had an identified surgical triggering factor. All nine patients rapidly developed refractory cardiogenic shock with very severe left ventricular (LV) impairment (LV ejection-fraction range 5–20%; LV outflow-tract velocity–time integral range 3–8 cm). Seven patients’ abdominal computed tomography scans showed pheochromocytoma-suggestive adrenal gland tumors (no scan during ICU stay for 2). Despite VA-ECMO implantation, three patients died of refractory multiple organ failure. For the six others, myocardial function improved and ECMO was removed 3–7 days post-implantation; α- and β-blockers were progressively introduced. Five survivors underwent pheochromocytoma excision 3 weeks–4 months post-ICU discharge, with satisfactory outcomes. One patient, whose pheochromocytoma was diagnosed 1 year after the index event, underwent uneventful surgical adrenalectomy. Systematic review retrieved 40 cases of pheochromocytoma-induced cardiogenic shock requiring mechanical support (mostly ECMO), with a mortality rate of 7%. Pheochromocytoma was removed surgically after mechanical support weaning in 31 patients and during mechanical support in 5. Four were not operated.\n\nConclusions\nPheochromocytoma is a rare but reversible cause of cardiogenic shock amenable to VA-ECMO rescue. Adrenal gland imaging should be obtained for all patients with unexplained cardiogenic shock. Lastly, it might be safer to perform adrenalectomy several weeks after the initial catastrophic presentation, once recovery of LV systolic function is complete.\n\nissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nPheochromocytoma, called paraganglioma when extra-adrenal, is a rare catecholamine-secreting neuroendocrine tumor arising from chromaffin cells in the adrenal medulla. Its usual clinical picture combines persistent or paroxysmal hypertension, palpitations, headache, diaphoresis, tremors and/or anxiety. However, life-threatening complications, such as Takotsubo-like cardiomyopathy and cardiogenic shock, have been described and are often fatal. In this setting, venoarterial-extracorporeal membrane oxygenation (VA-ECMO) might be the only way to prevent death, but only a few cases of ECMO-managed pheochromocytoma-induced cardiogenic shock have been published.\n\nMethods\nWe reviewed the presentations and outcomes of nine patients admitted to our ICU for pheochromocytoma-induced refractory cardiogenic shock rescued by VA-ECMO between January 2007 and March 2015 (Table 1). For our literature review, the MEDLINE database was searched using “pheochromocytoma” and “cardiogenic shock” as key words. Articles were screened and those reporting cardiogenic shock requiring mechanical circulatory support (except single intra-aortic balloon pump) were selected.Table 1 Clinical and biological characteristics of the nine patients\n\nCharacteristic\tCase 1\tCase 2\tCase 3\tCase 4\tCase 5\tCase 6\tCase 7\tCase 8\tCase 9\t\nSex\tMale\tFemale\tFemale\tFemale\tFemale\tFemale\tFemale\tMale\tFemale\t\nAge (years)\t41\t44\t36\t45\t43\t51\t49\t31\t37\t\nMedical history\t\t\t\t\t\t\t\t\t\t\n Palpitations/headaches/sweating/hypertension\tYes\tYes\tYes\t\t\t\t\tYes\t\t\n Other\t\t\tType 1 neurofibromatosis\t\tTakotsubo\t\t\t\t\t\nBlood pressure at admission (mmHg)\t160/120\t180/108\t157/107\t130/110\t140/100\t130/85\t141/107\t160/100\t129/99\t\nPre-ECMO LVEF (%)\t5\t20\t15\t20\t30\t20\t20\t30\t20\t\nMaximum troponin I (ng/L)\t2200\t34,000\t43,000\t15,000\t2000\t18,000\t237\t4994\t2083\t\nNT pro-BNP at admission (ng/L)\t\t\t18,363\t\t25,282\t6363\t18,471\t\t9264\t\nECMO duration (days)\t4\t1\t6\t7\t3\t3\t2\t7\t4\t\nUrinary metanephrine (N < 340 µg/24 h)\tND\tND\tND\tND\t1894\t7192\t8738\t2862\t2582\t\nUrinary normetanephrine (N < 440 µg/24 h)\tND\tND\tND\tND\t4973\t3650\t11,910\t11,268\t9254\t\nPheochromocytoma size (mm), side\t78 × 75 × 70, right\t60 mm, left\tND, autopsy\t29, left\t70, left\t103 × 95 × 75, right\t57 × 47, right\t59 × 38, left\t88 × 74×91, left\t\n\nECMO extracorporeal membrane oxygenation, LVEF left ventricle ejection fraction, N normal value, ND not done\n\n\n\n\nResults\nCase reports\nCase 1\nA 41-year-old man consulted the emergency department (ED) for acute abdominal pain with nausea and vomiting. He had a 1-year history of hypertension and stated having had palpitations and headaches for several years. At admission, his blood pressure was 160/120 mmHg; physical examination and chest X-ray were consistent with severe pulmonary edema. His electrocardiogram indicated sinus tachycardia and ST-segment elevation in leads V1–V3. Transthoracic echocardiography (TTE) showed very severe left myocardial impairment with left ventricular ejection fraction (LVEF) at 5%. Dobutamine then epinephrine infusion obtained no improvement. Under VA-ECMO implanted before he was transferred to our ICU, he rapidly recovered cardiac function, allowing ECMO weaning on day 4. Post-weaning, he developed severe hypertension that required nicardipine infusion. Abdominal ultrasonography visualized a 7-cm-diameter lesion in the right adrenal gland, confirmed by computed tomography (CT). Four days after ECMO weaning, while under nicardipine infusion, labetalol and ramipril, he developed malignant hypertension (blood pressure at 270/120 mmHg) and cardiogenic shock complicated by cardiac arrest. VA-ECMO was re-implanted, but he died of refractory multiorgan failure. Autopsy confirmed the pheochromocytoma diagnosis.\n\nCase 2\nA 44-year-old woman underwent elective hysteroscopic resection of a bleeding uterine fibroid. Her medical history included migraines, sweating episodes, appendicular peritonitis in childhood and uterine fibroids. While in the recovery room, she became hypertensive (blood pressure 180/108 mmHg) and polypneic, with clinically and radiographically diagnosed pulmonary edema. TTE-estimated LVEF was 20%. Despite nitrates and diuretics, her clinical status abruptly deteriorated with cardiogenic shock, renal and hepatic failures, and hyperlactatemia (9 mmol/L). She was intubated, epinephrine infusion was started and progressively increased to 4 mg/h, and our ECMO mobile team implanted VA-ECMO. Post-implantation, her severe hypertension (mean blood pressure at 150 mmHg) required antihypertensive therapy. Abdominal CT revealed a 6-cm tumor in the right adrenal gland. Her hemodynamic status worsened under VA-ECMO with major capillary leak syndrome requiring vascular filling; she died several hours later.\n\nCase 3\nAfter 1 week of ineffective antibiotics, a 36-year-old woman was referred to her local ED for persistent febrile headaches, cough and vomiting. Her history consisted of type 1 neurofibromatosis, headaches and palpitations. At admission, her blood pressure was 157/107 mmHg and her heart rate 162 beats/min. Suddenly, she developed massive pulmonary edema with cardiogenic shock requiring mechanical ventilation and dobutamine infusion. TTE revealed severe global hypokinesia with LVEF at 20%. She developed multiorgan failure, and our ECMO mobile team implanted VA-ECMO. On day 4, she suffered a massive ischemic stroke, cerebral herniation and cerebral death. During her stay, abdominal ultrasonography found a left adrenal tumor; autopsy confirmed a left adrenal pheochromocytoma.\n\nCase 4\nAfter 2 weeks of antibiotics and corticosteroids for bronchitis, a 45-year-old woman went to her local ED for acute chest pain. She had no remarkable medical history. At admission, BP was 130/110 mmHg, her heart rate was 86 beats/min, and oxygen saturation was 98% breathing ambient air. She rapidly developed signs of respiratory and hemodynamic failure, and mechanical ventilation was started. Her electrocardiogram indicated sinus tachycardia and ST-segment elevation in leads V2–V3. TTE revealed severe LV dysfunction with LVEF at 20%. Refractory electrical storm ensued, requiring VA-ECMO implantation by the ECMO mobile team after 45 min of cardiopulmonary resuscitation. Peripheral ECMO was switched to central ECMO during her ICU stay. Cardiac biopsies taken during the switch contained fibrosis and lymphocytic infiltration without necrosis, suggestive of borderline myocarditis. Heart function recovered and ECMO was removed 7 days post-implantation. After 5 weeks in ICU complicated by ischemic stroke, she was discharged from the hospital. Several months later, a CT scan for abdominal pain visualized an adrenal mass, whose radiologic appearance suggested pheochromocytoma. She underwent laparoscopic adrenalectomy under stable hemodynamic conditions; histologic examination of the mass confirmed the pheochromocytoma diagnosis.\n\nCase 5\nA 43-year-old woman went to her ED for acute chest pain, palpitations, dyspnea and vomiting a few hours after dental care. She had been hospitalized 8 months earlier for acute coronary syndrome with normal coronary angiography after mammoplasty, and 4 months ago for Takotsubo syndrome following dental care. At admission, her BP was 140/100 mmHg and pulse rate 97/min. Acute respiratory distress required immediate mechanical ventilation. Her electrocardiogram revealed negative T waves on lateral leads. Troponin I was at 2 µg/L. TTE found severe LV systolic dysfunction (LVEF at 20%), with apical ballooning. Despite infused dobutamine and epinephrine (gradually increased to 15 mg/h), circulatory failure worsened and femoral–femoral VA-ECMO was implanted. Within few hours, the patient’s hemodynamics improved and, after discontinuing catecholamine infusion, a hypertensive crisis occurred. Abdominal ultrasonography discovered a 7-cm left adrenal lesion confirmed by CT. ECMO was removed on day 3 with full recovery of heart systolic function; α- and β-blockers (prazosin and atenolol) were started. Six weeks after admission, she underwent uncomplicated adrenalectomy; histologic examination of the mass confirmed the pheochromocytoma diagnosis.\n\nCase 6\nA 51-year-old woman, with no remarkable medical history, underwent elective abdominal hernia repair. During surgery, she developed hypertensive cardiogenic pulmonary edema. TTE revealed Takotsubo cardiomyopathy, with LV apical akinesis and LVEF at 25%. Her electrocardiogram indicated ST-segment depression on lateral leads. Inotropic support was ineffective, and VA-ECMO was implanted. Abdominal CT showed a 10-cm-diameter lesion in the right adrenal gland with central necrosis. Elevated urinary metanephrine and normetanephrine, and scintigraphy with metaiodobenzylguanidine confirmed the pheochromocytoma diagnosis. Prazosin (α-blocker) was initiated, and she was weaned off ECMO on day 3. During hospitalization, she developed numerous hypertensive crises that were controlled medically. The lesion/mass was successfully excised 6 weeks post-admission. Histology of the surgical specimen confirmed necrotic pheochromocytoma. The patient was well at 3-year follow-up.\n\nCase 7\nA 49-year-old woman, with no remarkable medical history, had fever, cough and myalgia of 2-week duration. She was referred to the ED for acute dyspnea and circulatory failure. At admission, her blood pressure was 120/100 mmHg, pulse 137/min and severe cardiogenic pulmonary edema required rapid intubation. TTE-measured LVEF was at 20%. Antibiotics and oseltamivir were started for suspected fulminant myocarditis. Despite maximal inotropic support, adequate perfusion could not be achieved and femoral–femoral VA-ECMO was implanted, complicated a few hours later by acute right inferior limb ischemia with compartment syndrome. On day 2, partial hemodynamic improvement allowed ECMO removal and right limb aponeurotomy. Abdominal ultrasonography visualized a large right adrenal mass. LV systolic function recovered fully. Antihypertensive medications (prazosin and β-blockers) were started. Right adrenalectomy was performed 6 weeks later; histologic examination of the mass confirmed the pheochromocytoma diagnosis.\n\nCase 8\nA 31-year-old man consulted his local ED for palpitations, and headaches associated with chest and abdominal pain. During the preceding year, he had experienced episodic headaches, sweating and palpitations. At physical examination BP was 160/100 mmHg, pulse 160/min, temperature 38.5 °C. His electrocardiogram indicated ST-segment depression in inferior–lateral leads, and troponin I was at 4994 ng/L. Emergency coronary artery angiography was normal. His respiratory and hemodynamic status worsened, necessitating mechanical ventilation and hemodynamic support. TTE showed severe LV hypokinesia with LVEF at 30%. VA-ECMO was implanted for refractory cardiogenic shock. Abdominal CT discovered a 5-cm left adrenal mass. Prazosin was started and controlled hemodynamic variations. ECMO was removed 7 days post-implantation. The patient underwent surgery 6 weeks later and was discharged in good condition.\n\nCase 9\nTwo days after the onset of flu-like symptoms, a 47-year-old woman with a history of morbid obesity and depression went to the ED for abdominal pain, vomiting and myalgia. Physical examination found temperature at 38.4 °C, BP 129/99 mmHg, pulse 138/min, respiratory rate 24/min and initial oxygen saturation 97% breathing ambient air, but the rapid deterioration of her respiratory and hemodynamic status required oxygen therapy and mechanical ventilation. Her echocardiography revealed severe LV dysfunction, with apical thrombosis. Troponin I was at 2083 ng/L. Despite inotropic support, her hemodynamics worsened and VA-ECMO was implanted. Hemodynamics quickly improved, and ECMO was removed on day 4. She suffered an embolic stroke that caused left hemiplegia. Abdominal CT showed a multinodular formation near the left adrenal gland, whose enhancement and density were compatible with a paraganglioma. She was started on α- and β-blockers and discharged to a neurologic rehabilitation center. Her tumor was excised 4 months later; histology confirmed a voluminous paraganglioma.\n\nLiterature review\nWe conducted a systematic MEDLINE database literature review through the PubMed search engine, between 2000 and 2016, using the following criteria: pheochromocytoma and cardiogenic shock, pheochromocytoma and ECMO, pheochromocytoma and mechanical circulatory support, Takotsubo and cardiogenic shock, adrenergic cardiomyopathy and cardiogenic shock. We also searched the references of identified studies. Observational studies and case series reporting on adult patients having required mechanical circulatory support for pheochromocytoma-induced cardiogenic shock were eligible. Studies on children or newborns, those without any outcome information, were excluded.\n\nTwo authors (G.H. and N.B.) independently reviewed the retrieved abstracts and assessed eligibility. A third author (C.E.L.) determined eligibility in the case of disagreement.\n\nThe following data were extracted: study design, participants’ characteristics (including echocardiographic data), type of mechanical circulatory support, outcome data (hospital mortality).\n\nForty cases of patients suffering from pheochromocytoma-induced cardiogenic shock requiring mechanical circulatory support (except use of intra-aortic balloon pump alone) were reported in the literature (Table 2). Twenty (50%) were women, and their median age was 40 years (IQR 31–49 years). Left ventricular dysfunction was very severe in all cases with a median LVEF of 15% (IQR 10–20%). ECMO was used in 35 patients, 2 patients had Impella device, 1 had Tandem Heart device, 2 had cardiopulmonary bypass to facilitate pheochromocytoma surgery, and 4 patients had long-term mechanical circulatory support. Median duration of mechanical circulatory support was 4 days (IQR 1.5–6.5 days). Pheochromocytoma was removed surgically after mechanical circulatory support weaning in 29 patients and while on mechanical circulatory support in 7. Two patients died before surgery, one patient declined, and the timing of surgery was not reported in the last case. The median ICU-admission-to-surgery interval was 23 days (IQR 1–46 days). Thirty-seven of the 40 (93%) reported cases survived.Table 2 Case reports of pheochromocytoma-induced cardiogenic shock requiring mechanical circulatory support\n\nFirst author\tYear\tPatients with cardiac assist device, n\n\tMean age (years)\tSex\tInitial LVEF (%)\tMechanical circulatory support; duration (days)\tICU-admission -to-surgery interval (days)\tHospital survival\t\nTakagi [17]\t2000\t1\t52\tM\t9\tECMO and IABP; 3\tNR, after ECMO weaning\tYes\t\nGrinda [18]\t2006\t1\t49\tM\t12\tECMO, then LVAD; 4, then 70, respectively\t4\tYes\t\nOuchikhe [19]\t2006\t1\t23\tM\t20\tECMO, then Thoratec BiVAD; 84\t93\tYes\t\nKim [20]\t2007\t1\t47\tM\t23\tECMO and IABP; 10\t15\tYes\t\nChao [21]\t2008\t1\t42\tM\t20\tECMO and IABP; 7\t18\tYes\t\nZegdi [22]\t2008\t1\t51\tF\t30\tECMO; 6\t30\tYes\t\nHuang [23]\t2008\t3\t25\tF\tNR\tECMO and IABP; 4\tNR, after ECMO weaning\tYes\t\n\t\t\t42\tM\tNR\tECMO and IABP; 7\tNR, after ECMO weaning\tYes\t\n\t\t\t41\tF\t<NR\tECMO and IABP; 2\tNR, after ECMO weaning\tYes\t\nGrasselli [24]\t2008\t1\t47\tF\t30\tECMO; 4\t7\tYes\t\nSuh [25]\t2008\t1\t43\tM\t27\tECMO and IABP; 4\t56\tYes\t\nWu [26]\t2008\t2\t42\tM\t34\tECMO and IABP; 8\t21\tYes\t\n\t\t\t40\tM\t30\tECMO and IABP; 4\t12\tYes\t\nNewton [27]\t2008\t1\t45\tM\t10\tCBP to facilitate pheochromocytoma surgery; 1\t1\tYes\t\nPark [28]\t2009\t1\t41\tM\t20\tECMO and IABP; 2\t30\tYes\t\nWestaby [12]\t2009\t1\t27\tM\t15\tCBP and adrenalectomy, then LVAD; 6\t1\tYes\t\nRaikhelkar [29]\t2010\t1\t38\tM\t5\tThoratec BiVAD; 4\t24\tYes\t\nXeridat [25]\t2011\t1\t16\tF\t20\tECMO; 6\t21\tYes\t\nRitter [30]\t2011\t1\t49\tF\t10\tECMO; 8\t8\tYes\t\nNakajima [31]\t2011\t1\t33\tF\t19\tECMO and IABP; 4\t120\tYes\t\nContargyris [32]\t2012\t1\t20\tM\t20\tECMO; 2\t30\tYes\t\nSojod [33]\t2012\t1\t37\tF\t15\tECMO; 11\t21\tYes\t\nSheinberg [34]\t2012\t1\t45\tF\t5\tECMO and IABP; 3\t56\tNo\t\nNoorani [35]\t2012\t1\t39\tF\tNR\tCentral ECMO; 5\t3\tYes\t\nBanfi [36]\t2012\t1\t20\tF\t20\tCentral ECMO; 6\t120\tYes\t\nKaese [37]\t2013\t1\t43\tM\tNR\tECMO; 9\tNR, after ECMO weaning\tYes\t\nLaw [38]\t2013\t1\t23\tF\t5\tECMO; 1\tNR, after ECMO weaning\tYes\t\nShawa [39]\t2014\t1\t38\tF\t15\tTandem Heart; 1\t26\tYes\t\nRiester [1]\t2015\t2\t18\tF\tNR\tImpella; 2\tNo surgery\tNo\t\n\t\t\t25\tF\tNR\tECMO; NR\tNR, after ECMO weaning\tYes\t\nChao [2]\t2015\t4, 2 with IABPa\n\t25\tF\tNR\tECMOa\n\tNR, after ECMO weaning\tYes\t\n\t\t\t52\tM\tNR\tECMOa\n\tNR, after ECMO weaning\tYes\t\n\t\t\t40\tM\tNR\tECMOa\n\tNR, after ECMO weaning\tYes\t\n\t\t\t65\tM\tNR\tECMOa\n\tRefused surgery\tYes\t\nZhou [40]\t2015\t1\t35\tM\t20\tECMO and IABP during cardiac paraganglioma resection; 16\tCardiac paraganglioma resection, date unknown\tYes\t\nFlam [10]\t2015\t1\t46\tF\t15\tECMO; 5\t66\tYes\t\nVagner [41]\t2015\t1\t55\tF\t15\tImpella, then ECLS; 2\t56\tYes\t\nSpangenberg [14]\t2015\t1\t29\tF\t10\tECMO and IABP; 1\tNo surgery\tNo\t\nKodama [9]\t2016\t1\t37\tF\t10\tECMO; NR\tNR, before ECMO weaning\tYes\t\nDang Van [42]\t2016\t1\t57\tM\t10\tECMO, 7\tNR, concomitant from the ECMO implantation\tYes\t\n\nIABP intra-aortic balloon pump, NR not reported, CPB cardiopulmonary bypass, LVAD left ventricular assist device, BiVAD biventricular assist device, ECLS extracorporeal life support\n\n\naChao et al. did not specify which two patients had ECMO and IABP and individual ECMO durations were not given\n\n\n\n\nDiscussion\nWe described nine critical presentations of undiagnosed pheochromocytoma with refractory cardiogenic shock requiring VA-ECMO salvage therapy.\n\nMany cardiac manifestations of pheochromocytoma have been reported, including Takotsubo-like cardiomyopathy, myocardial infarction, pulmonary edema and/or hypertensive crisis [1], but only rarely inaugural refractory cardiogenic shock requiring VA-ECMO (Table 2). This is, to our knowledge, the largest case series of pheochromocytoma-induced refractory cardiogenic shock. As previously reported [1, 2], the major clinical feature was the sequence of initial hypertensive crisis followed by hypotensive shock, probably caused by severe LV failure. Following ECMO implantation, all our patients suffered paroxysmal hypertension with wide and rapid blood pressure fluctuations.\n\nCoronary angiography should be considered in every patient with unexplained cardiogenic shock, especially in cases of ST-segment deviation. It was performed in patient 8, and patient 5 had a normal coronary catheterization a few months ago. In our study, the other patients did not have this examination because three had a clinical presentation highly suggestive of myocarditis and four had clinical characteristics suggestive of pheochromocytoma with early diagnosis performed on abdominal imaging.\n\nCardiogenic shock is a rare but potentially lethal pheochromocytoma manifestation, and in our series, three of the nine patients died. For the six survivors, mechanical circulatory support was probably the only way to prevent death. Because ECMO allows quick and easy percutaneous insertion of cannulae, full circulatory support and improved tissue oxygenation in situations of cardiogenic shock combined with severe pulmonary edema [3, 4], it was preferred over other assisted support options for all these patients. Pertinently, cardiac dysfunction reversibility in these pheochromocytoma-induced cardiomyopathies is well established; all six survivors were all weaned off ECMO within a week and recovered normal myocardial systolic function.\n\nCatecholamine-mediated cardiomyopathy is not completely understood. Proposed mechanisms include coronary artery or microvascular spasms leading to focal myocardial necrosis [5], direct cellular toxicity through increased intracellular calcium concentrations [6] or damage induced by reactive oxygen species [7], and myocardial stunning due to receptor desensitization and/or downregulation [8]. When obtained, endomyocardial biopsies contained nonspecific contraction band necrosis [9]. Our patient 4’s suspected myocarditis biopsy contained lymphocytic infiltration and focal fibrosis, without necrosis.\n\nIn reported cases [10] and our experience, once the initial critical context has been controlled, heart failure is fully reversible within a few days, suggesting stunning or metabolic anomaly rather than myocardial necrosis.\n\nMedical management of pheochromocytoma-induced cardiogenic shock raises some concerns. Various drugs, including adrenaline, noradrenaline, dobutamine, vasopressin and levosimendan, were used in case reports. Because exposure to elevated epinephrine levels may engender cardiac dysfunction and sympathetic receptor downregulation, catecholamines usually used to treat cardiogenic shock could be less effective or even exacerbate pheochromocytoma-induced cardiogenic shock. Some authors proposed alternative agents that do not act via adrenergic receptors, such as calcium-sensitizing agents or phosphodiesterase III inhibitors, but no available evidence supports those decisions [11, 12].\n\nCardiogenic shock was the first main manifestation of undiagnosed pheochromocytoma for most of our patients, but some clinical manifestations could help guide the diagnosis. The major characteristic was hypertension at admission contrasting with evidence of circulatory failure. Symptoms suggestive of pheochromocytoma, e.g., headaches, sweating and palpitations, were retrospectively found in four patients, one had type 1 neurofibromatosis, and one had experienced two Takotsubo cardiomyopathy episodes. During recovery, four of them developed severe paroxysmal hypertension, also evocative of pheochromocytoma.\n\nPrecipitating circumstances were identified for some patients. Three relatively asymptomatic patients’ previously undiagnosed pheochromocytomas were unmasked by elective surgery, manifesting as peri- or postoperative hypertensive crises and subsequent cardiogenic shock. Johnston et al. described two similar patients with hypertensive crises and cardiogenic shock unmasked by elective surgical procedures [11]. In such perioperative situations, acute intra-tumor hemorrhagic necrosis may precipitate catecholamine release, thereby inducing acute cardiogenic shock. Four patients had flu-like symptoms (fever, cough, myalgia) and acute heart failure with LV dysfunction and pulmonary edema, suggestive of myocarditis [13]. This particular clinical picture of pheochromocytoma mimicking fulminant myocarditis has been described previously [14] and should be known to physicians.\n\nFor our patients, pheochromocytoma was diagnosed based on abdominal CT or ultrasonography and then confirmed by elevated urinary catecholamines. Pheochromocytoma diagnosis usually relies on measuring plasma or urine metanephrines. However, cardiogenic shock and hypertensive crisis can physiologically increase catecholamine release and these patients frequently receive adrenaline or noradrenaline infusions. For those two reasons, metanephrine levels cannot be used in this setting to diagnose pheochromocytoma. As Amar and Eisenhofer suggested, this situation requires immediate imaging studies to search for a pheochromocytoma without prior biochemical evidence of a catecholamine-producing tumor [15].\n\nA difficult issue is the optimal timing of pheochromocytoma excision. In a recent retrospective cohort study and literature review, emergency surgery during hypertensive crisis was associated with higher mortality and morbidity [16]. Stabilization with α-blockade prior to elective surgery was associated with shorter hospital stays and fewer postoperative complications. It seems useful to minimize the risk of catecholamine-induced hemodynamic fluctuations during anesthesia or pre-ablation tumor mobilization during surgery. Calcium channel blockers may be added, if necessary.\n\nIn our case series, α-blockers were gradually introduced in hemodynamically stabilized patients, followed by β-blockers to prevent tachycardia once cardiac systolic function had recovered and ECMO had been removed.\n\nFive survivors underwent adrenalectomy 3 weeks to 4 months after the initial emergency presentation; the sixth pheochromocytoma was diagnosed 1 year later and removed under stable conditions and without perioperative complications. Celioscopic adrenalectomy was achievable in the six patients once heart function had fully recovered. None of these patients experienced another severe hypertensive crisis on α- and β-blockers before surgery. All six have been asymptomatic since the intervention.\n\nAs compared to previously reported cases, we described nine consecutive patients whereas most reported cases were single cases. Our patients were globally similar to previously reported cases: They shared same clinical characteristics and same short duration of ECMO support, and most adrenalectomy procedures were delayed after myocardial recovery. Contrasting with the good outcome (37/40 patients survived) of the previously reported patients, three of our nine patients died. This could be explained by publication bias related to single case reports; authors report most often successes than failures. Clinicians should be aware of this rare but curable cause of cardiogenic shock; it can be suspected in patients with cardiogenic shock associated with hypertension and easily confirmed using abdominal imaging. Moreover, we describe here a homogenous and successful single-center strategy for pheochromocytoma-induced cardiogenic shock management from the initial critical presentation to the scheduled adrenalectomy after heart recovery.\n\nConclusion\nPheochromocytoma should systematically be considered for patients with Takotsubo cardiomyopathy, myocarditis, perioperative hypertensive crisis and/or unexplained cardiogenic shock. The definitive diagnosis is based on characteristic clinical features and abdominal imaging. For the most severe cases, ECMO support can be a life-saving therapy, allowing myocardial recovery within a few days. After hemodynamic stabilization, treatment should include α-blockade, with elective pheochromocytoma removal scheduled after myocardial recovery under stable conditions.\n\nGuillaume Hekimian and Fatima Kharcha contributed equally to this work\n\nAuthors’ contributions\nGH, FK, GL, NB, MS, CG, XG, CT, PL, JLT, JC, AC and CEL conceived the study. GH, FK and CEL wrote the manuscript. GH, FK, GL, NB, MS, CG, XG, CT, PL, JLT, JC, AC and CEL reviewed, and revised the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nDr. Combes is the primary investigator of the EOLIA trial (NCT01470703), a randomized trial of VV-ECMO supported in part by MAQUET. Drs. Bréchot, Schmidt, Lebreton and Combes have received honoraria for lectures by MAQUET. Other authors declare that they have no competing interests.\n\nConsent to publish\nConsent to publish has been obtained from the participants or their legal parents to report individual patients’ data.\n==== Refs\nReferences\n1. Riester A Weismann D Quinkler M Lichtenauer UD Sommerey S Halbritter R Life-threatening events in patients with pheochromocytoma Eur J Endocrinol/Eur Fed Endocr Soc 2015 173 6 757 764 10.1530/EJE-15-0483 \n2. Chao A Wang C-H You H-C Chou N-K Yu H-Y Chi N-H Highlighting Indication of extracorporeal membrane oxygenation in endocrine emergencies Sci Rep 2015 5 13361 10.1038/srep13361 26299943 \n3. Werdan K Gielen S Ebelt H Hochman JS Mechanical circulatory support in cardiogenic shock Eur Heart J 2014 35 3 156 167 10.1093/eurheartj/eht248 24014384 \n4. Muller G Flecher E Lebreton G Luyt C-E Trouillet J-L Bréchot N The ENCOURAGE mortality risk score and analysis of long-term outcomes after VA-ECMO for acute myocardial infarction with cardiogenic shock Intensive Care Med 2016 42 3 370 378 10.1007/s00134-016-4223-9 26825953 \n5. Simons M Downing SE Coronary vasoconstriction and catecholamine cardiomyopathy Am Heart J 1985 109 2 297 304 10.1016/0002-8703(85)90597-6 3966346 \n6. Opie LH Walpoth B Barsacchi R Calcium and catecholamines: relevance to cardiomyopathies and significance in therapeutic strategies J Mol Cell Cardiol 1985 17 Suppl 2 21 34 10.1016/0022-2828(85)90005-7 2863385 \n7. Costa VM Carvalho F Bastos ML Carvalho RA Carvalho M Remião F Contribution of catecholamine reactive intermediates and oxidative stress to the pathologic features of heart diseases Curr Med Chem 2011 18 15 2272 2314 10.2174/092986711795656081 21517751 \n8. Rosenbaum JS Billingham ME Ginsburg R Tsujimoto G Lurie KG Hoffman BB Cardiomyopathy in a rat model of pheochromocytoma. Morphological and functional alterations Am J Cardiovasc Pathol 1988 1 3 389 399 3207483 \n9. Kodama T Agozzino M Pellegrini C Narula N Pietrabissa A Concardi M Endomyocardial Biopsy in acute cardiogenic shock: diagnosis of pheochromocytoma Int J Cardiol 2016 202 897 899 10.1016/j.ijcard.2015.10.053 26479955 \n10. Flam B Broomé M Frenckner B Bränström R Bell M Pheochromocytoma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation J Intensive Care Med 2015 30 6 365 372 10.1177/0885066614552992 25286918 \n11. Johnston PC Silversides JA Wallace H Farling PA Hutchinson A Hunter SJ Phaeochromocytoma crisis: two cases of undiagnosed phaeochromocytoma presenting after elective nonrelated surgical procedures Case Rep Anesthesiol 2013 2013 514714 24288628 \n12. Westaby S Shahir A Sadler G Flynn F Ormerod O Mechanical bridge to recovery in pheochromocytoma myocarditis Nat Rev Cardiol 2009 6 7 482 487 10.1038/nrcardio.2009.58 19554007 \n13. Mirabel M Luyt C-E Leprince P Trouillet J-L Léger P Pavie A Outcomes, long-term quality of life, and psychologic assessment of fulminant myocarditis patients rescued by mechanical circulatory support Crit Care Med 2011 39 5 1029 1035 10.1097/CCM.0b013e31820ead45 21336134 \n14. Spangenberg T Freker C Niggemann C Reißmann B Meincke F van der Schalk H Differential diagnosis of a fulminant myocarditis: the pheochromocytoma crisis Eur Heart J Acute Cardiovasc Care 2015 4 6 577 578 10.1177/2048872614552058 25225188 \n15. Amar L Eisenhofer G Diagnosing phaeochromocytoma/paraganglioma in a patient presenting with critical illness: biochemistry versus imaging Clin Endocrinol (Oxf) 2015 83 3 298 302 10.1111/cen.12745 25683095 \n16. Scholten A Cisco RM Vriens MR Cohen JK Mitmaker EJ Liu C pheochromocytoma crisis is not a surgical emergency J Clin Endocrinol Metab 2013 98 2 581 591 10.1210/jc.2012-3020 23284003 \n17. Takagi S Miyazaki S Fujii T Daikoku S Sutani Y Morii I Dexamethasone-induced cardiogenic shock rescued by percutaneous cardiopulmonary support (PCPS) in a patient with pheochromocytoma Jpn Circ J 2000 64 10 785 788 10.1253/jcj.64.785 11059621 \n18. Grinda J-M Bricourt M-O Salvi S Carlier M Grossenbacher F Brasselet C Unusual cardiogenic shock due to pheochromocytoma: recovery after bridge-to-bridge (extracorporeal life support and DeBakey ventricular assist device) and right surrenalectomy J Thorac Cardiovasc Surg 2006 131 4 913 914 10.1016/j.jtcvs.2005.12.021 16580454 \n19. Ouchikhe A Lehoux P Gringore A Renouf P Deredec R Tasle M Phaeochromocytoma as an unusual aetiology of cardiogenic shock Ann Fr Anesth Rèanim 2006 25 1 46 49 10.1016/j.annfar.2005.08.020 16386403 \n20. Kim HS Chang WI Kim YC Yi SY Kil JS Hahn J-Y Catecholamine cardiomyopathy associated with paraganglioma rescued by percutaneous cardiopulmonary support: inverted Takotsubo contractile pattern Circ J 2007 71 12 1993 1995 10.1253/circj.71.1993 18037760 \n21. Chao A Yeh YC Yen TS Chen YS Phaeochromocytoma crisis—a rare indication for extracorporeal membrane oxygenation Anaesthesia 2008 63 1 86 88 10.1111/j.1365-2044.2007.05251.x 18086076 \n22. Zegdi R Parisot C Sleilaty G Deloche A Fabiani J-N Pheochromocytoma-induced inverted Takotsubo cardiomyopathy: a case of patient resuscitation with extracorporeal life support J Thorac Cardiovasc Surg 2008 135 2 434 435 10.1016/j.jtcvs.2007.08.068 18242283 \n23. Huang J-H Huang S-C Chou N-K Ko W-J Chen Y-S Wang S-S Extracorporeal membrane oxygenation rescue for cardiopulmonary collapse secondary to pheochromocytoma: report of three cases Intensive Care Med 2008 34 8 1551 1552 10.1007/s00134-008-1117-5 18427776 \n24. Grasselli G Foti G Patroniti N Rona R Perlangeli MV Pesenti A Extracorporeal cardiopulmonary support for cardiogenic shock caused by pheochromocytoma: a case report and literature review Anesthesiology 2008 108 5 959 962 10.1097/ALN.0b013e31816c8a78 18431133 \n25. Suh I-W Lee CW Kim Y-H Hong M-K Lee J-W Kim J-J Catastrophic catecholamine-induced cardiomyopathy mimicking acute myocardial infarction, rescued by extracorporeal membrane oxygenation (ECMO) in pheochromocytoma J Korean Med Sci 2008 23 2 350 354 10.3346/jkms.2008.23.2.350 18437026 \n26. Wu X-M Chen J-J Wu C-K Lin L-Y Tseng C-D Pheochromocytoma presenting as acute myocarditis with cardiogenic shock in two cases Intern Med 2008 47 24 2151 2155 10.2169/internalmedicine.47.1360 19075541 \n27. Newton JD Munir S Bhindi R Ormerod O What a headache: rare neuroendocrine indication for cardiopulmonary bypass for severe left ventricular dysfunction and shock Circ Heart Fail 2008 1 2 143 145 10.1161/CIRCHEARTFAILURE.108.766865 19808283 \n28. Park S-M Kim D-H Kwak Y-T Jeong I-K Cho J-M Jin E-S Pheochromocytoma-induced cardiogenic shock rescued by percutaneous cardiopulmonary bypass system Circ J 2009 73 9 1753 1755 10.1253/circj.CJ-08-0287 19145042 \n29. Raikhelkar J Anyanwu A Gist RS Somal J Mechanick JI Scher C Pheochromocytoma presenting as severe biventricular failure requiring insertion of a biventricular assist device J Cardiothorac Vasc Anesth 2010 24 6 985 987 10.1053/j.jvca.2009.06.008 19700348 \n30. Ritter S Guertler T Meier CA Genoni M Cardiogenic shock due to pheochromocytoma rescued by extracorporeal membrane oxygenation Interact CardioVasc Thorac Surg 2011 13 1 112 113 10.1510/icvts.2011.266023 21422159 \n31. Nakajima Y Masaoka N Sodeyama M Tsuduki Y Sakai M Pheochromocytoma-related cardiomyopathy during the antepartum period in a preterm pregnant woman J Obstet Gynaecol Res 2011 37 7 908 911 10.1111/j.1447-0756.2010.01423.x 21736670 \n32. Contargyris C Nee L Saby C Kerbaul F Peytel E Phaeochromocytoma revealed by a cardiogenic shock treated by extracorporeal life support Ann Fr Anesth Rèanim 2012 31 12 965 968 10.1016/j.annfar.2012.10.006 23164653 \n33. Sojod G Diana M Wall J D’Agostino J Mutter D Marescaux J Successful extracorporeal membrane oxygenation treatment for pheochromocytoma-induced acute cardiac failure Am J Emerg Med 2012 30 6 1017.e1 1017.e3 10.1016/j.ajem.2011.05.006 \n34. Sheinberg R Gao WD Wand G Abraham S Schulick R Roy R Case 1—2012. A perfect storm: fatality resulting from metoclopramide unmasking a pheochromocytoma and its management J Cardiothorac Vasc Anesth 2012 26 1 161 165 10.1053/j.jvca.2011.10.003 22221507 \n35. Noorani A Vuylsteke A Lewis C Parameshwar J Catarino P A moribund athlete Lancet 2012 380 9836 74 10.1016/S0140-6736(12)60910-6 22770460 \n36. Banfi C Juthier F Ennezat P-V de Saint Denis T Carnaille B Leteurtre E Central extracorporeal life support in pheochromocytoma crisis Ann Thorac Surg 2012 93 4 1303 1305 10.1016/j.athoracsur.2011.09.018 22450084 \n37. Kaese S Schülke C Fischer D Lebiedz P Pheochromocytoma-induced takotsubo-like cardiomyopathy and global heart failure with need for extracorporal life support Intensive Care Med 2013 39 8 1473 1474 10.1007/s00134-013-2942-8 23670051 \n38. Law C Khaliq A Guglin M Reversible cardiogenic shock due to catecholamine-induced cardiomyopathy: a variant of takotsubo? Am J Emerg Med 2013 31 11 1621.e1 1621.e3 10.1016/j.ajem.2013.05.042 \n39. Shawa H Bajaj M Cunningham GR Pheochromocytoma-induced atrial tachycardia leading to cardiogenic shock and cardiac arrest: resolution with atrioventricular node ablation and pacemaker placement Tex Heart Inst J 2014 41 6 660 663 10.14503/THIJ-13-3692 25593537 \n40. Zhou X Liu D Su L Long Y Du W Miao Q Pheochromocytoma crisis with severe cyclic blood pressure fluctuations in a cardiac pheochromocytoma patient successfully resuscitated by extracorporeal membrane oxygenation: a case report Medicine (Baltimore) 2015 94 17 e790 10.1097/MD.0000000000000790 25929929 \n41. Vagner H, Hey TM, Elle B, Jensen MK. Embolisation of pheochromocytoma to stabilise and wean a patient in cardiogenic shock from emergency extracorporeal life support. BMJ Case Rep. 2015. pii: bcr2014206069.\n42. Van Dang S Hamy A Hubert N Fouquet O Cardiogenic shock induced by a voluminous phaeochromocytoma rescued by concomitant extracorporeal life support and open left adrenalectomy Eur J Cardiothorac Surg. 2016 50 4 782 783 10.1093/ejcts/ezw122 27068551\n\n",
"fulltext_license": "CC BY",
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"references": "24288628;26299943;16580454;11059621;21741786;26346138;26479955;18437026;23670051;25683095;22221507;23164653;19700348;21736670;25225188;25593537;19075541;18427776;23284003;2863385;3207483;18037760;3966346;25929929;18086076;21336134;18431133;26825953;19145042;25737217;25286918;19808283;16386403;27068551;22450084;24014384;23810075;18242283;22770460;21517751;19554007;21422159",
"title": "Extracorporeal membrane oxygenation for pheochromocytoma-induced cardiogenic shock.",
"title_normalized": "extracorporeal membrane oxygenation for pheochromocytoma induced cardiogenic shock"
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"abstract": "Posttransplant high-dose cyclophosphamide (pT-HDCy) following T-cell-replete haploidentical bone marrow (BM) transplantation has been successfully utilized to control alloreactivity, mainly in ameliorating graft-versus-host disease (GVHD) and graft rejection. Recently, peripheral blood stem cells (PBSCs) have also been suggested to be a feasible and effective graft alternative to BM in the same setting. We report a case with refractory Hodgkin lymphoma treated with haploidentical PBSC transplantation with nonmyeloablative conditioning and pT-HDCy. Although engraftment with complete donor chimerism was achieved without classical GVHD, the patient suffered from idiopathic pneumonia syndrome followed by thrombotic microangiopathy. Although idiopathic pneumonia syndrome and thrombotic microangiopathy improved after treatment, the patient's lymphoma rapidly progressed nonetheless. This outcome may suggest that the alloreactivity against the classical GVHD targets is successfully eradicated by pT-HDCy, but alloreactivity against the lungs and endothelial cells is differentially preserved when utilizing granulocyte colony-stimulating factor-mobilized PBSCs as the graft source. The graft-versus-Hodgkin lymphoma effect was not observed in our patient.",
"affiliations": "From the Department of Hematology and Oncology (W-HL); Department of Internal Medicine (W-TC); Department of Pharmacy (L-HF); and Department of Pediatric Hematology and Oncology (R-LC), Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan.",
"authors": "Liu|Wei-Hsin|WH|;Chen|Wei-Ting|WT|;Fang|Li-Hua|LH|;Chen|Rong-Long|RL|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2620063510.1097/MD.0000000000001200012004800Research ArticleClinical Case ReportIdiopathic Pneumonia Syndrome and Thrombotic Microangiopathy Following Nonmyeloablative Haploidentical Peripheral Blood Stem Cell Transplantation and Posttransplant Cyclophosphamide A Case ReportLiu Wei-Hsin MDChen Wei-Ting MDFang Li-Hua MSChen Rong-Long MDYong Wang. From the Department of Hematology and Oncology (W-HL); Department of Internal Medicine (W-TC); Department of Pharmacy (L-HF); and Department of Pediatric Hematology and Oncology (R-LC), Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan.Correspondence: Rong-Long Chen, Department of Pediatric Hematology and Oncology, Koo Foundation Sun Yat-Sen Cancer Center, No. 125, Lih-Der Road, Pei-Tou District, Taipei 11259, Taiwan (e-mail: ronglongchen@yahoo.com.tw).7 2015 24 7 2015 94 29 e12001 3 2015 22 6 2015 29 6 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nPosttransplant high-dose cyclophosphamide (pT-HDCy) following T-cell-replete haploidentical bone marrow (BM) transplantation has been successfully utilized to control alloreactivity, mainly in ameliorating graft-versus-host disease (GVHD) and graft rejection. Recently, peripheral blood stem cells (PBSCs) have also been suggested to be a feasible and effective graft alternative to BM in the same setting.\n\nWe report a case with refractory Hodgkin lymphoma treated with haploidentical PBSC transplantation with nonmyeloablative conditioning and pT-HDCy. Although engraftment with complete donor chimerism was achieved without classical GVHD, the patient suffered from idiopathic pneumonia syndrome followed by thrombotic microangiopathy.\n\nAlthough idiopathic pneumonia syndrome and thrombotic microangiopathy improved after treatment, the patient's lymphoma rapidly progressed nonetheless.\n\nThis outcome may suggest that the alloreactivity against the classical GVHD targets is successfully eradicated by pT-HDCy, but alloreactivity against the lungs and endothelial cells is differentially preserved when utilizing granulocyte colony-stimulating factor-mobilized PBSCs as the graft source. The graft-versus-Hodgkin lymphoma effect was not observed in our patient.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nAccording to the pioneering work of Johns Hopkins University, haploidentical bone marrow (BM) transplantation with nonmyeloablative conditioning and posttransplant high-dose cyclophosphamide (pT-HDCy) has been successfully applied in the treatment of hematologic malignancies.1 BM is a preferred graft source in this setting because of the theoretical concerns that the larger number of T cells, typically present in granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (PBSCs), may overwhelm pT-HDCy to suppress detrimental alloreactivity posttransplant. A recent report demonstrated that PBSCs can be safely and effectively utilized in haploidentical transplantations with similar nonmyeloablative conditioning and pT-HDCy to deliver results comparable to that of the BM transplantation in terms of engraftment, graft-versus-host disease (GVHD), and infection control.2 In addition, both BM and PBSCs have been demonstrated to be particularly effective as graft sources in the patients with poor prognosis Hodgkin lymphoma.3–5 Therefore, we applied the haploidentical PBSC transplantation strategy to treat a patient with Hodgkin lymphoma who had had relapses after 4 lines of treatments including autologous PBSC transplantation. She unexpectedly suffered from idiopathic pneumonia syndrome (IPS) followed by thrombotic microangiopathy (TMA) possibly related to nonsuppressed donor PBSC alloreactivity following pT-HDCy. Although she attained complete donor chimerism in the absence of classical acute GVHD, as seen in some reports, her tumor still rapidly progressed.\n\nCASE REPORT\nA 17-year-old girl was diagnosed with an initial stage IIB nodular sclerosis-type Hodgkin lymphoma in November 2012 at an outside hospital. She suffered from recurrent disease after 4 lines of treatments including autologous PBSC transplantation on December 8, 2013, after BCNU/etoposide/ara-C/melphalan conditioning. Intermittent coughs and epigastric pain was noted; she was transferred to our hospital where a positron emission tomography-computed tomography (CT) scan on July 18, 2014, revealed extensive disease (Figure 1). She subsequently received 3 cycles of gemcitabine/vinorelbine6 chemotherapy from July to September, during which she remained dyspneic from persistent thoracic lesions.\n\nFIGURE 1 A positron emission tomography-computed tomography scan on July 18, 2014, revealed extensive [18F]fluorodeoxyglucose uptake within lymph nodes in the bilateral supraclavicular, mediastinal, pulmonary hilar, retrocardiac, cardiophrenic, gastrohepatic, abdominal paraaortic, left lower pelvic regions; bones in the left mandible, skull, spine, pelvic bones, bilateral scapulae, ribs, left femur; bilateral lungs and pleura; and pancreatic tail.\n\nA decision was made for haploidentical PBSC transplantation with her elder brother as the donor. The conditioning treatment consisted of fludarabine (30 mg/m2 daily intravenous from day −6 to −2) and cyclophosphamide (14.5 mg/kg daily intravenous from day −6 to −5) as well as 2 Gy total body irradiation on day −1. For GVHD prophylaxis, the patient received pT-HDCy (50 mg/kg daily intravenous from day +3 to +4), whereas cyclosporine and mycophenolate mofetil were given from day +5. On October 7, 2014, she received PBSCs containing 14.5 × 108 total nucleated cells/kg, 7.4 × 106 CD34+ cells/kg, and 1.4 × 108 CD3+ cells/kg. The patient and donor were human leukocyte antigen-5/10 matched (A 3101/2402, B 4001/1502, Cw 0304/0801, DQ 0301/0301, DR 1101/1202 to A 3101/0207, B 4001/4601, Cw 0304/0102, DQ 0301/0502, DR 1101/1454) and ABO nonidentical (B to A).\n\nThe postinfusion course was complicated by the rapid accumulation of pericardial and pleural effusions (Figure 2A) necessitating intermittent drainage. The fluid was serosanguinous without evidence of any microbial pathogens, whereas CD30/CD15/PAX-5+ cells were only detectable in the first of 2 pericardial (day +27) and last of 4 pleural (day +59) samples. Neutrophil engraftment with complete donor chimerism was documented on day +19. She received frequent red cell transfusions. She also received platelet transfusions every 2 to 3 days until day +32; thereafter, she did not require platelet transfusion until day +46.\n\nFIGURE 2 The serial chest x-rays perihaploidentical transplantation showing the following: (A) the appearance of bilateral pleural and pericardial effusions just after conditioning (day −1); (B) the rapid development of bilateral diffuse pulmonary infiltrates after engraftment (day +44); (C) the resolution of the pulmonary infiltrates after treatment with methylprednisolone and etanercept (day +50); (D) rapid tumor progression, including a mass in the neck, supraclavicular, axilla, mediastinum, lungs and pleura (day +83).\n\nHowever, cytomegalovirus reactivation was detected beginning on day +34. At the same time, reactivation of polyomavirus BK viruria caused grade III hemorrhagic cystitis. Epstein–Barr virus DNAemia was never detected throughout the entire course. She received ganciclovir (from day +36) along with intravenous immunoglobulins (a total of 7 doses from day +37 to day +69). Cytomegalovirus DNAemia was undetectable after day +55. However, the respiratory distress progressed and elective intubation with mechanical ventilation was started on day +44 (Figure 2B). IPS was diagnosed by negative microbial and cytology panel studies from repeated bronchoalveolar lavages on days +44 and +56, respectively, according to the definition updated by the American Thoracic Society Committee.7 The pneumonia improved after treatment with methylprednisolone along with etanercept (a total of 7 doses from days +44 to +69) (Figure 2C). No evidence of other microbial infections was documented throughout the entire course.\n\nAfter she was extubated on day +57, she still suffered from intermittent exacerbation of respiratory distress. Hypertension developed (from a baseline of 100/60 mm Hg until day +55 to >150/100 mm Hg after day +57) and renal function deteriorated (baseline blood urea nitrogen/creatinine of 56/1.05 mg/dL on day +54 elevated to 152/2.54 mg/dL on day +59). In addition, episodes of complex partial seizure were also noted. Multiple infarct-like lesions in the left frontal lobe, right middle cerebellar peduncle, and bilateral occipital white matter were found on day +72 by brain magnetic resonance imaging (Figure 3). TMA was diagnosed according to the proposed criteria8: marked elevation of lactate dehydrogenase (from 617 to 1074 U/L), aggravated anemia and thrombocytopenia, presence of schistocytes in the peripheral blood, absence of a coagulopathy, and a negative Coombs test. Tracheostomy was performed because of the unstable respiratory status on day +70. Cyclosporine A was discontinued from day +69. After supportive treatments, hemodialysis was discontinued after day +76 and no attacks of seizure/severe hypertension occurred after day +80.\n\nFIGURE 3 Brain magnetic resonance imaging on day +72 posttransplant showing T2-hyperintense lesions (arrows) in the (A) deeper site of left frontal lobe and in (B) right middle cerebellar peduncle.\n\nLast, rapidly progressive hypercalcemia (from 9.4 mg/dL on day +73 to 13.7 mg/dL on day +82) was noted, and disease progression was documented by images including a CT scan on day +83, indicating abnormal lymph nodes at the bilateral lower neck, axilla, mediastinum, and retroperitoneum, and lesions at the pericardium, bilateral lungs, and hepatic lobes with progression of effusions (Figure 2D and data not shown). The patient and her family decided on hospice care and she finally passed away on day +94. Throughout the entire course, there was no evidence of classical acute GVHD whereas complete donor chimerism was documented until day +89.\n\nDISCUSSION\nOur case report is consistent with the theory, as described by Bashey and Solomon,9 that application of pT-HDCy at the correct time following infusion of haploidentical donor cells can eliminate highly activated and proliferative T cells responsible for classical GVHD and graft rejection, whereas it spares the pluripotent hematopoietic stem cells in the graft. However, IPS and TMA still developed in our patient. Although cytomegalovirus infection of the respiratory as well as microvascular system cannot be fully excluded, the development of full-blown IPS and TMA despite the effective control of cytomegalovirus DNAemia suggests a major role for immune reactivity.\n\nA mouse model using a major histocompatibility complex class I/II mismatched donor/recipient strain combination reproduces acute, early-onset IPS caused by the influx of host monocytes and donor alloreactive T cells into the lungs within the first 2 weeks of hematopoietic stem cell transplantation (HSCT). Intensifying the pre-HSCT conditioning with cyclophosphamide accelerates the development of IPS.10 This finding is consistent with the pulmonary microenvironment in our patient who had extensive pulmonary lesions and received irradiation along with cyclophosphamide-containing chemotherapy. Although the lung has not been traditionally recognized as a classical GVHD target organ, the association between IPS and severe GVHD has been reported with acute GVHD often preceding IPS.11 Therefore, the specific role of alloreactive donor T lymphocytes in the pathogenesis of IPS remains a debatable topic that has been extensively discussed in a published official research statement of the American Thoracic Society.7\n\nMultiple factors contributed to the endothelial damage in TMA, including the toxic effect of the conditioning and cyclosporine; however, the alloreactivity from the T cells of the haploidentical PBSC graft must be of importance. Although the exact pathophysiology of transplantation-associated TMA remains unclear, it has been speculated that TMA represents a form of “endothelial GVHD.”12 Actually, acute GVHD has also been found to be associated with the development of TMA, indicating that donor alloreactivity may play an important role in transplantation-associated TMA.13,14\n\nIt seems that pT-HDCy successfully eliminated alloreactivity targeting the epithelial tissues of the skin, liver, and gastrointestinal systems, as classical acute GVHD was completely abrogated in our patient. The immunity to infections also seemed to be preserved because no other microbial infections were documented throughout the entire course except for cytomegalovirus and polyoma BK virus reactivation. However, the alloreactivity from the haploidentical donor PBSCs against the lungs and endothelial cells was not suppressed, which resulted in the development of IPS and TMA in our patient. This outcome may mean that when PBSCs are used for the graft in the context of nonmyeloablative conditioning, pT-HDCy may not be sufficient to eradicate detrimental alloreactive immunity targeting nonconventional acute GVHD sites such as the lungs and endothelial cells, despite the previously documented benefits of this method. Furthermore, the higher T-cell dose in donor PBSCs did not result in an adequate graft-versus-Hodgkin lymphoma effect in our patient.\n\nAbbreviations: BM = bone marrow, GVHD = graft-versus-host disease, IPS = idiopathic pneumonia syndrome, PBSC = peripheral blood stem cell, pT-HDCy = posttransplant high-dose cyclophosphamide, TMA = thrombotic microangiopathy.\n\nAll interventions were part of standard health care practices; thus, ethical approval was neither required nor sought. Approval from the patient to publish the case report was obtained.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Luznik L O’Donnell PV Symons HJ \nHLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide . Biol Blood Marrow Transplant \n2008 ; 14 :641 –650 .18489989 \n2. Castagna L Crocchiolo R Furst S \nBone marrow compared with peripheral blood stem cells for haploidentical transplantation with a nonmyeloablative conditioning regimen and post-transplantation cyclophosphamide . Biol Blood Marrow Transplant \n2014 ; 20 :724 –729 .24530426 \n3. Burroughs LM O’Donnell PV Sandmaier BM \nComparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical related hematopoietic cell transplantation following non-myeloablative conditioning for relapsed or refractory Hodgkin lymphoma . Biol Blood Marrow Transplant \n2008 ; 14 :1279 –1287 .18940683 \n4. Raiola A Dominietto A Varaldo R \nUnmanipulated haploidentical BMT following non-myeloablative conditioning and post-transplantation CY for advanced Hodgkin's lymphoma . Bone Marrow Transplant \n2014 ; 49 :190 –194 .24185585 \n5. Castagna L Bramanti S Furst S \nNonmyeloablative conditioning, unmanipulated haploidentical SCT and post-infusion CY for advanced lymphomas . Bone Marrow Transplant \n2014 ; 49 :1475 –1480 .25222502 \n6. Cole PD Schwartz CL Drachtman RA \nPhase II study of weekly gemcitabine and vinorelbine for children with recurrent or refractory Hodgkin's disease: a Children's Oncology Group report . J Clin Oncol \n2009 ; 27 :1456 –1461 .19224841 \n7. Panoskaltsis-Mortari A Griese M Madtes DK \nAn official American Thoracic Society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome . Am J Respir Crit Care Med \n2011 ; 183 :1262 –1279 .21531955 \n8. Cho BS Yahng SA Lee SE \nValidation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation . Transplantation \n2010 ; 90 :918 –926 .20717073 \n9. Bashey A Solomon SR \nT-cell replete haploidentical donor transplantation using post-transplant CY: an emerging standard-of-care option for patients who lack an HLA-identical sibling donor . Bone Marrow Transplant \n2014 ; 49 :999 –1008 .24842530 \n10. Panoskaltsis-Mortari A Taylor PA Yaeger TM \nThe critical early proinflammatory events associated with idiopathic pneumonia syndrome in irradiated murine allogeneic recipients are due to donor T cell infusion and potentiated by cyclophosphamide . J Clin Invest \n1997 ; 100 :1015 –1027 .9276718 \n11. Crawford SW Hackman RC \nClinical course of idiopathic pneumonia after bone marrow transplantation . Am Rev Respir Dis \n1993 ; 147 :1393 –1400 .8503550 \n12. Tichelli A Gratwohl A \nVascular endothelium as “novel” target of graft-versus-host disease . Best Pract Res Clin Haematol \n2008 ; 21 :139 –148 .18503982 \n13. Uderzo C Bonanomi S Busca A \nRisk factors and severe outcome in thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation . Transplantation \n2006 ; 82 :638 –644 .16969286 \n14. Labrador J López-Corral L López-Godino O \nRisk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus . Bone Marrow Transplant \n2014 ; 49 :684 –690 .24566710\n\n",
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"mesh_terms": "D000293:Adolescent; D003520:Cyclophosphamide; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006689:Hodgkin Disease; D006801:Humans; D036102:Peripheral Blood Stem Cell Transplantation; D011014:Pneumonia; D013577:Syndrome; D057049:Thrombotic Microangiopathies",
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"title": "Idiopathic Pneumonia Syndrome and Thrombotic Microangiopathy Following Nonmyeloablative Haploidentical Peripheral Blood Stem Cell Transplantation and Posttransplant Cyclophosphamide: A Case Report.",
"title_normalized": "idiopathic pneumonia syndrome and thrombotic microangiopathy following nonmyeloablative haploidentical peripheral blood stem cell transplantation and posttransplant cyclophosphamide a case report"
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"abstract": "BACKGROUND\nThe Danish Anaesthesia Allergy Centre (DAAC) investigated 89 adult patients with suspected perioperative cefuroxime-associated hypersensitivity reactions between 2004 and 2013. The goals were to determine whether the time to index reaction after cefuroxime exposure could be used to implicate cefuroxime as the cause of the reactions and explore different test modalities in diagnosing cefuroxime hypersensitivity.\n\n\nMETHODS\nSkin tests, in vitro tests, and titrated provocations were used to determine cefuroxime hypersensitivity. Patients were deemed cefuroxime positive on the basis of at least two positive tests and/or a positive provocation.\n\n\nRESULTS\nOne or more tests were positive for cefuroxime in 24 of 89 (27.0%) patients. One was only specific IgE positive and was deemed cefuroxime negative. Twenty-three (25.8%) were deemed cefuroxime positive. There were four specific IgE-, 4 histamine release test-, 13 skin test-, and 14 provocation positive patients. There were eight (34.8%) patients who were only provocation positive. Data on time to index reaction after cefuroxime exposure were available for 80 patients (22 in the positive group and 58 in the negative group), 22 of 22 (100%) of positive patients reacted in <15 min vs. only 38 of 58 (65.5%) of negative patients.\n\n\nCONCLUSIONS\nAll patients with confirmed hypersensitivity to cefuroxime reacted within 15 min of administration, but so did 65.5% of Cefuroxime negative patients, making timing of administration an unreliable predictor of causation in the perioperative setting. Provocations were always positive when carried out in skin test positive patients; however, eight patients had positive provocations only, highlighting the need for provocation in skin test negative patients.",
"affiliations": "Danish Anaesthesia Allergy Centre, Allergy Clinic, Copenhagen University Hospital Gentofte, Hellerup, Denmark.",
"authors": "Christiansen|I S|IS|;Krøigaard|M|M|;Mosbech|H|H|;Skov|P S|PS|;Poulsen|L K|LK|;Garvey|L H|LH|",
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"title": "Clinical and diagnostic features of perioperative hypersensitivity to cefuroxime.",
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"abstract": "We present a case of anaphylaxis to suxamethonium and/or vecuronium in a patient who had previously suffered an anaphylactic reaction, presumably to rocuronium. The patient had not been referred for formal allergy testing after the first anaphylactic reaction. Subsequent formal allergy testing revealed sensitivities to suxamethonium, rocuronium and vecuronium. Her next anaesthetic, using cisatracurium, was uneventful. It is recommended that all patients with suspected perioperative anaphylaxis are referred for testing. This is the responsibility of the anaesthetist. Particular caution should be used with suspected neuromuscular blocking drug allergy as cross-reactivity is common and not predictable by drug structure.",
"affiliations": "Department of Anaesthesia, Royal North Shore Hospital, Sydney, New South Wales, Australia.",
"authors": "Pedersen|A F|AF|;Green|S|S|;Rose|M A|MA|",
"chemical_list": "D000732:Androstanols; D009467:Neuromuscular Depolarizing Agents; D003473:Neuromuscular Nondepolarizing Agents; D001279:Atracurium; D014673:Vecuronium Bromide; D013390:Succinylcholine; C101584:cisatracurium; D000077123:Rocuronium",
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"mesh_terms": "D000368:Aged; D000707:Anaphylaxis; D000732:Androstanols; D001279:Atracurium; D003429:Cross Reactions; D005260:Female; D006801:Humans; D009467:Neuromuscular Depolarizing Agents; D003473:Neuromuscular Nondepolarizing Agents; D000077123:Rocuronium; D012882:Skin Tests; D013390:Succinylcholine; D014673:Vecuronium Bromide",
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"title": "Failure to investigate anaesthetic anaphylaxis resulting in a preventable second anaphylactic reaction.",
"title_normalized": "failure to investigate anaesthetic anaphylaxis resulting in a preventable second anaphylactic reaction"
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"abstract": "To report a unique presentation of ciliochoroidal effusion syndrome with central serous-like chorioretinopathy and secondary angle closure following exogenous testosterone use.\nA 37 year-old man presented with a two week history of blurred vision, elevated intraocular pressure, and myopic shift in his right eye. Gonioscopy showed angle closure. After YAG iridotomy, ultrasound biomicroscopy (UBM) showed ciliochoroidal effusion and anterior rotation of the ciliary processes. Subsequent color fundus photography, enhanced depth imaging optical coherence tomography (EDI-OCT) and near-infrared reduced-illuminance autofluorescence imaging (NIR-RAFI) showed macular striae, choroidal folds, and increased choroidal thickness without presence of subretinal fluid (SRF) or pigment epithelial detachment (PED). Further questioning revealed the patient was using dermal testosterone gel for six months for treatment of hypogonadism. The patient stopped using the testosterone gel, and his visual acuity and intraocular pressure significantly improved six weeks later. Follow-up UBM showed significant improvement of the ciliochoroidal effusion, and repeat multimodal images demonstrated resolution of the macular striae and choroidal folds, and slightly improved choroidal thickness.\nOur patient demonstrates a rare case of ciliochoroidal effusion, central serous-like chorioretinopathy, and secondary angle closure that dramatically improved with cessation of testosterone. We believe that this unique clinical constellation is the first to be reported associated with exogenous testosterone use.",
"affiliations": "Henry Ford Health System, Department of Ophthalmology, Detroit, MI, USA.;Henry Ford Health System, Department of Ophthalmology, Detroit, MI, USA.;Henry Ford Health System, Department of Ophthalmology, Detroit, MI, USA.;Henry Ford Health System, Department of Ophthalmology, Detroit, MI, USA.;Henry Ford Health System, Department of Ophthalmology, Detroit, MI, USA.;Henry Ford Health System, Department of Ophthalmology, Detroit, MI, USA.",
"authors": "Brill|Daniel|D|;Albert|Desiree|D|;Fields|Taylor|T|;Mikkilineni|Shravani|S|;Crandall|David|D|;Gao|Hua|H|",
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"doi": "10.1016/j.ajoc.2019.100482",
"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(18)30201-910.1016/j.ajoc.2019.100482100482Case ReportCiliochoroidal effusion syndrome with central serous-like chorioretinopathy and secondary angle closure following exogenous testosterone use Brill Daniel Albert Desiree Fields Taylor Mikkilineni Shravani Crandall David Gao Hua hgao1@hfhs.org∗Henry Ford Health System, Department of Ophthalmology, Detroit, MI, USA∗ Corresponding author. Henry Ford Health System, Department of Ophthalmology, 2799 West Grand Boulevard, Detroit, MI, 48202, USA. hgao1@hfhs.org05 6 2019 9 2019 05 6 2019 15 10048225 7 2018 30 5 2019 30 5 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/).Purpose\nTo report a unique presentation of ciliochoroidal effusion syndrome with central serous-like chorioretinopathy and secondary angle closure following exogenous testosterone use.\n\nObservations\nA 37 year-old man presented with a two week history of blurred vision, elevated intraocular pressure, and myopic shift in his right eye. Gonioscopy showed angle closure. After YAG iridotomy, ultrasound biomicroscopy (UBM) showed ciliochoroidal effusion and anterior rotation of the ciliary processes. Subsequent color fundus photography, enhanced depth imaging optical coherence tomography (EDI-OCT) and near-infrared reduced-illuminance autofluorescence imaging (NIR-RAFI) showed macular striae, choroidal folds, and increased choroidal thickness without presence of subretinal fluid (SRF) or pigment epithelial detachment (PED). Further questioning revealed the patient was using dermal testosterone gel for six months for treatment of hypogonadism. The patient stopped using the testosterone gel, and his visual acuity and intraocular pressure significantly improved six weeks later. Follow-up UBM showed significant improvement of the ciliochoroidal effusion, and repeat multimodal images demonstrated resolution of the macular striae and choroidal folds, and slightly improved choroidal thickness.\n\nConclusions and importance\nOur patient demonstrates a rare case of ciliochoroidal effusion, central serous-like chorioretinopathy, and secondary angle closure that dramatically improved with cessation of testosterone. We believe that this unique clinical constellation is the first to be reported associated with exogenous testosterone use.\n\nKeywords\nCentral serous chorioretinopathyCiliochoroidal effusion syndromeSecondary angle closure glaucomaTestosteroneUltrasound biomicroscopy\n==== Body\n1 Introduction\nSeveral drug classes are known to induce angle closure glaucoma, including adrenergic agonists, anticholinergics, anticoagulants, antihistamines, cholinergics, selective serotonin reuptake inhibitors, sulfonamide derivatives, tetrahydrocannabinol, and tricyclic/tetracyclic antidepressants.1 Sulfonamides are associated with inducing ciliochoroidal effusion syndrome via choroidal effusion and ciliary body edema.1,2 This may result in a secondary anterior displacement of the lens-iris diaphragm with acute angle closure, myopic shift, and macular striae.1,2\n\nExogenous steroid use is known to cause or exacerbate open angle glaucoma through decreased uveoscleral outflow.3 While elevated serum glucocorticoid levels are also known to be associated with central serous chorioretinopathy (CSCR),4, 5, 6, 7 there is not evidence of an association between exogenous steroid use and ciliochoroidal effusion.8\n\nHere we describe a unique case of ciliochoroidal effusion, central serous-like chorioretinopathy, and secondary angle closure glaucoma associated with exogenous testosterone use, all of which significantly improved with drug cessation.\n\n2 Case report\nA 37 year-old male presented to the glaucoma clinic with a two-week history of blurred vision in his right eye. He had no past ocular diagnoses or surgeries. He was not using any ocular medications or refractive correction. He reported no significant medical problems.\n\nOn exam, his uncorrected visual acuity was 20/400 in the right eye and 20/20 in the left. Manifest refraction corrected his right eye to 20/20 with −3.50 sphere. His intraocular pressure (IOP) was 30 mmHg in the right eye and 18 mmHg in the left. He had peripheral iridocorneal touch in the right eye. On gonioscopy of the right eye, there were no visible angle structures, and he was open to bare trabecular meshwork OS. The patient was diagnosed with acute angle closure glaucoma and sudden myopic shift in the right eye, and shallow anterior chamber in the left eye. YAG laser peripheral iridotomy was performed in the right eye to remove any component of pupillary block. Patient was started on bimatoprost and timolol.\n\nThe patient was seen for follow-up examination two days later. His right eye uncorrected visual acuity improved to 20/200 and IOP improved to 19 mmHg. Topical atropine 1% was started to shift the lens-iris diaphragm posteriorly for treatment of any component of posterior pushing.\n\nAt one week, the patient's right eye manifest refraction decreased to −2.00 sphere. His IOP was 22 mmHg. Gonioscopy showed no angle structures temporally and superiorly and bare trabecular meshwork nasally and inferiorly. UBM 360° radial scans showed slit-like and closed angles, 360° of ciliochoroidal effusion, and anterior rotation of the ciliary processes (Fig. 1A). In the left eye, UBM showed slit-like to narrow angles, anterior rotation of the ciliary body, and anterior bowing of the peripheral iris with trace ciliochoroidal effusion (Fig. 1B).Fig. 1 Ultrasound biomicroscopy. 1A.Right eye before cessation of testosterone showing large ciliochoroidal effusion. 1B. Left eye before cessation of testosterone showing minimal ciliochoroidal effusion. 1C. Right eye six weeks after cessation of testosterone showing resolution of ciliochoroidal effusion.\n\nFig. 1\n\nAt 10 weeks, the patient was referred to retina clinic. His uncorrected visual acuity improved to 20/50 in the right eye. His IOP was 20 mmHg. Dilated fundus exam showed macular striae extending across the fovea in the right eye, and no such striae were noted in the left eye (Fig. 2A). The macular striae were most notable with NIR-RAFI (Fig. 2B). EDI-OCT images of the macula showed significantly increased choroidal thickness in both eyes, right eye greater than the left, and choroidal folds in the right eye (Fig. 2C). Fluorescein angiogram showed no evidence of any leakage, and fundus autofluorescence imaging showed trace irregularity right eye, and normal left eye (Fig. 2D). There was no SRF or PED present.Fig. 2 Right eye before cessation of testosterone. 2A. Fundus photograph showing macular striae. 2B. NIR-RAFI highlighting choroidal folds. 2C. OCT showing choroidal folds, and increased choroidal thickness. 2D. FA late stage showing no leakage.\n\nFig. 2\n\nThorough medical history revealed the patient was taking a topical testosterone gel, AndroGel™ (AbbVie Inc., North Chicago, Illinois), for the last 6 months for treatment of hypogonadism. The patient was advised to decrease the dosage of his testosterone, but the patient decided to stop taking it after this visit.\n\nAt 16 weeks (six weeks after cessation of testosterone), the patient's uncorrected visual acuity improved to 20/20 and IOP was 24 mmHg. Repeat UBM in both eyes showed continued anterior bowing of the peripheral iris with slit-like angles and anteriorly rotated ciliary processes, and nearly resolved ciliochoroidal effusion in the right eye (Fig. 1C). Repeat color fundus photographs, NIR-RAFI, and OCT showed near complete resolution of macular striae and choroidal folds (Fig. 3A–C). Final exam at 20 weeks was stable.Fig. 3 Right eye at six weeks after cessation of testosterone. 3A. Fundus photograph showing completely resolved macular striae. 3B. NIR-RAFI highlighting completely resolved choroidal folds. 3C. EDI-OCT showing resolved choroidal folds and slightly improved choroidal thickness.\n\nFig. 3\n\n3 Discussion\nOur patient demonstrates a rare case of bilateral ciliochoroidal effusion syndrome demonstrated by UBM after exogenous testosterone use. AndroGel™ is a hydroalcoholic gel containing testosterone and inactive components carbomer 980, ethanol 67%, isopropyl myristate, purified water, and sodium hydroxide.9 Reviewing the AndroGel™ package insert does not reveal components previously associated with angle closure or ciliochoroidal effusion.9 AndroGel™ can be prescribed for primary or secondary hypogonadism.9\n\nAs we have no prior ophthalmologic exams or imaging prior to initial presentation, it is possible that the patient may have had preexisting narrow angles or plateau iris configuration despite his relatively emmetropic eyes. Mydriatic agents, such as sympathomimetics and anticholinergics, can lead to angle closure via pupillary dilation in eyes with originally narrow angles. However, these preexisting conditions do not explain why he developed bilateral ciliochoroidal effusions that dramatically improved after cessation of testosterone therapy.\n\nOur patient's asymmetric exam findings are unexpected, but not uncommon. Bilateral pathology affecting the eyes can be asymmetrical. The findings of trace ciliochoroidal effusion and narrow angle in his left eye are supportive of an asymmetric systemic process. Without initiating topical therapy and cessation of testosterone use, we believe this eye would have been eventually involved as well.\n\nAfter YAG iridotomy, our patient's manifest refraction and intraocular pressure did improve. Of note, the patient was also given intraocular pressure lowering therapy and atropine. We believe these agents, rather than YAG iridotomy, improved his ciliochoroidal effusion syndrome, as there was no component of pupillary block on UBM and significant ciliochoroidal effusion remained 10 weeks after YAG iridotomy. Furthermore, the patient's ciliochoroidal effusion and symptoms nearly resolved 6 weeks after cessation of exogenous testosterone.\n\nCannabis and sulfonamide derivatives have been reported to cause ciliochoroidal effusion syndrome. As with our patient, drug induced cilichoroidal effusion resulted in anterior displacement of the lens-iris diaphragm and anterior rotation of the ciliary body, causing angle closure. Thus, we believe this is the first reported case of testosterone associated angle closure glaucoma.2,10 Fortunately, our patient's myopic shift, intraocular pressure, macular striae, and choroidal folds drastically improved after cessation of testosterone.\n\nThe exact mechanism by which elevated testosterone causes CSCR is not fully understood, but there is a generally accepted pathogenesis theory by J. Donald Gass.11,12 There is laboratory evidence of human retinal pigment epithelium (RPE) having androgen receptors and messenger RNA for 5α-reductase, which can convert testosterone to dihydrotestosterone, a more potent form of testosterone.13,14 Testosterone is a vasoactive hormone, which causes vasodilation and may increase the permeability of the choriocapillaris.15, 16, 17, 18 Subsequent choroidal thickening may damage the RPE, resulting in subretinal fluid (SRF) and pigment epithelial detachment (PED).11,19,20\n\nWhile our patient does not have SRF or PED indicative of classical CSCR, this case may demonstrate a central serous-like chorioretinopathy. Our patient presented with choroidal folds and increased choroidal thickness, but without SRF and PED or leakage on fluorescence angiogram. These findings may support Gass’ stepwise pathogenesis theory of CSCR.11,12 Specifically, CSCR secondary to testosterone occurs via its vasodilatory properties causing increased choroidal permeability and secondary RPE damage.15, 16, 17, 18 Afterwards, SRF and PED may occur, which fortunately never developed in our patient.\n\nAs with other associations of drug induced ciliochoroidal effusion syndrome, exogenous testosterone should be stopped immediately. In patients without hyperopia, cycloplegic agents may reduce intraocular pressure via their ability to retract the ciliary processes and deepen the anterior chamber. Intraocular pressure lowering eye drops and peripheral iridoplasty may be effective. Although the exact mechanism of our patient's angle closure is unknown, we believe exogenous testosterone should be added to the possible causative agents of cilichoroidal effusion syndrome.\n\nPatient consent\nConsent to publish case details was obtained from our patient.\n\nConflicts of interest\nNone of the authors have any financial disclosures.\n\nFunding\nNo funding or grant support received.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nAppendix A Supplementary data\nThe following is the supplementary data related to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgements\nNone.\n\nAppendix A Supplementary data related to this article can be found at https://doi.org/10.1016/j.ajoc.2019.100482.\n==== Refs\nReferences\n1 Tripathi R.C. Tripathi B.J. Haggerty C. Drug-induced glaucomas: mechanism and management Drug Saf 26 2003 749 767 12908846 \n2 Abtahi M.A. Abtahi S.H. Fazel F. Topiramate and the vision: a systematic review Clin Ophthalmol 6 2012 117 131 22275816 \n3 Ritch R. Pathophysiology of glaucoma in uveitis Trans Ophthalmol Soc U K 101 Pt 3 1981 321 324 6963820 \n4 Bouzas E.A. Karadimas P. Pournaras C.J. Central serous chorioretinopathy and glucocorticoids Surv Ophthalmol 47 2002 431 448 12431693 \n5 Carvalho-Recchia C.A. Yannuzzi L.A. Negrao S. Corticosteroids and central serous chorioretinopathy Ophthalmology 109 2002 1834 1837 12359603 \n6 Garg S.P. Dada T. Talwar D. Biswas N.R. Endogenous cortisol profile in patients with central serous chorioretinopathy Br J Ophthalmol 81 1997 962 964 9505819 \n7 Karadimas P. Bouzas E.A. Glucocorticoid use represents a risk factor for central serous chorioretinopathy: a prospective, case-control study Graefes Arch Clin Exp Ophthalmol 242 2004 800 802 14986014 \n8 Razeghinejad M.R.M.J. Katz L.J. Iatrogenic glaucoma secondary to medications Am J Med 124 2011 20 25 21092926 \n9 Androgel (Testosterone Gel) [package Insert] 2013 AbbVie Inc. North Chicago, Illinois \n10 Hanna R. Tiosano B. Dbayat N. Gaton D. Unilateral angle-closure glaucoma with ciliochoroidal effusion after the consumption of cannabis: a case report Case Rep Ophthalmol 5 2014 439 443 25606036 \n11 Nudleman E. Witmer M.T. Kiss S. Williams G.A. Wolfe J.D. Central serous chorioretinopathy in patients receiving exogenous testosterone therapy Retina 34 2014 2128 2132 24946102 \n12 Hussain D.G.J. Idiopathic central serous chorioretinopathy Indian J Ophthalmol 46 1998 131 137 10085624 \n13 Wickham L.A. Gao J. Toda I. Rocha E.M. Ono M. Sullivan D.A. Identification of androgen, estrogen and progesterone receptor mRNAs in the eye Acta Ophthalmol Scand 78 2000 146 153 10794246 \n14 Rocha E.M. Wickham L.A. da Silveira L.A. Identification of androgen receptor protein and 5 alpha-reductase mRNA in human ocular tissues Br J Ophthalmol 84 2000 76 84 10611104 \n15 Yildiz O. Seyrek M. Vasodilating mechanisms of testosterone Exp Clin Endocrinol Diabetes 115 2007 1 6 official journal, German Society of Endocrinology [and] German Diabetes Association 17286226 \n16 Kim Y.T. Kang S.W. Bai K.H. Choroidal thickness in both eyes of patients with unilaterally active central serous chorioretinopathy Eye 25 2011 1635 1640 22020172 \n17 Iliescu R. Reckelhoff J.F. Testosterone and vascular reactivity Clin Sci 111 2006 251 252 London, England : 1979 16681461 \n18 Hougaku H. Fleg J.L. Najjar S.S. Relationship between androgenic hormones and arterial stiffness, based on longitudinal hormone measurements Am J Physiol Endocrinol Metab 290 2006 E234 E242 16159908 \n19 Kitaya N. Nagaoka T. Hikichi T. Features of abnormal choroidal circulation in central serous chorioretinopathy Br J Ophthalmol 87 2003 709 712 12770966 \n20 Ciloglu E. Unal F. Dogan N.C. The relationship between the central serous chorioretinopathy, choroidal thickness, and serum hormone levels Graefes Arch Clin Exp Ophthalmol 256 2018 1111 1116 29671064\n\n",
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"keywords": "Central serous chorioretinopathy; Ciliochoroidal effusion syndrome; Secondary angle closure glaucoma; Testosterone; Ultrasound biomicroscopy",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
"other_id": null,
"pages": "100482",
"pmc": null,
"pmid": "31198887",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": "10085624;10611104;10794246;12359603;12431693;12770966;12908846;14986014;16159908;16681461;17286226;21092926;22020172;22275816;24946102;25606036;29671064;6963820;9505819",
"title": "Ciliochoroidal effusion syndrome with central serous-like chorioretinopathy and secondary angle closure following exogenous testosterone use.",
"title_normalized": "ciliochoroidal effusion syndrome with central serous like chorioretinopathy and secondary angle closure following exogenous testosterone use"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-213167",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TESTOSTERONE"
},
"dr... |
{
"abstract": "We report the end result of clonazepam (CZP) withdrawal in 13 patients with significant side effects felt to be due to CZP. The present observations supplement the recent report in Seizure by Chataway et al., in proposing a safe CZP withdrawal rate of 0.2 mg/day. Eight of the patients had withdrawal seizures, five had withdrawal symptoms and four patients had no withdrawal problems at all. Ultimately all the patients came off CZP, mainly quite rapidly (3-30 days) with the initial side effects regressing totally in 11 patients.",
"affiliations": "Epilepsy Unit, Westmead Hospital, Australia.",
"authors": "Buchanan|N|N|;Sharpe|C|C|",
"chemical_list": "D002998:Clonazepam",
"country": "England",
"delete": false,
"doi": "10.1016/s1059-1311(05)80174-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1059-1311",
"issue": "3(4)",
"journal": "Seizure",
"keywords": null,
"medline_ta": "Seizure",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002998:Clonazepam; D004827:Epilepsy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013375:Substance Withdrawal Syndrome; D016896:Treatment Outcome",
"nlm_unique_id": "9306979",
"other_id": null,
"pages": "271-5",
"pmc": null,
"pmid": "7894837",
"pubdate": "1994-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clonazepam withdrawal in 13 patients with active epilepsy and drug side effects.",
"title_normalized": "clonazepam withdrawal in 13 patients with active epilepsy and drug side effects"
} | [
{
"companynumb": "AU-ROCHE-1481903",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nPrimary breast angiosarcoma is an extremely rare malignancy. Association of this type of tumor with Kasabach-Merritt syndrome has only been reported in 3 cases in the past. To our knowledge, this is the first reported case of a solid-organ recipient.\n\n\nMETHODS\nA 53-year-old woman who underwent a deceased-donor renal transplantation 5 years previously presented with a 12-month history of a giant ulcerated lesion on her left breast. Biopsy of the overlying skin suggested primary angiosarcoma. Concurrently, the patient's bleeding from the site of the biopsy and hematology investigations indicated the presence of Kasabach-Merritt syndrome.\n\n\nRESULTS\nThe case was discussed in a multidisciplinary setting. The decision was to use anthracycline-based chemotherapy as up-front treatment to assess tumor response and gain a local benefit for a subsequent resection. After the completion of 1 cycle of chemotherapy, the patient died of cardiovascular insufficiency. Primary angiosarcoma of the breast occurs in the third to fourth decade and has been reported only in women.\n\n\nCONCLUSIONS\nA high clinical suspicion and referral to a specialized center are necessary. Total mastectomy appears to be the only treatment conferring benefit; chemotherapy and radiation therapy are of little value.",
"affiliations": "Transplantation Unit, Athens University School of Medicine, Laiko General Hospital, Athens, Greece. Electronic address: mike_vailas@yahoo.com.;Transplantation Unit, Athens University School of Medicine, Laiko General Hospital, Athens, Greece.;Transplantation Unit, Athens University School of Medicine, Laiko General Hospital, Athens, Greece.;Transplantation Unit, Athens University School of Medicine, Laiko General Hospital, Athens, Greece.",
"authors": "Vailas|M G|MG|;Vernadakis|S|S|;Moris|D|D|;Zavos|G|G|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "47(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000970:Antineoplastic Agents; D001706:Biopsy; D001943:Breast Neoplasms; D017809:Fatal Outcome; D005260:Female; D006394:Hemangiosarcoma; D006801:Humans; D059885:Kasabach-Merritt Syndrome; D016030:Kidney Transplantation; D008875:Middle Aged",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2537-40",
"pmc": null,
"pmid": "26518966",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Surgical Dead End in a Renal Transplant Recipient Associated With a Rare Thrombohemorrhagic Syndrome.",
"title_normalized": "surgical dead end in a renal transplant recipient associated with a rare thrombohemorrhagic syndrome"
} | [
{
"companynumb": "GR-ASTELLAS-2015US043479",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nDermatophytes are the most common cause of superficial fungal infections in humans. Deep dermatophytosis, however, is rare, described to date only in isolated case reports, usually in the setting of systemic immunosuppression.\n\n\nOBJECTIVE\nTo present the 15-year experience of a tertiary dermato-mycology clinic with the diagnosis and treatment of deep dermatophytosis.\n\n\nMETHODS\nPatients were identified by database search. Clinical, mycological, histological, and treatment data were collected from the medical files.\n\n\nRESULTS\nTen patients were identified: nine after solid-organ transplantation and one undergoing chemotherapy, all diagnosed within 3 years after beginning immunosuppression (average 7.5 months). The infective agent in nine cases was Trichophyton rubrum. All patients presented with concurrent superficial fungal infections. Complete resolution was noted in response to systemic antifungal agents. There was no histological evidence of hair-follicle involvement.\n\n\nCONCLUSIONS\nThe limitations of the study were the retrospective design and the small cohort size.\n\n\nCONCLUSIONS\nThis case-series study suggests that deep dermatophytosis is a separate entity, distinct from Majocchi's granuloma. It occurs only in immunocompromised patients and is characterized by discrete nodules, an indolent course, the absence of follicular invasion, and proximity to a superficial dermatophyte infection. Systemic antifungal treatment leads to complete resolution. The urgent need for the treatment of superficial fungal infections in immunocompromised patients is emphasized.",
"affiliations": "Department of Dermatology, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., Petach Tikva, 4941492, Israel.;Department of Dermatology, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., Petach Tikva, 4941492, Israel. shanyshnush@gmail.com.;Department of Dermatology, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., Petach Tikva, 4941492, Israel.;Department of Dermatology, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., Petach Tikva, 4941492, Israel.;Institute of Pathology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel.;Department of Dermatology, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., Petach Tikva, 4941492, Israel.;Department of Dermatology, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., Petach Tikva, 4941492, Israel.;Department of Dermatology, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., Petach Tikva, 4941492, Israel.",
"authors": "Kershenovich|Ruben|R|;Sherman|Shany|S|;Reiter|Ofer|O|;Huss|Shiran Reiss|SR|;Didkovsky|Elena|E|;Mimouni|Daniel|D|;Hodak|Emmilia|E|;Segal|Rina|R|",
"chemical_list": "D000935:Antifungal Agents",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40257-017-0276-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1175-0561",
"issue": "18(5)",
"journal": "American journal of clinical dermatology",
"keywords": "Dermatophytosis; Fluconazole; Hair Follicle; Invasive Aspergillosis; Terbinafine",
"medline_ta": "Am J Clin Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D005260:Female; D018859:Hair Follicle; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D015994:Incidence; D007557:Israel; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D012189:Retrospective Studies; D062606:Tertiary Care Centers; D014005:Tinea; D014249:Trichophyton",
"nlm_unique_id": "100895290",
"other_id": null,
"pages": "697-704",
"pmc": null,
"pmid": "28389891",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Unique Clinicopathological Manifestation of Fungal Infection: A Case Series of Deep Dermatophytosis in Immunosuppressed Patients.",
"title_normalized": "a unique clinicopathological manifestation of fungal infection a case series of deep dermatophytosis in immunosuppressed patients"
} | [
{
"companynumb": "IL-ACCORD-070098",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "To report a case of statin-induced bilateral foot myopathy that resulted from 2 different statins. Case Summary: A 44-year-old Caucasian male with a history of ventricular fibrillation cardiac arrest, hyperlipidemia, and coronary artery disease experienced bilateral foot pain, weakness, and soreness while taking atorvastatin 20 mg daily. The pain subsided within weeks of discontinuing atorvastatin but returned years later after the initiation of rosuvastatin. The Naranjo probability scale indicates that this is a definite association between bilateral foot myopathy and statin use.\nThere is an association with statin use and lowering cardiovascular risk in patients with dyslipidemia and cardiovascular disease. However, statin metabolites can accumulate in the myocytes of muscle groups to cause a common side effect of myopathy. Statin myopathy typically occurs in large, bilateral, or proximal muscle groups, such as the thighs, back, calves, or buttocks. This patient was unusual in that his muscle symptoms only occurred in his feet and was severe enough to affect his ambulation.\nStain-associated muscle symptoms have been reported to lessen medication adherence. There is also a risk with muscle symptoms that the patient could develop rhabdomyolysis, a rare but serious condition. Recognizing statin-associated muscle symptoms even in uncommon locations is important, so that alternative lipid-lowering strategies can be implemented to lower cardiovascular risk.",
"affiliations": "15473College of Pharmacy and Health Sciences, Mercer University, Atlanta, GA, USA.;Department of Pharmacy Practice, 15473College of Pharmacy, Mercer University, Atlanta, GA, USA.",
"authors": "Baggett|Mary Caitlin|MC|;Nykamp|Diane|D|https://orcid.org/0000-0001-8702-4387",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000069059:Atorvastatin",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190019857851",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "33(6)",
"journal": "Journal of pharmacy practice",
"keywords": "atorvastatin; extremity; foot; muscle pain; myopathy; rosuvastatin; statin",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000328:Adult; D000069059:Atorvastatin; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D009135:Muscular Diseases; D012206:Rhabdomyolysis",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "899-902",
"pmc": null,
"pmid": "31248326",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Statin-Associated Bilateral Foot Myopathy.",
"title_normalized": "statin associated bilateral foot myopathy"
} | [
{
"companynumb": "US-BIOCON-BCN-2019-000502",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASCORBIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Embolia cutis medicamentosa (ECM) is a rare and unpredictable injection site reaction, occurring after intramuscular, subcutaneous, and even after intraarticular injection of various drugs. We report a very rare case of necrotizing ECM after injection of glatiramer acetate for multiple sclerosis, include a photo documentation over the entire disease course, and discuss hypotheses as to etiology and treatment.",
"affiliations": "Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany.;Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany.;Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany.;Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany.",
"authors": "Vlahova|Lyubomira|L|;Kretschmer|Lutz|L|;Schön|Michael P|MP|;Mössner|Rotraut|R|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000510017",
"fulltext": "\n==== Front\nCase Rep Dermatol\nCase Rep Dermatol\nCDE\nCase Reports in Dermatology\n1662-6567\nS. 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.com\n\n10.1159/000510017\ncde-0013-0114\nSingle Case\nEmbolia Cutis Medicamentosa after Subcutaneous Injection with Glatiramer Acetate\nVlahova Lyubomira *\nKretschmer Lutz\nSchön Michael P.\nMössner Rotraut\nDepartment of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany\n*Lyubomira Vlahova, Department of Dermatology, Venereology and Allergology, Robert-Koch-Strasse 40, DE–37099 Göttingen (Germany), lyubomira.vlahova@med.uni-goettingen.de\nJan-Apr 2021\n16 2 2021\n16 2 2021\n13 1 114120\n29 2 2020\n8 7 2020\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nThis 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.\nEmbolia cutis medicamentosa (ECM) is a rare and unpredictable injection site reaction, occurring after intramuscular, subcutaneous, and even after intraarticular injection of various drugs. We report a very rare case of necrotizing ECM after injection of glatiramer acetate for multiple sclerosis, include a photo documentation over the entire disease course, and discuss hypotheses as to etiology and treatment.\n\nKeywords\n\nEmbolia cutis medicamentosa\nGlatiramer acetate\nInjection site reaction\n==== Body\nIntroduction\n\nCopaxone® (glatiramer acetate, GA) is a mixture of synthetic tetrapeptides which reduces relapse frequency in patients with relapsing-remitting multiple sclerosis. Its most common side effects are injection site reactions, such as erythema, pain, and pruritus, and immediate postinjection reactions, such as dyspnea, flushing, and tachycardia [1, 2]. We report a patient who developed embolia cutis medicamentosa (ECM) as a severe injection site reaction.\n\nCase Report/Case Presentation\n\nA 55-year-old man with a 5-year history of multiple sclerosis had been treated subcutaneously for 4 years with GA 40 mg 3 times weekly. He changed injection sites every time (abdomen, ventral thighs, buttocks) and experienced occasional mild injection site reactions with coin-sized skin swelling and induration which resolved within weeks. Approximately 30 s after the last injection in the lower left abdomen the patient experienced a sudden-onset intense, radiating pain. Two minutes later, he developed an extended urticarial swelling with erythematous borders mainly on the left side of his abdomen. The irregular reticular and serrated lesions also extended to the right side (Fig. 1a). There were no systemic symptoms. He was treated with intravenous glucocorticoids and the swelling resolved within hours.\n\nTwo days later, a livid erythematous macula with irregularly serrated margins developed. The patient suffered from severe abdominal pain and was admitted to hospital. He received intravenous meropenem and linezolid for 2 days.\n\nA week later, he presented at our department with a well-demarcated reticular erythema of 10 × 15 cm with central blisters and peripheral induration (Fig. 1b). Routine blood test revealed mildly increased C-reactive protein and creatine kinase, serological autoimmune parameters including autoantibodies to extractable nuclear antigens and double stranded DNA, lupus anticoagulant, and cryoglobulins were negative. Skin swabs showed resident flora. Ultrasound showed a diffuse increase in echogenicity of subcutaneous tissue (Fig. 2), as nonspecific demonstration of inflammation, observed for example in lymphedema and cellulitis [3]. Histopathologically, there was necrosis of the epithelium and sweat glands, thrombosed small vessels, neutrophil infiltration and hematoma in the dermis, but no evidence of primary vasculitis (Fig. 3). Direct immunofluorescence was without pathological findings. We made the diagnosis of ECM. Vascular thrombosis and cutaneous necrosis in the absence of signs of vasculitis are the histological hallmarks of ECM [4].\n\nOver the next 6 weeks, the necrotic area demarcated and continued to extend. Surgical debridement, vacuum-assisted closure therapy, topical antiseptics, and dressings led to complete resolution and formation of an atrophic scar during the following 12 weeks (Fig. 1c–f). After this episode, the patient refused to resume GA therapy.\n\nDiscussion/Conclusion\n\nECM, also termed Nicolau syndrome, was first described by Freudenthal and Nicolau in 1924 and 1925, respectively, after intramuscular injection of bismuth salts in syphilis patients [5, 6]. It typically presents with sudden-onset, severe pain occurring immediately after the injection, followed by swelling, bizarre-looking erythema, and induration within hours [7]. The peripheral erythema diminishes within days. Blisters can occur as a sign of skin damage. Necrotic areas demarcate within several weeks [7]. Several cases of ECM have been reported after intramuscular, subcutaneous, and even after intraarticular injection of various drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), vitamin K, vitamin B12, penicillin, antihistamines, corticosteroids, local anesthetics, vaccines, and interferon-α and -β [8, 9]. There are only few descriptions of necrotic ECM after treatment with GA (20 and 40 mg/day) [7, 8, 10, 11, 12, 13, 14]. In 2 of these patients, further injections of GA led to another episode of ECM after well-tolerated injections in-between [10, 11]. Thus, ECM remains unpredictable and does not necessarily contraindicate continuation of the treatment [10, 11]. Injection site reactions were the most common adverse events in a randomized placebo-controlled trial with GA 40 mg 3 times weekly (35.2% over 12 months in GA-treated patients compared to 5% in placebo-treated patients) [1]. After 3 years of follow-up, there were no cases of skin necrosis in the open-label extension study of Khan et al. [2]. The pathogenesis of ECM remains poorly understood. Various factors may play a role, including accidental intravascular injection with embolic occlusion, reflexive vasospasm, and vascular rupture with perivascular inflammation and cytotoxic reaction to the drug [15]. In addition, lipophilic drugs may penetrate the blood vessels and induce physical occlusion as a more drug-specific reaction. The differential diagnosis of ECM includes direct drug-related cutaneous toxicity including skin necrosis, more commonly seen with interferon-β, occurring multilocularly and not accompanied by intense immediate pain [7]. No standard therapy exists for ECM. Recommendations depend on severity and include analgesics, antibiotics, anticoagulants, and topical or systemic corticosteroids. In case of necrosis, therapy also includes local dressings and surgical debridement [7, 8, 15].\n\nIn conclusion, development of ECM is rare and cannot be avoided despite correct injection technique including aspiration. It is unpredictable and discontinuation of the therapy should depend on careful consideration of risks and benefits in the individual setting.\n\nStatement of Ethics\n\nThis case report was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The patient has given his written informed consent to use images and clinical information in scientific publications without publishing of his name and initials.\n\nConflict of Interest Statement\n\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\n\nThe authors have no funding sources to declare.\n\nAuthor Contributions\n\nAll named authors took care of the patient, took responsibility for the integrity of the work as a whole, and gave final approval to the version to be published.\n\nFig. 1 a Extended urticarial swelling with erythematous borders mainly on the abdomen 2 min after subcutaneous injection with glatiramer acetate. b Livedo-like erythema, centrally with bullae formation on day 8. c, d Demarcated necrotic area (days 17 and 24, respectively). e Lesion after surgical wound debridement and under vacuum-assisted closure therapy (day 57). f Atrophic scar (day 173).\n\nFig. 2 Dermatological ultrasound paraumbilically on the right (a) and left abdomen (b). On the primarily affected left abdomen (b), diffuse increase in the echogenicity of the fatty lobules with unclear borders to the septa is seen compared to the clinically only slightly affected right abdomen (a).\n\nFig. 3 HE staining (a, b) of a biopsy specimen shows necrobiotic epidermis with subepidermal cleft formation (exemplified by arrows in b), dilated and congested blood vessels in the dermis and erythrocyte extravasates (asterisks in b). PAS staining (c) also reveals fibrinoid degeneration of individual blood vessels (arrow in c). Scale bars, 100 μm.\n==== Refs\nReferences\n\n1 Khan O Rieckmann P Boyko A Selmaj K Zivadinov R GALA Study Group Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis Ann Neurol 2013 6 73 (6) 705 13 23686821\n2 Khan O Rieckmann P Boyko A Selmaj K Ashtamker N Davis MD Efficacy and safety of a three-times-weekly dosing regimen of glatiramer acetate in relapsing-remitting multiple sclerosis patients: 3-year results of the Glatiramer Acetate Low-Frequency Administration open-label extension study Mult Scler 2017 5 23 (6) 818 29 27503905\n3 Suehiro K Morikage N Murakami M Yamashita O Samura M Hamano K Significance of ultrasound examination of skin and subcutaneous tissue in secondary lower extremity lymphedema Ann Vasc Dis 2013 6 (2) 180 8 23825499\n4 Tabor D Bertram CG Williams AJ Mathers ME Biswas A Nicolau Syndrome (Embolia Cutis Medicamentosa): A Rare and Poorly Recognized Iatrogenic Cause of Cutaneous Thrombotic Vasculopathy Am J Dermatopathol 2018 3 40 (3) 212 5 28816739\n5 Freudenthal W Lokales embolisches Bismogenol-Exanthem Arch Dermatol Syph 1924 147 (1) 155 60\n6 Nicolau S Dermite livedoide et gangreneuse de la fesse, consecutive aux injections intramusculaires dans la syphilis Ann Mal Venereol 1925 20 321 9\n7 Harde V Schwarz T Embolia cutis medicamentosa following subcutaneous injection of glatiramer acetate J Dtsch Dermatol Ges 2007 12 5 (12) 1122 3 18042092\n8 Koller S Kränke B Nicolau syndrome following subcutaneous glatiramer-acetate injection J Am Acad Dermatol 2011 2 64 (2) e16 7 21238820\n9 Luton K Garcia C Poletti E Koester G Nicolau Syndrome: three cases and review Int J Dermatol 2006 11 45 (11) 1326 8 17076716\n10 Zecca C Mainetti C Blum R Gobbi C Recurrent Nicolau syndrome associated with subcutaneous glatiramer acetate injection—a case report BMC Neurol 2015 12 15 (1) 249 26630967\n11 Martínez-Morán C Espinosa-Lara P Nájera L Romero-Maté A Córdoba S Hernández-Núñez A Embolia cutis medicamentosa (síndrome de Nicolau) tras inyección de acetato de glatirámero Actas Dermosifiliogr 2011 11 102 (9) 742 4 21741603\n12 Kimbrough DJ Newsome SD Case Report: Two Cases of Nicolau Syndrome Associated with Glatiramer Acetate Int J MS Care 2017 May-Jun 19 (3) 148 50 28603463\n13 Wolinsky JS Borresen TE Dietrich DW Wynn D Sidi Y Steinerman JR GLACIER Study Group GLACIER: an open-label, randomized, multicenter study to assess the safety and tolerability of glatiramer acetate 40 mg three-times weekly versus 20 mg daily in patients with relapsing-remitting multiple sclerosis Mult Scler Relat Disord 2015 7 4 (4) 370 6 26195058\n14 Blind A Lenormand C Schissler C Cribier B Lipsker D [Suprapubic Nicolau syndrome following subcutaneous injection of glatiramer acetate] Ann Dermatol Venereol 2018 11 145 (11) 671 5 30217685\n15 Kim SK Kim TH Lee KC Nicolau syndrome after intramuscular injection: 3 cases Arch Plast Surg 2012 5 39 (3) 249 52 22783535\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6567",
"issue": "13(1)",
"journal": "Case reports in dermatology",
"keywords": "Embolia cutis medicamentosa; Glatiramer acetate; Injection site reaction",
"medline_ta": "Case Rep Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101517685",
"other_id": null,
"pages": "114-120",
"pmc": null,
"pmid": "33790754",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "28603463;22783535;17076716;21238820;28816739;26195058;23825499;27503905;18042092;26630967;30217685;21741603;23686821",
"title": "Embolia Cutis Medicamentosa after Subcutaneous Injection with Glatiramer Acetate.",
"title_normalized": "embolia cutis medicamentosa after subcutaneous injection with glatiramer acetate"
} | [
{
"companynumb": "DE-TEVA-2021-DE-1940368",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GLATIRAMER ACETATE"
},
"drugadditional": "1",
... |
{
"abstract": "Extensive data support the safety of direct oral anticoagulants compared with vitamin K antagonists in patients with non-valvular atrial fibrillation, leading to a significantly increase in the use of these compounds in clinical practice. However, there is no compelling evidence supporting the use of direct oral anticoagulant in individuals who are intubated or have a percutaneous endoscopic gastrostomy (PEG): patients with several co-morbidities are underrepresented in clinical trials, so the best long-term strategy for anticoagulation is difficult to ascertain. The aim of the present report was to evaluate the safety and efficacy of edoxaban administered via PEG in a patient with heart failure and a history of atrial fibrillation affected by amyotrophic lateral sclerosis (ALS). A 71-year-old man with atrial fibrillation, advanced ALS, type II diabetes mellitus, and hypertension presented to the emergency department with dyspnoea and tachycardia. Because vitamin K antagonist and rivaroxaban 15 mg were dropped because of difficult international normalized ratio control (time in therapeutic range <30%) and severe haematuria, respectively, edoxaban 30 mg (crushed pill) daily was administered based on the patient's weight of 58 kg. Mean edoxaban plasma concentration-time profiles were measured, as anti-Xa activity, 2 h before and at 2, 6, and 22 h after drug administration and then compared with the pharmacokinetic profile of edoxaban 30 mg in healthy subjects. An additional testing of steady-state peak plasma concentration of edoxaban after 10 days and a 30 day follow-up were evaluated. The values of the pharmacokinetic parameters, analysed with a non-compartmental analysis by PKSolver module, showed that Cmax and AUC0→t were only slightly higher than those observed in healthy subjects, while the half-life and observed clearance were significantly longer and lower, respectively, than in normal subjects. Steady-state peak plasma concentration of edoxaban was very similar to the levels reported in healthy subjects, and neither relevant bleeding nor thromboembolic event was reported at a 30 day follow-up. These results support safe and effective anticoagulation with edoxaban 30 mg but suggest caution with the use of full dose of edoxaban (60 mg daily) in this kind of patients. We report, for the first time, a safe and effective anticoagulation based on the administration of edoxaban 30 mg daily through PEG in a patient with advanced ALS, acute respiratory, and heart failure, presenting with Takotsubo syndrome and atrial fibrillation.",
"affiliations": "Dipartimento di Scienze Cardiovascolari e Toraciche, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00167, Rome, Italy.;Dipartimento di Scienze Cardiovascolari e Toraciche, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00167, Rome, Italy.;Dipartimento di Scienze Cardiovascolari e Toraciche, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00167, Rome, Italy.;Cardiovascular Disease Unit, Ospedale Policlinico San Martino, IRCCS, University of Genoa, Genoa, Italy.;Dipartimento di Scienze Cardiovascolari e Toraciche, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00167, Rome, Italy.;NEuroMuscular Omnicentre (NEMO), Serena Onlus Foundation-Pol. Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Catholic University of the Sacred Heart School of Medicine, Rome, Italy.;Institute of Internal Medicine & Geriatrics, Haemostasis and Thrombosis Center, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Area of Hematology, Catholic University of the Sacred Heart School of Medicine, Rome, Italy.;NEuroMuscular Omnicentre (NEMO), Serena Onlus Foundation-Pol. Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Catholic University of the Sacred Heart School of Medicine, Rome, Italy.;Institute of Internal Medicine & Geriatrics, Haemostasis and Thrombosis Center, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Area of Hematology, Catholic University of the Sacred Heart School of Medicine, Rome, Italy.;Dipartimento di Scienze Cardiovascolari e Toraciche, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00167, Rome, Italy.",
"authors": "Galli|Mattia|M|;D'Amario|Domenico|D|;Andreotti|Felicita|F|;Porto|Italo|I|;Vergallo|Rocco|R|;Sabatelli|Mario|M|;Lancellotti|Stefano|S|;Meleo|Emiliana|E|;De Cristofaro|Raimondo|R|;Crea|Filippo|F|",
"chemical_list": "D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; C552171:edoxaban",
"country": "England",
"delete": false,
"doi": "10.1002/ehf2.12434",
"fulltext": "\n==== Front\nESC Heart FailESC Heart Fail10.1002/(ISSN)2055-5822EHF2ESC Heart Failure2055-5822John Wiley and Sons Inc. Hoboken 10.1002/ehf2.12434EHF212434ESCHF-18-00219Case ReportCase ReportsSustained safe and effective anticoagulation using Edoxaban via percutaneous endoscopic gastrostomy Anticoagulation using edoxaban via percutaneous endoscopic gastrostomyM. Galli et al.Galli Mattia \n1\n\n†\nD'Amario Domenico domenico.damario@gmail.com \n1\n\n†\nAndreotti Felicita \n1\nPorto Italo \n2\nVergallo Rocco \n1\nSabatelli Mario \n3\nLancellotti Stefano \n4\nMeleo Emiliana \n3\nDe Cristofaro Raimondo \n4\nCrea Filippo \n1\n\n1 \nDipartimento di Scienze Cardiovascolari e Toraciche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS\nUniversità Cattolica del Sacro Cuore\nLargo F. Vito 1\n00167\nRome\nItaly\n\n2 \nCardiovascular Disease Unit, Ospedale Policlinico San Martino, IRCCS\nUniversity of Genoa\nGenoa\nItaly\n\n3 \nNEuroMuscular Omnicentre (NEMO), Serena Onlus Foundation‐Pol. Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS\nCatholic University of the Sacred Heart School of Medicine\nRome\nItaly\n\n4 \nInstitute of Internal Medicine & Geriatrics, Haemostasis and Thrombosis Center, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Area of Hematology\nCatholic University of the Sacred Heart School of Medicine\nRome\nItaly\n* \nCorrespondence to: Domenico D'Amario, Dipartimento di Scienze Cardiovascolari e Toraciche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00167 Rome, Italy. Email: domenico.damario@gmail.com\n† \nThese authors equally contributed to this work.\n\n11 6 2019 8 2019 6 4 10.1002/ehf2.v6.4884 888 19 10 2018 22 2 2019 © 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of CardiologyThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nExtensive data support the safety of direct oral anticoagulants compared with vitamin K antagonists in patients with non‐valvular atrial fibrillation, leading to a significantly increase in the use of these compounds in clinical practice. However, there is no compelling evidence supporting the use of direct oral anticoagulant in individuals who are intubated or have a percutaneous endoscopic gastrostomy (PEG): patients with several co‐morbidities are underrepresented in clinical trials, so the best long‐term strategy for anticoagulation is difficult to ascertain. The aim of the present report was to evaluate the safety and efficacy of edoxaban administered via PEG in a patient with heart failure and a history of atrial fibrillation affected by amyotrophic lateral sclerosis (ALS). A 71‐year‐old man with atrial fibrillation, advanced ALS, type II diabetes mellitus, and hypertension presented to the emergency department with dyspnoea and tachycardia. Because vitamin K antagonist and rivaroxaban 15 mg were dropped because of difficult international normalized ratio control (time in therapeutic range <30%) and severe haematuria, respectively, edoxaban 30 mg (crushed pill) daily was administered based on the patient's weight of 58 kg. Mean edoxaban plasma concentration–time profiles were measured, as anti‐Xa activity, 2 h before and at 2, 6, and 22 h after drug administration and then compared with the pharmacokinetic profile of edoxaban 30 mg in healthy subjects. An additional testing of steady‐state peak plasma concentration of edoxaban after 10 days and a 30 day follow‐up were evaluated. The values of the pharmacokinetic parameters, analysed with a non‐compartmental analysis by PKSolver module, showed that C\nmax and AUC0→t were only slightly higher than those observed in healthy subjects, while the half‐life and observed clearance were significantly longer and lower, respectively, than in normal subjects. Steady‐state peak plasma concentration of edoxaban was very similar to the levels reported in healthy subjects, and neither relevant bleeding nor thromboembolic event was reported at a 30 day follow‐up. These results support safe and effective anticoagulation with edoxaban 30 mg but suggest caution with the use of full dose of edoxaban (60 mg daily) in this kind of patients. We report, for the first time, a safe and effective anticoagulation based on the administration of edoxaban 30 mg daily through PEG in a patient with advanced ALS, acute respiratory, and heart failure, presenting with Takotsubo syndrome and atrial fibrillation.\n\nTakotsubo syndromeEdoxabanAmyotrophic lateral sclerosisAtrial fibrillationPercutaneous endoscopic gastrostomy source-schema-version-number2.0component-idehf212434cover-dateAugust 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.7 mode:remove_FC converted:02.08.2019\n\n\nGalli \nM. \n, \nD'Amario \nD. \n, \nAndreotti \nF. \n, \nPorto \nI. \n, \nVergallo \nR. \n, \nSabatelli \nM. \n, \nLancellotti \nS. \n, \nMeleo \nE. \n, \nDe Cristofaro \nR. \n, and \nCrea \nF. \n (2019 ) Sustained safe and effective anticoagulation using Edoxaban via percutaneous endoscopic gastrostomy , ESC Heart Failure , 6 , 884 –888 . 10.1002/ehf2.12434 .\n==== Body\nIntroduction\nAmyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, characterized by both upper and lower motor neuron dysfunction.1 Most patients die of respiratory complications 3–5 years after its onset. Patients treated with invasive ventilation through tracheostomy show an average further survival of 2 years.1, 2 Difficult swallowing is another frequent complication often requiring percutaneous endoscopic gastrostomy (PEG) in order to provide proper nutritional support and minimize the risk of aspiration pneumonia. Although autonomic dysfunction is not considered a main feature of the disease, sudden hypertensive or hypotensive crises, followed by circulatory collapse, have been described, especially in the advanced stages of ALS.1, 3 Recent publications have reported that heart diseases, including atrial fibrillation and heart failure, are common in ALS patients and are independently associated with reduced survival.4, 5\n\n\nTakotsubo syndrome (TTS), also known as stress‐induced cardiomyopathy, represents an acute heart failure syndrome characterized by ST‐segment elevation and reversible left ventricular regional wall motion abnormalities (typically involving the apex).6, 7 The precise pathogenesis of TTS remains unknown; a neurogenic origin with excessive catecholamine production causing microvascular spasm and direct cardiotoxicity may be involved.6 Several recent publications suggest that TTS, presenting with acute exacerbation of dyspnoea and chest discomfort, is relatively common in ALS patients, particularly in the advanced stages of ALS.8, 9\n\n\nAdditionally, atrial fibrillation (AF) is a common complication of both TTS and ALS,5, 7 and the use of anticoagulation in such fragile patients may be particularly challenging.\n\nCase report\nA 71‐year‐old man with advanced ALS, type II diabetes mellitus, and hypertension presented to the emergency department with dyspnoea and tachycardia. The family reported a history of paroxysmal atrial fibrillation treated with subcutaneous low molecular weight heparin (4000 IU twice daily). Vitamin K antagonist and rivaroxaban 15 mg had been tried and then suspended because of difficult international normalized ratio control (time in therapeutic range <30%) and severe haematuria, respectively. The patient was bedridden and had a PEG—placed 2 years before—and a permanent urinary catheter. On admission, blood pressure was 80/60 mmHg, heart rate was 118 b.p.m., oxygen saturation was 84%, and body temperature was 38.1 °C. Blood tests showed 19.95 × 109/L white blood cells, C‐reactive protein 249.9 mg/dL, and creatinine 0.28 mg/dL. The calculated estimated glomerular filtration rate was 138 mL/min/1.73 m2. On admission, high‐sensitivity troponin I levels were 2.874 ng/mL (normal range <0.040 ng/mL). Chest X‐rays documented bilateral interstitial pulmonary oedema and pleural effusion. Antibiotic therapy with levofloxacin and piperacillin–tazobactam was empirically started. However, the 12‐lead electrocardiogram showed anterior ST‐segment elevation with diffuse repolarization abnormalities (Figure\n\n1\n), and ultra‐sensitive serum troponin I concentrations were elevated (peak 3.589 ng/mL). Urgent coronary angiography revealed no significant epicardial coronary artery obstructions, while ventricular angiography showed apical ballooning typical of TTS (Figure\n\n2\n). Because of respiratory failure and severe hypotension, the patient was treated in the coronary care unit with inotropes and orotracheal intubation. Echocardiography showed a left ventricular ejection fraction of 30%, with akinesia of the mid and apical segments. The patient required prolonged respiratory support (5 days) followed by tracheostomy. AF at high ventricular rate occurred after coronary angiography. A rate control strategy was initiated along with low molecular weight heparin 4000 IU twice daily (CHA₂DS₂‐VASc score: 4). Nevertheless, a long‐term oral anticoagulation strategy was needed in order to avoid chronic subcutaneous administration of heparin by the caregivers. Edoxaban 30 mg (crushed pill) daily was administered based on the patient's weight of 58 kg.\n\nFigure 1 A 12‐lead electrocardiogram showing sinus tachycardia with anterior ST‐segment elevation and diffuse repolarization abnormalities.\n\nFigure 2 Ventricular angiography showing apical ballooning.\n\nMean edoxaban plasma concentration–time profiles were measured as anti‐Xa activity using the STA®‐Liquid Anti‐Xa assays and STA®‐Edoxaban Calibrator (0–500 ng/mL) on a STA Compact Max® instrument (all from Diagnostica Stago, Asnières‐sur‐Seine, France). Edoxaban concentration was measured 2 h before and 2, 6, and 22 h after drug administration and compared with the pharmacokinetic profile of edoxaban 30 mg in healthy subjects (Figure\n\n3\n).10 An additional blood sample 2 h after edoxaban administration was performed 10 days later to assess the steady‐state peak plasma concentration of edoxaban. In our patient, edoxaban peak plasma concentrations, both after the first administration and at steady state, were similar to the values reported for healthy subjects treated with edoxaban 30 mg (Figure\n\n3\n).10, 11, 12, 13, 14 However, the values of the pharmacokinetic parameters, analysed with a non‐compartmental analysis by PKSolver module of the Excel software, showed that C\nmax and AUC0→t were only slightly higher than those observed in healthy subjects,15 while the half‐life and observed clearance were significantly longer and lower, respectively, than in normal subjects15 (Table\n1). These results suggest great caution with the use of full dose of edoxaban (60 mg daily) in this kind of patients, as supra‐normal edoxaban concentrations might occur even in the presence of apparently normal kidney and liver function.\n\nFigure 3 The patient underwent tracheostomy and had a permanent urinary catheter and percutaneous endoscopic gastrostomy (PEG). Edoxaban 30 mg daily (crushed with a dedicated tool) was administered with 10 mL of saline solution through the PEG.\n\nTable 1 Pharmacokinetic parameters of the patient analysed with a non‐compartmental analysis by PKSolver module of the Excel software\n\ntabular imageAfter 7 days, echocardiography showed improved ejection fraction (45%). At the 30 day follow‐up, only minimal and self‐limiting haematuria (Bleeding Academic Research Consortium Type 1) was reported related to replacement of the urinary catheter, not requiring drug suspension; no thromboembolic event occurred.\n\nDiscussion\nThe use of direct oral anticoagulants has not been described in patients with PEG, and the pharmacokinetics of these agents in such patients is unknown. Our report is the first to describe the successful administration of edoxaban 30 mg daily (crushed and diluted in 10 mL of saline solution) through a PEG in a patient with advanced ALS, tracheostomy, atrial fibrillation, and acute heart failure (Figure\n\n4\n). Edoxaban was ultimately chosen, given its good safety profile and its balanced renal and biliary clearance (respectively 50 and 50%).10, 12, 13 This precaution was considered necessary because the Cockcroft–Gault estimate of renal function (based on serum creatinine, sex, body weight, and age) might have been distorted by the extremely low muscle mass of this totally bedridden patient with advanced ALS.14\n\n\nFigure 4 The edoxaban plasma concentration after a single dose of edoxaban 30 mg in a patient with percutaneous endoscopic gastrostomy was compared with that reported by Parasrampuria and Truitt10 in healthy subjects. Steady‐state concentration after 10 days in the patient with percutaneous endoscopic gastrostomy was also assessed and compared with that reported by Chung et al.11 in healthy subjects after 28 days (steady state is reached on average after 4 days10).\n\nWe support the evaluation of the effect on anticoagulation by using a calibrated quantitative anti‐factor Xa assay, which may help to inform clinical decisions in particular situations.\n\nAlthough further data are needed to confirm that edoxaban administration via PEG is safe and effective, this case supports its feasibility and potential favourable profile to treat fragile, complex, co‐morbid patients with AF, acute heart failure, advanced ALS, and PEG.\n\nConflict of interest\nF.A. is a consultant or speaker for Actelion, Amgen, Bayer, BMS/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo. The other authors do not have any conflicts of interest to declare.\n==== Refs\nReferences\n1 \n\nFoster \nLA \n, \nSalajegheh \nMK \n. Motor neuron disease: pathophysiology, diagnosis, and management . Am J Med \n2019 ; 132 : 32 –37 .30075105 \n2 \n\nNiedermeyer \nS \n, \nMurn \nM \n, \nChoi \nPJ \n. Respiratory failure in amyotrophic lateral sclerosis . Chest \n2019 ; 155 : 401 –408 .29990478 \n3 \n\nShimizu \nT \n, \nHayashi \nH \n, \nKato \nS \n, \nHayashi \nM \n, \nTanabe \nH \n, \nOda \nM \n. Circulatory collapse and sudden death in respirator‐dependent amyotrophic lateral sclerosis . J Neurol Sci \n1994 ; 124 : 45 –55 .7931421 \n4 \n\nCorcia \nP \n, \nPradat \nPF \n, \nSalachas \nF \n, \nBruneteau \nG \n, \nForestier \nN \n, \nSeilhean \nD \n, \nHauw \nJJ \n, \nMeininger \nV \n. Causes of death in a post‐mortem series of ALS patients . Amyotroph Lateral Scler \n2008 ; 9 : 59 –62 .17924236 \n5 \n\nMandrioli \nJ \n, \nFerri \nL \n, \nFasano \nA \n, \nZucchi \nE \n, \nFini \nN \n, \nMoglia \nC \n, \nLunetta \nC \n, \nMarinou \nK \n, \nTicozzi \nN \n, \nDrago Ferrante \nG \n, \nScialo \nC \n, \nSoraru \nG \n, \nTrojsi \nF \n, \nConte \nA \n, \nFalzone \nYM \n, \nTortelli \nR \n, \nRusso \nM \n, \nSansone \nVA \n, \nMora \nG \n, \nSilani \nV \n, \nVolanti \nP \n, \nCaponnetto \nC \n, \nQuerin \nG \n, \nMonsurro \nMR \n, \nSabatelli \nM \n, \nChio \nA \n, \nRiva \nN \n, \nLogroscino \nG \n, \nMessina \nS \n, \nCalvo \nA \n. Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis . Eur J Neurol \n2018 ; 25 : 861 –868 .29512869 \n6 \n\nPelliccia \nF \n, \nKaski \nJC \n, \nCrea \nF \n, \nCamici \nPG \n. Pathophysiology of Takotsubo syndrome . Circulation \n2017 ; 135 : 2426 –2441 .28606950 \n7 \n\nLyon \nAR \n, \nBossone \nE \n, \nSchneider \nB \n, \nSechtem \nU \n, \nCitro \nR \n, \nUnderwood \nSR \n, \nSheppard \nMN \n, \nFigtree \nGA \n, \nParodi \nG \n, \nAkashi \nYJ \n, \nRuschitzka \nF \n, \nFilippatos \nG \n, \nMebazaa \nA \n, \nOmerovic \nE \n. Current state of knowledge on Takotsubo syndrome: a position statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology . Eur J Heart Fail \n2016 ; 18 : 8 –27 .\n8 \n\nChoi \nSJ \n, \nHong \nYH \n, \nShin \nJY \n, \nYoon \nBN \n, \nSohn \nSY \n, \nPark \nCS \n, \nSung \nJJ \n. Takotsubo cardiomyopathy in amyotrophic lateral sclerosis . J Neurol Sci \n2017 ; 375 : 289 –293 .28320151 \n9 \n\nPeters \nS \n. Tako tsubo cardiomyopathy in respiratory stress syndrome in amyotrophic lateral sclerosis . Int J Cardiol \n2014 ; 177 : 187 .25499374 \n10 \n\nParasrampuria \nDA \n, \nTruitt \nKE \n. Pharmacokinetics and pharmacodynamics of edoxaban, a non‐vitamin K antagonist oral anticoagulant that inhibits clotting factor Xa . Clin Pharmacokinet \n2016 ; 55 : 641 –655 .26620048 \n11 \n\nChung \nN \n, \nJeon \nHK \n, \nLien \nLM \n, \nLai \nWT \n, \nTse \nHF \n, \nChung \nWS \n, \nLee \nTH \n, \nChen \nSA \n. Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non‐valvular atrial fibrillation . Thromb Haemost \n2011 ; 105 : 535 –544 .21136011 \n12 \n\nBathala \nMS \n, \nMasumoto \nH \n, \nOguma \nT \n, \nHe \nL \n, \nLowrie \nC \n, \nMendell \nJ \n. Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans . Drug Metab Dispos \n2012 ; 40 : 2250 –2255 .22936313 \n13 \n\nLip \nGY \n, \nAgnelli \nG \n. Edoxaban: a focused review of its clinical pharmacology . Eur Heart J \n2014 ; 35 : 1844 –1855 .24810388 \n14 \n\nBaxmann \nAC \n, \nAhmed \nMS \n, \nMarques \nNC \n, \nMenon \nVB \n, \nPereira \nAB \n, \nKirsztajn \nGM \n, \nHeilberg \nIP \n. Influence of muscle mass and physical activity on serum and urinary creatinine and serum cystatin C . Clin J Am Soc Nephrol \n2008 ; 3 : 348 –354 .18235143 \n15 \n\nHanada \nK \n, \nMatsumoto \nS‐I \n, \nShibata \nS \n, \nMatsubara \nH \n, \nTsukimura \nY \n, \nTakahashi \nH \n. A quantitative LC/MSMS method for determination of edoxaban, a Xa inhibitor and its pharmacokinetic application in patients after total knee arthroplasty . Biomed Chromatogr \n2018 ; 32 : e4213.29451685\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2055-5822",
"issue": "6(4)",
"journal": "ESC heart failure",
"keywords": "Amyotrophic lateral sclerosis; Atrial fibrillation; Edoxaban; Percutaneous endoscopic gastrostomy; Takotsubo syndrome",
"medline_ta": "ESC Heart Fail",
"mesh_terms": "D000368:Aged; D065427:Factor Xa Inhibitors; D005773:Gastroscopy; D005774:Gastrostomy; D006801:Humans; D008297:Male; D011725:Pyridines; D013844:Thiazoles; D016896:Treatment Outcome",
"nlm_unique_id": "101669191",
"other_id": null,
"pages": "884-888",
"pmc": null,
"pmid": "31184800",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24810388;22936313;26548803;21136011;29990478;30075105;25499374;29512869;31184800;28606950;17924236;7931421;18235143;26620048;29451685;28320151",
"title": "Sustained safe and effective anticoagulation using Edoxaban via percutaneous endoscopic gastrostomy.",
"title_normalized": "sustained safe and effective anticoagulation using edoxaban via percutaneous endoscopic gastrostomy"
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"companynumb": "IT-PFIZER INC-2019165741",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "LEVOFLOXACIN"
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{
"abstract": "BACKGROUND\nAcute lower gastrointestinal haemorrhage can potentially be life-threatening. We present a case of a massive rectal bleed which was managed successfully with a balloon tamponade device designed for upper gastrointestinal haemorrhage.\n\n\nMETHODS\nA 75-year-old gentleman, with a history of human immunodeficiency virus and cirrhosis with portal hypertension, presented with bright red rectal bleeding. Investigations showed a low haemoglobin level (74 g/L) and deranged clotting. Oesophago-gastro-duodenoscopy demonstrated no fresh or altered blood. Flexible sigmoidoscopy revealed active bleeding from a varix within the anterior rectal wall 4 cm from the anal verge. Efforts to stop the bleeding, including endoscopic clips, adrenaline injection and rectal packing, were unsuccessful and the patient became haemodynamically unstable. A Sengstaken-Blakemore tube was inserted per rectum and the gastric balloon was inflated to tamponade the lower rectum. The oesophageal balloon was then inflated to hold the gastric balloon firmly in place. A computed tomography angiogram demonstrated no evidence of haemorrhage with balloon tamponade. After 36 h, the balloon was removed with no further episodes of bleeding.\n\n\nCONCLUSIONS\nThe application of a balloon tamponade device should be considered in the management algorithm for acute lower gastrointestinal bleed. Advantages include its rapid insertion, immediate results and ability to measure further bleeding after the catheter has been placed.\n\n\nCONCLUSIONS\nSengstaken-Blakemore tube per rectum may effectively control massive low rectal bleeding when alternative methods have been unsuccessful.",
"affiliations": "Department of Colorectal Surgery, Chelsea and Westminster Hospital, London, United Kingdom. Electronic address: michael.fadel@ucl.ac.uk.;Department of Colorectal Surgery, Chelsea and Westminster Hospital, London, United Kingdom; Department of Surgery and Cancer, Imperial College, London, United Kingdom. Electronic address: prb03@ic.ac.uk.;Department of Colorectal Surgery, Chelsea and Westminster Hospital, London, United Kingdom; Department of Surgery and Cancer, Imperial College, London, United Kingdom. Electronic address: a.howell@ic.ac.uk.;Department of Colorectal Surgery, Chelsea and Westminster Hospital, London, United Kingdom. Electronic address: mohamad.iskandarani@chelwest.nhs.uk.;Department of Colorectal Surgery, Chelsea and Westminster Hospital, London, United Kingdom; Department of Surgery and Cancer, Imperial College, London, United Kingdom; Department of Colorectal Surgery, Royal Marsden Hospital, London, United Kingdom. Electronic address: p.tekkis@imperial.ac.uk.;Department of Colorectal Surgery, Chelsea and Westminster Hospital, London, United Kingdom; Department of Surgery and Cancer, Imperial College, London, United Kingdom; Department of Colorectal Surgery, Royal Marsden Hospital, London, United Kingdom. Electronic address: c.kontovounisios@imperial.ac.uk.",
"authors": "Fadel|Michael G|MG|;Boshier|Piers R|PR|;Howell|Ann-Marie|AM|;Iskandarani|Mohamad|M|;Tekkis|Paris|P|;Kontovounisios|Christos|C|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2020.09.066",
"fulltext": "\n==== Front\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612 Elsevier \n\nS2210-2612(20)30739-2\n10.1016/j.ijscr.2020.09.066\nCase Report\nThe management of acute lower gastrointestinal bleeding using a Sengstaken-Blakemore tube\nFadel Michael G. michael.fadel@ucl.ac.uka Boshier Piers R. prb03@ic.ac.ukab Howell Ann-Marie a.howell@ic.ac.ukab Iskandarani Mohamad mohamad.iskandarani@chelwest.nhs.uka Tekkis Paris p.tekkis@imperial.ac.ukabc Kontovounisios Christos c.kontovounisios@imperial.ac.ukabc⁎ a Department of Colorectal Surgery, Chelsea and Westminster Hospital, London, United Kingdom\nb Department of Surgery and Cancer, Imperial College, London, United Kingdom\nc Department of Colorectal Surgery, Royal Marsden Hospital, London, United Kingdom\n⁎ Corresponding author at: Department of Colorectal Surgery, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, United Kingdom. c.kontovounisios@imperial.ac.uk\n21 9 2020 \n2020 \n21 9 2020 \n75 394 397\n12 7 2020 7 9 2020 7 9 2020 © 2020 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.2020This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• Acute lower gastrointestinal bleeding can potentially be life-threatening.\n\n• Sengstaken-Blakemore tube per rectum may effectively control rectal bleeding.\n\n• Advantages of balloon tamponade include rapid insertion and immediate results.\n\n• This method could be considered in the management algorithm of rectal bleeding.\n\n\n\nIntroduction\nAcute lower gastrointestinal haemorrhage can potentially be life-threatening. We present a case of a massive rectal bleed which was managed successfully with a balloon tamponade device designed for upper gastrointestinal haemorrhage.\n\nPresentation of case\nA 75-year-old gentleman, with a history of human immunodeficiency virus and cirrhosis with portal hypertension, presented with bright red rectal bleeding. Investigations showed a low haemoglobin level (74 g/L) and deranged clotting. Oesophago-gastro-duodenoscopy demonstrated no fresh or altered blood. Flexible sigmoidoscopy revealed active bleeding from a varix within the anterior rectal wall 4 cm from the anal verge. Efforts to stop the bleeding, including endoscopic clips, adrenaline injection and rectal packing, were unsuccessful and the patient became haemodynamically unstable. A Sengstaken-Blakemore tube was inserted per rectum and the gastric balloon was inflated to tamponade the lower rectum. The oesophageal balloon was then inflated to hold the gastric balloon firmly in place. A computed tomography angiogram demonstrated no evidence of haemorrhage with balloon tamponade. After 36 h, the balloon was removed with no further episodes of bleeding.\n\nDiscussion\nThe application of a balloon tamponade device should be considered in the management algorithm for acute lower gastrointestinal bleed. Advantages include its rapid insertion, immediate results and ability to measure further bleeding after the catheter has been placed.\n\nConclusion\nSengstaken-Blakemore tube per rectum may effectively control massive low rectal bleeding when alternative methods have been unsuccessful.\n\nKeywords\nLower gastrointestinal bleedingBalloon tamponadeSengstaken-Blakemore tubeCase report\n==== Body\n1 Introduction\nLower gastrointestinal (LGI) haemorrhage is defined as bleeding distal to the ligament of Treitz [1], with approximately 90% bleeding originating from the colon [2,3]. The incidence of LGI haemorrhage is 33-87/100,000 [4] and accounts for 3% of emergency surgical referrals [5]. Without prompt diagnosis and intervention, LGI haemorrhage may be life-threatening. Treatment options include: conservative medical therapy (blood transfusion, antifibrinolytic agents and withholding oral anticoagulants); endoscopy; interventional radiology, and surgery. Endoscopic methods, such as injection therapy, clipping or band ligation, endoloops or thermal coagulation, are usually sufficient in arresting the bleeding [[6], [7], [8]]. Radiological embolisation can also be performed using coils, liquid agents or particles. Emergency laparotomy should be reserved for cases where life-threatening bleeding persists despite other interventions.\n\nThe application of balloon tamponade devices is well established in the management of upper gastrointestinal and postpartum haemorrhage [[9], [10], [11], [12]]. Tamponade devices, such as the Minnesota tube or Sengstaken-Blakemore tube, have been specifically designed for the management of upper gastrointestinal bleeding from oesophageal varices often in patients who are haemodynamically unstable providing time for definitive intervention. There are limited reports on the use of balloon tamponade devices for the management of LGI haemorrhage [[13], [14], [15], [16], [17], [18]].\n\nHerein we present an emergency case of a continuous rectal bleed in a patient with multiple co-morbidities who was a poor candidate for surgery. The lower GI bleed did not respond to several medical and endoscopic interventions and a decision was made to insert a Sengstaken-Blakemore tube per rectum. We describe our technique of application and show that the balloon tamponade device, if used correctly, can achieve rapid and effective haemostasis, providing an opportunity to rescue the patient from major haemorrhage. This work has been reported in line with the SCARE criteria [19].\n\n2 Case presentation\nA 75-year-old gentleman presented with a one-week history of bright red rectal bleeding and fever. His past medical history included: history of human immunodeficiency virus, hepatitis C, decompensated cirrhosis with ascites, portal hypertension, transient ischaemic attack, excess alcohol consumption and smoking. He also had severe aortic stenosis, for which he underwent a transcatheter aortic valve implantation, squamous cell carcinoma of the tongue, basal cell carcinoma and depression. His drug history included anti-retrovirals, aspirin, thiamine, vitamin B, folic acid, omeprazole and fluoxetine. On examination, the patient’s abdomen was distended with minimal tenderness. Digital rectal examination revealed active bleeding with no obvious masses or haemorrhoids. Blood investigations showed a haemoglobin level of 74 g/L, platelet count of 54 × 109/L and deranged clotting and liver function tests. A computed tomography (CT) angiogram demonstrated splenomegaly and ascites but did not identify any specific cause for rectal bleeding. He was optimised medically prior to endoscopy with intravenous antibiotics, tranexamic acid, vitamin K, human albumin solution and a transfusion of one unit of packed red blood cells.\n\nOesophago-gastro-duodenoscopy demonstrated patchy candidiasis and a single varix in the lower third of the oesophagus. There was mild portal hypertensive gastritis in the cardia and fundus of the stomach and the lower body of the stomach with no gastric varices. No fresh or altered blood was seen within the upper gastrointestinal tract. On flexible sigmoidoscopy, there was a visible point of continuous fresh bleeding on the anterior wall of rectum around 4 cm from the anal verge. With the exception of a possible rectal varix there was no overlying mucosal abnormality at this site. Bleeding persisted despite the application of eight resolution clips (Boston Scientific), adrenaline injections and rectal packing. The patient became haemodynamically unstable with a blood pressure of 70/46 mmHg. A massive haemorrhage protocol was activated with immediate transfusion of packed red blood cells, fresh frozen plasma, platelets and terlipressin.\n\nA decision was made to insert a Sengstaken-Blakemore tube per rectum and to inflate the gastric balloon using 100 mL of air to tamponade the lower rectum. The oesophageal balloon was then inflated (external to the anus) to provide gentle traction to ensure that the balloon was firmly situated in the rectum and exerting optimal pressure onto the bleeding point on the rectal wall. The luminal port was connected to the catheter bag for free drainage and the bleeding stopped immediately. The blood pressure responded and increased to 95/54 mmHg. A subsequent CT angiogram demonstrated no evidence of haemorrhage with the effects of balloon tamponade (Fig. 1). There was no free air noted in the abdomen and no obvious varices in the portal venous phase.Fig. 1 Coronal (A) and sagittal (B) views of computed tomography angiogram (non-enhanced, arterial and portal venous images were obtained) demonstrated no evidence of frank haemorrhage in the gastrointestinal tract. Sengstaken-Blakemore tube placement in the rectum is shown, with inflation of the gastric and oesophageal balloons, which immediately stopped the lower gastrointestinal bleed via balloon tamponade. Endoscopic clips applied during flexible sigmoidoscopy can also be seen.\n\nFig. 1\n\nThe patient was closely monitored in the intensive care unit following endoscopy where he remained haemodynamically stable. He was further managed with intravenous antibiotics and terlipressin. After 36 h, the haemoglobin level was 92 g/L with a platelet count of 70 × 109/L and the balloon was removed at this point to reduce the risk of pressure necrosis and ulceration of the compressed rectal wall. There were no further bleeding episodes with two months of follow-up.\n\n3 Discussion\nThe use of balloon tamponade devices in the management of LGI haemorrhage is not well established with only a few cases reported in the literature. Table 1 summarises the cases of LGI bleed treated with balloon tamponade present in the literature [[13], [14], [15], [16], [17], [18]]. There are different application techniques, gastric balloon inflation (ranging from 50 mL to 350 mL of air/water) and removal times (ranging from 24 h to 60 h) reported with either interval deflation or complete removal. There were no further episodes of bleeding in all the cases.Table 1 Summary of literature review on the placement of balloon tamponade devices for the management of lower gastrointestinal bleeding. There was successful tamponade in all cases with no further episodes of bleeding reported. List of abbreviations: M, male; F, female.\n\nTable 1Authors, year\tGender/Age\tPresentation of case\tType and inflation extent of balloon\tBalloon tamponade time\t\nMcGuinness et al. [13], 2004\tM/65 years\tBleeding following transanal excision of a large tubovillous adenoma of the rectum\tMinnesota tube (50 mL of water in gastric balloon and 100 mL of water in oesophageal balloon)\t24 h\t\nSu Min Cho et al. [14], 2006\tM/51 years\tBleeding following polypectomy and then rectal varices bleed after laparotomy\tMinnesota tube (200 mL of air in gastric balloon)\t24 h\t\nMarshall et al. [15], 2007\tM/54 years\tBleeding from a stapled ileorectal anastomosis in a patient who previously underwent an emergency total colectomy and defunctioning loop ileostomy\tMinnesota tube (200 mL of air in gastric balloon)\t60 h\t\nNeeki et al. [16], 2019\tM/76 years\tContinuous rectal haemorrhage from ulcerated mucosa at the dentate line\tMinnesota tube (200 mL of air in gastric balloon and 300 mL of air in oesophageal balloon)\t24 h\t\nRoy et al. [17], 1996\tF/75 years\tRectal bleeding due to angiodysplasia\tSengstaken-Blakemore tube (350 mL of air in gastric balloon)\t48 h\t\nMichopoulou et al. [18], 2013\tF/64 years\tMassive haemorrhage following rectal biopsies\tSengstaken-Blakemore tube (250 mL of normal saline in gastric balloon)\t48 h\t\n\n\nAdvantages of the Sengstaken-Blakemore or the Minnesota tube are ease of availability, rapid insertion into the rectum and patient acceptability. Benefits over alternative methods, such as packing, include immediate haemostasis and the ability to measure further bleeding after the catheter has been placed. Potential complications of balloon tamponade include ischaemic necrosis, ulceration and perforation of the intestine, particularly in cases of excessive or prolonged inflation [13,20]. To avoid this, close monitoring and gradual deflation in the case of visceral pain is recommended [13]. On the other hand, underfilling of the balloon may lead to migration of the tube proximally [15]. Careful digital palpation of the balloon can confirm that the balloon is optimally sited and pressurised.\n\n4 Conclusion\nWe describe how the application of a Sengstaken-Blakemore tube can control life-threatening bleeding and stabilise the patient during a significant LGI haemorrhage. The technique has proven to be particularly useful when the bleeding point is difficult to locate if the haemorrhage is brisk or there is no raised mucosal lesion found. Thus, the application of a balloon tamponade device should be considered in the management algorithm for acute LGI bleed and can be reserved for when all other alternative methods have failed. It is a simple, safe and effective technique to provide immediate haemostasis especially in patients who are not good candidates for general anaesthesia and surgery.\n\nDeclaration of Competing Interest\nAll authors declare that there is no financial or personal conflict of interest related to this work.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\nWe declare that our institution does not require ethical approval for case reports.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\nMF performed the collection, analysis and interpretation of the data and drafted the manuscript. PB, AH and MI contributed to the analysis of the data and critical revision of the manuscript. PT and CK performed the procedure and approved the final manuscript.\n\nRegistration of research studies\nNot applicable.\n\nGuarantor\nChristos Kontovounisios.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n==== Refs\nReferences\n1 Hoedema R.E. Luchtefeld M.A. The management of lower gastrointestinal haemorrhage Dis. Colon Rectum 48 2005 2010 2024 16175326 \n2 Wagner H.E. Stain S.C. Gilg M. Gertsch P. Systematic assessment of massive bleeding of the lower part of the gastrointestinal tract Surg. Gynecol. Obstet. 175 1992 445 449 1440174 \n3 Lanas A. García-Rodríguez L.A. Polo-Tomás M. Ponce M. Alonso-Abreu I. Perez-Asia M.A. Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice Am. J. Gastroenterol. 104 2009 1633 1641 19574968 \n4 Hreinsson J.P. Gumundsson S. Kalaitzakis E. Bjӧrnsson E.S. Lower gastrointestinal bleeding: incidence, etiology, and outcomes in a population-based setting Eur. J. Gastroenterol. Hepatol. 25 2013 37 43 23013623 \n5 Loperfido S. Baldo V. Piovesana E. Bellina L. Rossi K. Groppo M. Changing trends in acute upper-GI bleeding: a population-based study Gastrointest. Endosc. 70 2009 212 224 19409558 \n6 Oakland K. Isherwood J. Lahiff C. Goldsmith P. Desborough M. Colman K.S. Diagnostic and therapeutic treatment modalities for acute lower gastrointestinal bleeding: a systematic review Endosc. Int. Open 5 2017 E959 973 28975147 \n7 Strate L.L. Naumann C.R. The role of colonoscopy and radiological procedures in the management of acute lower intestinal bleeding Clin. Gastroenterol. Hepatol. 8 2010 333 343 20036757 \n8 Wedi E. von Renteln D. Jung C. Tchoumak I. Roth V. Gonzales S. Treatment of acute colonic diverticular bleeding in high risk patients, using an over-the-scope clip: a case series Endoscopy 48 2016 E383 385 27912217 \n9 Georgiou C. Balloon tamponade in the management of postpartum haemorrhage: a review BJOG 116 2009 748 757 19432563 \n10 Ball C.G. Wyrzykowski A.D. Nicholas J.M. Rozycki G.S. Feliciano D.V. A decade’s experience with balloon catheter tamponade for the emergency control of haemorrhage J. Trauma 70 2011 330 333 21307730 \n11 Brown H. Okeyo S. Mabeya H. Wilkinson J. Schmitt J. The Bakri tamponade balloon as an adjunct treatment for refractory postpartum haemorrhage Int. J. Gynaecol. Obstet. 135 2016 276 280 27612530 \n12 Gelsthorpe A. Patodi N. Ahmed M. PMO-185 Duodenal tamponade: a case series and fourth modality in gastrointestinal bleed control Gut 61 2012 A149 \n13 McGuinness J. Winter D.C. O’Connell P.R. Balloon tamponade to control haemorrhage following transanal rectal surgery Int. J. Colorectal Dis. 19 2004 395 396 15083324 \n14 Cho S.M. Al-Khafaji A. Ahmad J. Minnesota tube for bleeding rectal varices Am. J. Gastroenterol. 101 2006 S284 285 \n15 Marshall B.J. Seow C.H. Levitt M.D. Use of a Minnesota tube to tamponade bleeding from an ileorectal anastomosis ANZ J. Surg. 77 2007 916 917 17803569 \n16 Neeki M.M. Raj V. Archambeau B. Arabian S. Hussain F. Novel application of balloon tamponade in management of acute lower gastrointestinal hemorrhage Clin. Pract. Cases Emerg. Med. 3 2019 243 247 31404316 \n17 Roy M.K. Rhodes M. Ruttley M.S. Wheeler M.H. Sengstaken tube for bleeding rectal angiodysplasia Br. J. Surg. 83 1996 1111 8869319 \n18 Michopoulou A.T. Doulgerakis G.E. Pierrakakis S.K. Sengstaken-Blakemore tube for massive haemorrhage following rectal biopsies Int. J. Colorectal Dis. 28 2013 1595 1596 23322535 \n19 Agha R.A. Borelli M.R. Farwana R. Koshy K. Fowler A. Orgill D.P. For the SCARE Group The SCARE 2018 statement: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279 \n20 Chahla E. Cheesman A. Taylor J.R. Esophageal perforation caused by misplaced Minnesota tube Clin. Gastroenterol. Hepatol. 14 2016 A33 34\n\n",
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"title": "The management of acute lower gastrointestinal bleeding using a Sengstaken-Blakemore tube.",
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"abstract": "Thyroid abnormalities in patients with bipolar disorder (BD) have been linked to lithium treatment for decades, yet other drugs have been less well studied. Our objective was to compare hypothyroidism risk for lithium versus the anticonvulsants and second-generation antipsychotics commonly prescribed for BD.\n\n\n\nAdministrative claims data on 24,574 patients with BD were analyzed with competing risk survival analysis. Inclusion criteria were (i) one year of no prior hypothyroid diagnosis nor BD drug treatment, (ii) followed by at least one thyroid test during BD monotherapy on lithium carbonate, mood-stabilizing anticonvulsants (lamotrigine, valproate, oxcarbazepine, or carbamazepine) or antipsychotics (aripiprazole, olanzapine, risperidone, or quetiapine). The outcome was cumulative incidence of hypothyroidism per drug, in the presence of the competing risk of ending monotherapy, adjusted for age, sex, physician visits, and thyroid tests.\n\n\n\nAdjusting for covariates, the four-year cumulative risk of hypothyroidism for lithium (8.8%) was 1.39-fold that of the lowest risk therapy, oxcarbazepine (6.3%). Lithium was non-statistically significantly different from quetiapine. While lithium conferred a higher risk when compared to all other treatments combined as a group, hypothyroidism risk error bars overlapped for all drugs. Treatment (p = 3.86e-3), age (p = 6.91e-10), sex (p = 3.93e-7), and thyroid testing (p = 2.79e-87) affected risk. Patients taking lithium were tested for hypothyroidism 2.26-3.05 times more frequently than those on other treatments.\n\n\n\nThyroid abnormalities occur frequently in patients with BD regardless of treatment. Therefore, patients should be regularly tested for clinical or subclinical thyroid abnormalities on all therapies and treated as indicated to prevent adverse effects of hormone imbalances on mood.",
"affiliations": "Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.;Bioinformatics Core, Montana State University, Bozeman, MT, USA.;Department of Computer Science, University of New Mexico, Albuquerque, NM, USA.;New Mexico Behavioral Health Institute, Las Vegas, NM, USA.;CGStat, LLC, Raleigh, NC, USA.;Risk Benefit Statistics, LLC, Bella Vista, CA, USA.;Los Alamos National Laboratory, Los Alamos, NM, USA.;Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.;Department of Psychiatry and Behavioral Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.;Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.",
"authors": "Lambert|Christophe G|CG|;Mazurie|Aurélien J|AJ|;Lauve|Nicolas R|NR|;Hurwitz|Nathaniel G|NG|;Young|S Stanley|SS|;Obenchain|Robert L|RL|;Hengartner|Nicolas W|NW|;Perkins|Douglas J|DJ|;Tohen|Mauricio|M|;Kerner|Berit|B|",
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"fulltext": "\n==== Front\nBipolar DisordBipolar Disord10.1111/(ISSN)1399-5618BDIBipolar Disorders1398-56471399-5618John Wiley and Sons Inc. Hoboken 10.1111/bdi.12391BDI12391Original ArticleOriginal ArticlesHypothyroidism risk compared among nine common bipolar disorder therapies in a large US cohort Lambert et al.Lambert Christophe G \n1\n\n2\nMazurie Aurélien J \n3\nLauve Nicolas R \n4\nHurwitz Nathaniel G \n5\nYoung S Stanley \n6\nObenchain Robert L \n7\nHengartner Nicolas W \n8\nPerkins Douglas J \n1\nTohen Mauricio \n9\nKerner Berit \n10\n1 Center for Global HealthDepartment of Internal MedicineUniversity of New Mexico Health Sciences CenterAlbuquerqueNMUSA2 Division of Translational InformaticsDepartment of Internal MedicineUniversity of New Mexico Health Sciences CenterAlbuquerqueNMUSA3 Bioinformatics CoreMontana State UniversityBozemanMTUSA4 Department of Computer ScienceUniversity of New MexicoAlbuquerqueNMUSA5 New Mexico Behavioral Health InstituteLas VegasNMUSA6 CGStat, LLCRaleighNCUSA7 Risk Benefit Statistics, LLCBella VistaCAUSA8 Los Alamos National LaboratoryLos AlamosNMUSA9 Department of Psychiatry and Behavioral SciencesUniversity of New Mexico Health Sciences CenterAlbuquerqueNMUSA10 Semel Institute for Neuroscience and Human BehaviorDavid Geffen School of MedicineUniversity of CaliforniaLos AngelesCAUSA* \nCorresponding author:\n\nChristophe G Lambert, Ph.D.\n\nDepartment of Internal Medicine\n\nUniversity of New Mexico Health Sciences Center\n\nCenter for Global Health and Division of Translational Informatics\n\nMSC10‐5550, 915 Camino de Salud NE\n\nAlbuquerque, NM 87131\n\nUSA\n\nFax: +1 (505) 272‐8441\n\nE‐mail: cglambert@unm.edu\n26 5 2016 5 2016 18 3 10.1111/bdi.2016.18.issue-3247 260 11 11 2015 20 1 2016 26 2 2016 © 2016 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Objectives\nThyroid abnormalities in patients with bipolar disorder (BD) have been linked to lithium treatment for decades, yet other drugs have been less well studied. Our objective was to compare hypothyroidism risk for lithium versus the anticonvulsants and second‐generation antipsychotics commonly prescribed for BD.\n\nMethods\nAdministrative claims data on 24,574 patients with BD were analyzed with competing risk survival analysis. Inclusion criteria were (i) one year of no prior hypothyroid diagnosis nor BD drug treatment, (ii) followed by at least one thyroid test during BD monotherapy on lithium carbonate, mood‐stabilizing anticonvulsants (lamotrigine, valproate, oxcarbazepine, or carbamazepine) or antipsychotics (aripiprazole, olanzapine, risperidone, or quetiapine). The outcome was cumulative incidence of hypothyroidism per drug, in the presence of the competing risk of ending monotherapy, adjusted for age, sex, physician visits, and thyroid tests.\n\nResults\nAdjusting for covariates, the four‐year cumulative risk of hypothyroidism for lithium (8.8%) was 1.39‐fold that of the lowest risk therapy, oxcarbazepine (6.3%). Lithium was non‐statistically significantly different from quetiapine. While lithium conferred a higher risk when compared to all other treatments combined as a group, hypothyroidism risk error bars overlapped for all drugs. Treatment (p = 3.86e‐3), age (p = 6.91e‐10), sex (p = 3.93e‐7), and thyroid testing (p = 2.79e‐87) affected risk. Patients taking lithium were tested for hypothyroidism 2.26–3.05 times more frequently than those on other treatments.\n\nConclusions\nThyroid abnormalities occur frequently in patients with BD regardless of treatment. Therefore, patients should be regularly tested for clinical or subclinical thyroid abnormalities on all therapies and treated as indicated to prevent adverse effects of hormone imbalances on mood.\n\nanticonvulsantsantipsychoticsbipolar disordercompeting riskshypothyroidismlithiumReagan‐Udall FoundationRUFIMEDS‐SA_0010 source-schema-version-number2.0component-idbdi12391cover-dateMay 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.6 mode:remove_FC converted:01.11.2016\n\n\nLambert \nCG \n, \nMazurie \nAJ \n, \nLauve \nNR \n, \nHurwitz \nNG \n, \nYoung \nSS \n, \nObenchain \nRL \n, \nHengartner \nNW \n, \nPerkins \nDJ \n, \nTohen \nM \n, \nKerner \nB \n. Hypothyroidism risk compared among nine common bipolar disorder therapies in a large US cohort . Bipolar Disord \n2016 : 18 : 247 –260 . © 2016 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd.27226264\n==== Body\nBipolar disorder (BD) is characterized by recurrent episodes of mania, hypomania, and depression 1, occurring in about 2% of the population 2. While acute episodes can be dramatic and require hospitalization, successful treatment rests on the effective prevention of recurrences and of residual symptoms.\n\nLithium has been a cornerstone of the treatment of acute mania and the prevention of mood episodes during the maintenance phase of the disease 3, 4, 5, 6, 7, 8, 9. Despite its narrow therapeutic range, which requires careful monitoring of drug serum levels, lithium has proven effective in 30–50% of patients, particularly in those with a family history of BD, with non‐rapid cycling BD, and without comorbid substance use disorders 10, 11. Lithium appears to have neuroprotective properties 12, and reduces suicidal behavior 13, 14, 15, 16. However, potentially severe side effects have also been reported, including hypothyroidism 17, 18, particularly in middle‐aged women, for whom rates as high as 37% have been reported 19. The link between hypothyroidism and lithium treatment has been supported by case reports 20, 21, 22, and other observational studies as reflected in a recent meta‐analysis 23. These anticipated adverse effects have led to recommendations for frequent thyroid testing of patients treated with lithium as reflected in recent UpToDate guidelines 24, despite some negative findings 25, 26, 27.\n\nCurrent guidelines for lithium treatment in patients with BD recommend thyroid function studies prior to treatment, once or twice during the first 6 months of therapy, and every 6–12 months thereafter. Lithium is contraindicated with significant renal impairment, sodium depletion, dehydration, or significant cardiovascular disease. However, neither pretreatment hypothyroidism nor lithium‐induced hypothyroidism contraindicates lithium therapy, as it can be managed by thyroxine treatment 24.\n\nWhile alternative treatment options have emerged, including mood‐stabilizing anticonvulsants (lamotrigine, valproate, oxcarbazepine, and carbamazepine) and atypical antipsychotics (aripiprazole, olanzapine, risperidone, and quetiapine), less evidence exists about their risk for hypothyroidism, and less emphasis has been placed on thyroid testing in their product labeling (see Discussion).\n\nLarge‐scale administrative claims data provide the opportunity to obtain estimates of adverse medication effects in large populations across a range of geographical regions in “real‐world” health care settings, and often over long periods of exposure. Thus, such data capture a substantial amount of heterogeneity in disease severity and treatment response over the disease course, whereas most clinical trials enroll a homogeneous cohort, followed over relatively short time periods. Advantages of claims data, however, can be offset by their observational nature, and inconsistency in collection, coding and recording. As such, treatment biases and confounding factors require specific attention and have been addressed in our analyses 28, 29, 30.\n\nThe objective of this study was to determine the comparative risk of hypothyroidism with lithium monotherapy versus eight of the most commonly prescribed anticonvulsants and second‐generation antipsychotics used to treat patients with BD. The study is innovative in that it comprehensively utilizes medical claims data on over a million patients with BD in a competing risk survival analysis framework. It is also the first to compare all of the above‐mentioned therapies head to head in a single study.\n\nPatients and methods\nData source and sample selection\nPatient data were obtained from the MarketScan® Commercial Claims and Encounters Databases (Ann Arbor, MI, USA) provided by the Reagan‐Udall Foundation's Innovation in Medical Evidence Development and Surveillance (IMEDS) program 31. The IMEDS data include only de‐identified patient‐level information which fully adheres to Health Insurance Portability and Accountability Act (HIPAA) standards 32, 33. Data have been transformed to the Observational Medical Outcomes Partnership (OMOP) common data model version 4 34, in which different procedures and diagnoses are expressed using the SNOMED‐CT vocabulary. Drugs and treatments are coded based on the OMOP drug vocabulary, which is comprised of RxNorm for drugs and ingredients 35, and includes additional classification systems for higher level concept aggregation (e.g., analgesics). We analyzed data from 141,805,491 commercially insured individuals collected between 2003 and 2013 across the USA, to obtain 1,232,534 patients with BD. Data were collected in primary care and hospital care settings across nearly every US county. From the 1.2 million patients with BD, 24,574 patients (8,517 male and 16,057 female) aged 18–65 years met our inclusion criteria (Fig. 1).\n\nFigure 1 Study design and sample selection. We show the sample size and percentage of female patients at each junction point in our data staging. The final cohort of 24,574 samples is shown in green, along with subsets with >90 days and >182 days of monotherapy. BD = bipolar disorder.\n\nData staging\nThe database was first queried to identify the 1.2 million patients who had two or more bipolar diagnoses, followed by a second query to store to a database table each patient's sorted list of events. All records of conditions, visits, procedures, observations, and drug exposures were included. Using internally developed Python code, we then incrementally retrieved the >626 million event records, and, for each patient, two passes over the sorted event data were performed. The first pass verified that inclusion criteria were met, and determined the start of monotherapy, and whether, how, and when the exposure period ended. The second pass calculated drug exposures, pretreatment comorbidities, and thyroid testing information.\n\nInclusion criteria\nInclusion criteria were: (i) two or more diagnoses of BD at any time in the patient history; (ii) age at start of treatment ≥18 years; (iii) a minimum one year of no prior drug treatment for BD and no hypothyroid diagnosis or treatment; (iv) followed by monotherapy for BD and at least one thyroid test during monotherapy. Results are contrasted with cohort subsets on 3+ (n = 15,430) and 6+ (n = 10,594) months of monotherapy to account for patients with pre‐existing cases of hypothyroidism diagnosed shortly after treatment.\n\nExposure\nNine monotherapeutic exposures were considered: lithium carbonate (RxNorm ingredient: 42351), aripiprazole (89013), carbamazepine (2002), lamotrigine (28439), olanzapine (61381), oxcarbazepine (32624), quetiapine (51272), risperidone (35636), and valproate (40254). We required that drug exposures had no gaps of 30 days or longer to increase the likelihood that prescriptions were not only filled, but also continuously taken by the patients 36, 37.\n\nTime of follow‐up\nThe duration of observation ranged from 1 day to 3,255 days (8.9 years), with a mean of 269 days and median of 142 days. We report results up to four years from the start of monotherapy due to the paucity of longer term observations.\n\nMain outcome measures\nThe outcome was the cumulative incidence of clinically relevant hypothyroidism, as indicated by diagnosis codes (SNOMED: 40930008 and descendants) and filled hypothyroidism prescriptions: thyroxine (RxNorm: 10582 and descendants), desiccated thyroid (10572), triiodothyronine (10814) and thyroglobulin (10565), in the presence of the competing risk of ending monotherapy, adjusted for covariates. Note that the hypothyroidism hierarchy includes subclinical hypothyroidism.\n\nCompeting risk survival analysis\nOur competing risks were the occurrence of hypothyroidism versus ending monotherapy. Hypothyroidism was captured as the observation of any subcategory of hypothyroidism or prescription of thyroid medications. Ending monotherapy was defined as a ≥30‐day gap in treatment for a given one of our nine therapies, or the addition of one or more of the eight other therapies (polypharmacy). Treatment exposure was considered to start on the day the prescription was filled and continued for as many days as there were days’ supply. When prescriptions overlapped, the refill was added after the previous supply would have run out. Censored observations occurred if the data ended without the competing risks being observed, either because the patient left his/her provider, or the data ended in 2013. The censor time was taken as the last event observed for a given patient.\n\nFor a first (potentially biased) look at the data, we employed the counting process‐based non parametric estimation of the cumulative incidence function (CIF). This estimator makes no correction for covariates, but separates out the cumulative risk of hypothyroidism from the cumulative risk of ending monotherapy. For a given competing risk, the estimator is the cumulative sum over each time interval of the probability neither event occurs before time t (the Kaplan−Meier estimate where both competing risks are combined as an event, and the censored observations are treated as censored) multiplied by the fraction experiencing a given event type out of those still at risk at time t 38. Differences in CIFs between lithium and alternate therapies were calculated using Gray's test 39, the log‐rank test 40, and the Pepe and Mori test 41, as implemented in R by Pintilie 42.\n\nTo adjust for biases in treatment and observation, we employed the competing risks regression (CRR) approach of Fine and Gray 43, as implemented in the R package cmprsk (version 2.2‐7), taking the following approach to covariates.\n\nCovariates\nThe following covariates were examined for their effect on the CIF.\n\nTreatment: using lithium as the reference, binary dummy variables were created for the non‐lithium treatments.\n\n\nAge at treatment: accounts for the higher risk of hypothyroidism among older patients.\n\n\nSex: accounts for the higher risk of hypothyroidism among female patients.\n\n\nPatient visit days in the year preceding monotherapy: a proxy for engagement with the health care system before monotherapy.\n\n\nWhether thyroid testing was performed in the 14 days preceding monotherapy: accounts for observation bias—patients who tested positive for hypothyroidism were excluded since patients receiving lithium are more likely to be tested pretreatment than patients receiving other therapies.\n\n\nNonparametric thyroid testing rank during monotherapy: used to adjust for observation bias—hypothyroidism should not be diagnosed without a thyroid test, and not all treatments have comparable thyroid testing. We used the following SNOMED‐CT procedure concepts and their descendants to count thyroid tests: thyroid‐stimulating hormone measurement (61167004), thyroid hormone measurement (390780008), thyrotropin‐releasing hormone test (252219000), thyroid panel (35650009), and thyroid‐stimulating immunoglobulins measurement (104972000). To account for different observation times, covariates were calculated as follows. For each patient (p), we found the competition rank of p's number of thyroid tests among the smallest time interval centered around p's treatment time that included at least 50 patients, and normalized it to (0,1), with 1 being most frequent. While the post‐treatment thyroid testing rank covariate removes observation time from the covariate, thyroid testing due to standard monitoring for which we want to account remains confounded with thyroid testing ordered as a result of hypothyroidism symptomatology, for which we do not want to account post‐treatment.\n\n\nPretreatment prescriptions and comorbidities: in order to account for treatment biases and potential confounders with hypothyroidism risk, we create binary variables to indicate whether at least one prescription was filled for each of the following drug classes in the year before monotherapy, using the First Databank Enhanced Therapeutic Classification (FDB‐ETC) and Anatomical Therapeutic Chemical (ATC) vocabularies: analgesics (FDB‐ETC: 582), diuretics (FDB‐ETC: 248), opioids (ATC: N02A), pain (FDB‐ETC: 3079), and sedatives (FDB‐ETC: 541). We also use binary variables to indicate whether at least one diagnosis of any concept or descendant of the following occurred in the year before monotherapy, using the SNOMED‐CT vocabulary. Mental: attention‐deficit hyperactivity disorder (ADHD) (406506008), anxiety (48694002), BD (13746004), eating disorder (72366004), mental procedure (108310004), personality C (83890006), and psychosis (69322001). Other: autoimmune (85828009), cardiovascular (49601007), central nervous system (23853001), dermatological (95320005), drug dependence (191816009), endocrinopathy (362969004), hypertension (38341003), kidney (90708001), metabolic (75934005), musculoskeletal (928000), nervous system (118940003), pulmonary (19829001), seizure (128613002), or thyroidism (14304000). Note that we excluded hypothyroidism (40930008) and descendant codes from these categories. We also used a high‐level MedDRA vocabulary concept (10040978) to encompass 23 lower level sleep apnea SNOMED‐CT codes. We calculated p‐values using the R chisq.test procedure for the 2 × 9 table over the nine BD therapies to test whether the proportions were the same over all drugs.\n\n\n\n\nUsing CRR, a forward stepwise selection procedure was performed on the cohort, starting with a model that included sex, age, treatment, and thyroid testing rank, and incrementally added the next most significant variable in predicting hypothyroidism risk among the aforementioned covariates. To account for multiple testing of 30 covariates, we stopped when no variables achieved a significance of p < 1.67e‐3. A Wald test was employed for testing the overall significance of treatment as an eight‐level factor using the R ‘aod’ package, and Schoenfeld‐type residuals were examined for evidence of time‐varying covariates, as outlined by Scrucca et al. 44. The final resulting model was run a second time, without the thyroid testing rank covariate.\n\nResults\nSample\nOut of 141,805,491 patients, we identified 1,232,534 with at least two claims related to a BD diagnosis (Fig. 1). Almost 60% were female. Among the 1.2 million, 199,376 fulfilled our inclusion criteria of no drug treatment for BD and no diagnosis of hypothyroidism for at least one year prior to commencing monotherapy. A total of 45,550 of these patients were under the age of 18 years and were subsequently excluded. Of the remaining 153,826, 30.5% had a thyroid test before monotherapy, 40% ever, and 16% on or after commencing monotherapy. We retained these 16%, excluding 129,252 individuals who were not tested for thyroid abnormalities during monotherapy. In the remaining sample of 24,574 individuals, 65.3% were female, indicating a bias towards female patients being more likely to be tested for thyroid abnormalities.\n\nThe average age of the sample was 39.5 years (Table 1). Psychosis was present in 6.1% of the sample, drug dependence in 14.3%, anxiety disorders in 22.5%, and ADHD in 7.3%. At monotherapy commencement, 28.7% of patients received lamotrigine, 15.5% quetiapine, 14.8% lithium, 12.2% valproate, 12.1% aripiprazole, 6.2% risperidone, 5% olanzapine, 3.6% oxcarbazepine, and 2% carbamazepine. There were significant differences between the treatment groups regarding age (p = 1.80e‐4), sex (p = 8.60e‐141), and psychiatric comorbidities, such as psychosis (p = 8.20e‐232) and drug dependence (p = 1.86e‐68).\n\nTable 1 Cohort demographics by druga\n\n\n\tLITH\tARIP\tCBZ\tLTG\tOLAN\tOXC\tQUET\tRISP\tVPA\tTotal\tTreatment bias p‐value\tHypo‐thyroidism CRR p‐value\t\nn\t3,629\t2,964\t492\t7,056\t1,230\t890\t3,798\t1,518\t2,997\t24,574\t–\t–\t\nAge, years\t39.5\t39\t40.3\t39\t40.4\t39\t40.1\t39.4\t39.7\t39.5\t1.80E‐04\t\n6.91E‐10\n\t\nSex, female, %\t56.4\t72\t64.6\t74\t55.9\t70.4\t65.9\t60.4\t53.6\t65.4\t8.60E‐141\t\n3.93E‐07\n\t\nMedications (%)\t\nSedative\t30.8\t38.2\t35.2\t33.5\t38.5\t34.4\t44.4\t37.1\t34.8\t36.0\t5.09E‐37\t7.27E‐01\t\nAnalgesic\t39.1\t47.4\t48.4\t43.2\t45.1\t49.6\t51.8\t45.5\t46.5\t45.4\t3.19E‐28\t4.45E‐01\t\nOpioid\t24.1\t31.1\t32.9\t27\t30.1\t31.7\t35\t29.6\t28.9\t29.1\t1.04E‐25\t6.49E‐01\t\nPain\t24.1\t31.1\t32.9\t27\t30.1\t31.7\t35\t29.6\t28.9\t50.9\t1.04E‐25\t2.46E‐01\t\nDiuretic\t9.5\t12.9\t14.6\t11.7\t12.9\t13.8\t13.4\t13.6\t11.9\t12.1\t1.88E‐06\t8.55E‐01\t\nMental (%)\t\nPsychosis\t4.5\t8\t3.9\t2\t15.5\t2.9\t6.4\t21.6\t5\t6.1\t8.20E‐232\t5.05E‐01\t\nBipolar disorder\t71.1\t58.4\t67.7\t67.4\t53.7\t66.5\t54\t53.4\t68\t63.2\t2.26E‐95\t3.96E‐01\t\nMental procedure\t53.2\t56.9\t52.2\t61.9\t37.2\t62.6\t48.8\t52.7\t51.5\t54.7\t2.23E‐81\t1.79E‐01\t\nDrug dependence\t12.8\t13.7\t14.8\t9.6\t16.9\t13.3\t22\t15.5\t16.5\t14.3\t1.86E‐68\t2.45E‐01\t\nAnxiety\t18.6\t24.5\t20.1\t19.5\t27.2\t20.1\t29\t26.5\t21.4\t22.5\t1.43E‐39\t8.06E‐01\t\nEating disorder\t1\t2.1\t0.4\t1.8\t2\t1.3\t1.6\t1.8\t0.4\t1.5\t1.37E‐07\t4.25E‐01\t\nADHD\t6.1\t9.2\t7.1\t7.7\t6\t9\t6.5\t7\t7.2\t7.3\t1.58E‐05\t4.14E‐03\t\nPersonality C\t0.2\t0.3\t0.4\t0.1\t0.3\t0.1\t0.2\t0.3\t0.2\t0.2\t4.93E‐01\t8.24E‐01\t\nOther (%)\t\nCardiovascular\t31.5\t39.9\t37.4\t34.2\t38.7\t38\t42.9\t41\t40\t37.4\t1.42E‐30\t8.92E‐01\t\nCNS\t13.2\t16.7\t19.3\t14.5\t16.4\t20.1\t18.7\t19.3\t21.8\t16.8\t3.20E‐26\t7.73E‐02\t\nSeizure\t0.7\t0.9\t4.1\t1.6\t1.1\t4.2\t1.6\t2.1\t3.2\t1.7\t1.15E‐22\t6.32E‐01\t\nNervous system\t23.3\t28\t29.3\t24.4\t27.3\t31.3\t30.3\t28.3\t31.5\t27.2\t7.43E‐21\t3.72E‐01\t\nPulmonary\t5.3\t7\t7.7\t5\t8.7\t7.4\t9.5\t8.8\t7.1\t6.8\t3.76E‐20\t5.24E‐01\t\nHypertension\t17.9\t23.9\t21.1\t19\t22.8\t21.6\t25\t25.8\t22.6\t21.5\t4.52E‐20\t8.36E‐01\t\nMetabolic\t26.1\t33.8\t30.9\t28.5\t31.4\t29.6\t32.5\t31.4\t30.9\t30.1\t8.63E‐12\t2.96E‐01\t\nMusculoskeletal\t35.9\t42\t43.1\t40.3\t39.7\t39.6\t44.8\t40.7\t41\t40.7\t2.28E‐11\t3.14E‐01\t\nKidney\t3.2\t4.9\t4.7\t4.1\t4.9\t4.3\t5.7\t5.4\t4.9\t4.5\t2.15E‐05\t9.23E‐01\t\nEndrocrinopathy\t11.1\t15.6\t12.6\t12.5\t11.4\t12.1\t13\t13.6\t13.1\t12.8\t3.51E‐05\t9.26E‐01\t\nDermatological\t23.4\t27.8\t24.8\t27.4\t24.6\t26.9\t25.4\t25.5\t25.6\t26.0\t5.38E‐04\t8.77E‐01\t\nApnea\t6.1\t8.8\t6.1\t7.6\t5.8\t7.3\t6.8\t6.8\t7.1\t7.2\t9.77E‐04\t1.52E‐01\t\nAutoimmune\t1.2\t2.1\t1.6\t1.5\t1.5\t2.4\t2.2\t1.4\t1.7\t1.7\t5.78E‐03\t9.15E‐01\t\nThyroidism\t2.4\t3.2\t4.7\t2.8\t3\t2.6\t2.9\t3.9\t2.4\t2.9\t1.72E‐02\t\n6.37E‐06\n\t\nLITH = lithium; ARIP = aripiprazole; CBZ = carbamazepine; LTG = lamotrigine; OLAN = olanzapine; OXC = oxcarbazepine; QUET = quetiapine; RISP = risperidone; VPA = valproate; CRR = competing risks regression; ADHD = attention‐deficit hyperactivity disorder; CNS = central nervous system.\n\na For each drug we show the sample size, the age in years, and then the fraction that took various treatments and had various comorbidities in the year prior to monotherapy. Note that we excluded hypothyroidism codes from every category; thus, thyroidism would encompass all other thyroid conditions. The treatment bias p‐values come from chi‐squared tests comparing the proportions of treatment within each binary category, and an ANOVA F‐statistic for age. The hypothyroidism CRR p‐values show the significance of adding the variable in the model along with treatment, sex, pretreatment thyroidism, thyroid testing rank, and 14‐day pretreatment thyroid tested. Only the bold‐type variables in the rightmost column were significant in the full CRR model after multiple testing adjustment (p < 1.67e‐03), and thus were retained in the final model.\n\nJohn Wiley & Sons, LtdCompeting risk survival analysis\nHypothyroidism occurred in 7.5% of the sample (n = 1,850) and without bias correction, lithium appeared to have a higher risk for hypothyroidism than other therapies (Fig. 2A). The bias‐uncorrected difference between lithium and other treatment alternatives was significant in all three tests (p < 0.05) for all therapies except quetiapine and carbamazepine (Supplementary Table 1). The competing risk of ending monotherapy occurred in the majority of cases (73.1%, n = 17,954) (Fig. 2B). Censored data were present in 19.4% of the sample, including 38 deaths (n = 4,770). Not all drugs had the same risk of ending monotherapy: olanzapine had the highest risk, whereas lamotrigine had the lowest (Fig. 2B). Biases also existed in the number of thyroid tests administered per treatment group. Based on the moving average of the number of tests from the commencement of monotherapy by drug (Supplementary Fig. 1A), along with a linear fit calculating the slope (Supplementary Fig. 1B), we estimated that patients on lithium were administered thyroid tests 2.26–3.05 times as often as patients on the other drugs. Lithium also had the highest pretreatment thyroid testing frequency, patients on lithium being tested 2.2 times as often as those on the least tested therapy, lamotrigine (Supplementary Fig. 1A caption). We thus employed a regression framework to address these potential biases, along with pretreatment characteristics (Table 1).\n\nFigure 2 Cumulative incidence of hypothyroidism and ending monotherapy. We show the cumulative incidence function of (A) hypothyroidism and (B) ending monotherapy, calculated with the naïve non‐parametric counting process estimator (analogous to Kaplan−Meier), which separates out the risk of hypothyroidism from ending monotherapy. These curves represent the risk observed as the drugs are currently prescribed, without accounting for treatment and observation biases.\n\nCovariate selection and regression results\nBeing male (p = 3.93e‐7) and having a thyroid test in the 14 days preceding monotherapy (p = 2.69e‐7) were associated with fewer diagnoses of hypothyroidism. Conversely, hypothyroidism diagnoses increased with age at exposure (p = 6.91e‐10), thyroid testing rank during monotherapy (p = 2.79e‐87), and pretreatment thyroid disorders other than hypothyroidism (p = 6.37e‐6). Except for pretreatment thyroid disorders, these variables remained significant in subcohorts with >90 and >182 days of monotherapy (Table 2). All other covariates were not significant after multiple testing adjustment (p > 1.67E‐3) when they were included in the model (Table 1). Using a Wald test, the combined significance of non‐lithium treatment was p = 3.86e‐3, p = 6.22e‐3, and p = 3.61e‐3 at >0, >90, and >182 days, respectively. Adjusted for covariates, lithium had the highest risk for >0 days of monotherapy, closely followed by quetiapine (Fig. 3). When the patient population was restricted to >90 days of exposure, lithium non‐significantly improved over quetiapine (p = 0.506). The resampled four‐year cumulative risk of hypothyroidism ranged 1.39‐fold from 8.8% for lithium down to 6.3% for oxcarbazepine (Fig. 4), and the 95% confidence limits for the lithium CIFs overlapped with those of all of the other drugs (Supplementary Fig. 2). When adjusted for covariates, the competing risk of ending monotherapy remained biased. Lamotrigine had a significantly lower risk of ending monotherapy (p = 1.89e‐55) than alternative therapies, likely due to the longer time required to titrate lamotrigine to the initial target dose to reduce the risk of Stevens−Johnson syndrome (Supplementary Fig. 3, Supplementary Table 2). Results of the sex‐specific analyses corroborated the known increased risk of hypothyroidism in women (Supplementary Fig. 4). The Schoenfeld‐type residuals for the model covariates showed little evidence that the covariates were time‐varying (Supplementary Fig. 5).\n\nTable 2 Competing risk regression (CRR) model of hypothyroidism risk at >0 months, >3 months, and >6 months of monotherapya\n\n\n\tp‐value\tBeta coefficient\tStandard error\t\nCovariate\t>0\t>3\t>6\t>0\t>3\t>6\t>0\t>3\t>6\t\nTreatment (Wald)\t3.86E‐03\t6.22E‐03\t3.61E‐03\t–\t–\t–\t–\t–\t–\t\nAripiprazole\t7.39E‐03\t8.80E‐03\t2.44E‐03\t−2.37E‐01\t−3.63E‐01\t−5.98E‐01\t8.85E‐02\t1.39E‐01\t1.97E‐01\t\nCarbamazepine\t1.35E‐01\t6.14E‐02\t2.20E‐02\t−2.76E‐01\t−6.18E‐01\t−1.34E+00\t1.85E‐01\t3.30E‐01\t5.85E‐01\t\nLamotrigine\t1.47E‐03\t2.53E‐02\t3.48E‐02\t−2.27E‐01\t−2.26E‐01\t−2.70E‐01\t7.12E‐02\t1.01E‐01\t1.28E‐01\t\nOlanzapine\t1.11E‐02\t5.15E‐02\t2.47E‐02\t−3.24E‐01\t−4.02E‐01\t−6.84E‐01\t1.27E‐01\t2.06E‐01\t3.05E‐01\t\nOxcarbazepine\t1.51E‐02\t2.21E‐01\t4.50E‐01\t−3.41E‐01\t−2.42E‐01\t−1.79E‐01\t1.40E‐01\t1.97E‐01\t2.37E‐01\t\nQuetiapine\t4.16E‐01\t5.06E‐01\t8.51E‐01\t−6.36E‐02\t7.45E‐02\t2.68E‐02\t7.82E‐02\t1.12E‐01\t1.43E‐01\t\nRisperidone\t5.90E‐03\t3.88E‐01\t6.34E‐01\t−3.19E‐01\t−1.48E‐01\t−1.06E‐01\t1.16E‐01\t1.71E‐01\t2.22E‐01\t\nValproate\t8.96E‐03\t3.08E‐01\t4.41E‐01\t−2.32E‐01\t−1.29E‐01\t−1.25E‐01\t8.88E‐02\t1.27E‐01\t1.62E‐01\t\nAge at exposure\t6.91E‐10\t2.14E‐05\t1.12E‐04\t1.12E‐02\t1.10E‐02\t1.32E‐02\t1.81E‐03\t2.59E‐03\t3.41E‐03\t\nSex, male\t3.93E‐07\t9.79E‐05\t2.28E‐05\t−2.65E‐01\t−2.93E‐01\t−4.11E‐01\t5.23E‐02\t7.53E‐02\t9.70E‐02\t\nPre‐Tx thyroidism\t6.37E‐06\t8.50E‐02\t6.71E‐01\t4.68E‐01\t2.80E‐01\t9.73E‐02\t1.04E‐01\t1.63E‐01\t2.29E‐01\t\nPost‐Tx thyroid tests rank\t2.79E‐87\t3.25E‐53\t3.65E‐30\t2.88E+00\t3.13E+00\t2.84E+00\t1.46E‐01\t2.04E‐01\t2.49E‐01\t\nPre‐Tx thyroid tests 14 days\t2.69E‐07\t2.74E‐03\t9.58E‐03\t−4.16E‐01\t−4.05E‐01\t−5.06E‐01\t8.09E‐02\t1.35E‐01\t1.95E‐01\t\nTx = treatment.\n\na The final model includes six variables, with treatment coded as eight dummy variables with lithium as reference. The three treatment variable p‐values are the result of Wald tests that calculate the significance of the eight dummy variables combined. Results are contrasted with subcohorts on >3 and >6 months of monotherapy.\n\nJohn Wiley & Sons, LtdFigure 3 Cumulative incidence of hypothyroidism from competing risks regression (CRR): >0, >90, and >182 days after commencing monotherapy. We show the cumulative incidence function (CIF) of hypothyroidism from CRR at the average value of the covariates for the 24,574 bipolar disorder (BD) patient cohort. (A) includes all 24,574 patients with BD. We then exclude patients who experienced hypothyroidism, ended monotherapy, or were censored: (B) <90 days after commencing monotherapy (n = 15,313); and (C) <6 months after commencing monotherapy (n = 10,508). We set the covariates to the 24,574 patient cohort averages, and switch between setting the treatment covariates to 1 for each of the non‐lithium treatments, and then zero for all covariates to obtain the lithium CIF.\n\nFigure 4 Four‐year estimated risk of hypothyroidism by drug with 95% confidence limits. We contrast the 95% confidence limits of hypothyroidism risk at four years across drugs for >0 days of monotherapy, as estimated by resampling 10,000 times the competing risks regression predictions at the average values of the covariates, with model coefficients set to random normal values defined by the regression model coefficient means and standard errors (as seen in Table 2). The mean four‐year risks are as follows: lithium: 8.78%; quetiapine: 8.26%; lamotrigine: 7.06%; valproate: 7.02%; aripiprazole: 6.99%; carbamazepine: 6.73%; risperidone: 6.46%; olanzapine: 6.43%; oxcarbazepine: 6.32%. CIF = cumulative incidence function.\n\nWhen the final model was rerun, excluding the thyroid testing rank covariate, the Wald test of overall significance of treatment was, as expected, more significant: p = 2.69e‐6, p = 1.17e‐5, and p = 8.20e‐6 at >0, >90, and >182 days of monotherapy, respectively. This observation‐biased four‐year estimate for hypothyroidism risk ranged 1.54‐fold from 10.7% for lithium down to 7.0% for olanzapine.\n\nDiscussion\nThis is the first large‐scale comparison of all commonly prescribed mood stabilizers and atypical antipsychotics prescribed for the treatment of BD. Although lithium confers a significantly increased risk for hypothyroidism in patients with BD compared with the other therapies as a group, lithium risk was not significantly different from that of quetiapine. The predominant and clinically significant theme of this article is that there is a substantial risk of hypothyroidism developing during BD therapy, regardless of selected pharmacological intervention.\n\nIn addition to the longstanding literature on the risk of hypothyroidism under lithium treatment, there is an emerging literature demonstrating the risk of hypothyroidism associated with some, but not all, of the therapies we studied. We next summarize this evidence, first for mood stabilizers, and then for atypical antipsychotics.\n\nA large medical claims study on mood stabilizers in patients with BD found that lithium, carbamazepine and valproate increased hypothyroidism risk, and that a dose−response relationship existed between number of mood stabilizers and risk. Therefore, the authors recommended regular thyroid monitoring for mood stabilizers 45. The product labeling of the US Food and Drug Administration (FDA) for valproate reports altered thyroid function tests associated with valproate, but makes no thyroid testing recommendations 46. Other studies show that lithium and valproate alone or in combination confer additional risk 47, 48. Conversely, for the mood stabilizer lamotrigine, FDA labeling lists hypothyroidism as rare (<1 in 1000 patients) 49, and recent reviews found little to no evidence for an effect of lamotrigine on thyroid hormones 50, 51. Despite the overlapping characteristics, and shared pharmacology of BD and epilepsy 52, 53, 54, 55, we could only find literature on carbamazepine and oxcarbazepine associated with hypothyroidism in epilepsy, a disease in which the pathogenesis may involve thyroid hormones 56. Evidence from epilepsy studies shows adverse thyroid effects from valproate 51, 57, 58, 59, carbamazepine 51, 57, 59, and oxcarbazepine 51, 59. Having similar mechanisms of action, both carbamazepine and oxcarbazepine see a reduction in T4, but little impact on thyroid‐stimulating hormone (TSH), with the effects reversible with discontinuation of therapy 60. Carbamazepine FDA labeling mentions that thyroid function tests “have been reported to show decreased values with Tegretol administered alone” 61, and oxcarbazepine labeling mentions association of the drug with decreases in T4, without changes in T3 or TSH 62, but neither labeling recommends thyroid testing. The effects of oxcarbazepine and carbamazepine seem consistent with central hypothyroidism, via a disruption of the hypothalamic‐pituitary axis 63. We did not differentiate between primary and the rarer central hypothyroidism, whose incidence has been estimated at 1:80:000 to 1:120,000 in the general population 64.\n\nConsistent with our findings, among atypical antipsychotics, evidence of increased hypothyroidism risk has also accumulated for quetiapine 65, 66, 67, 68, 69, 70, 71. However, not all studies agreed. In some studies only changes in T4 were noticed, and not in TSH 72, 73, and in other studies the hormone changes were transient, returning to normal after only 6 weeks of treatment without discontinuation of quetiapine 74. A large, longitudinal, double‐blind clinical trial showed that a combination therapy of quetiapine plus lithium or divalproex had significantly increased hypothyroidism (p = 6.96e‐4) over placebo plus lithium or divalproex 75. Two cases of hypothyroidism with combination quetiapine and valproate were also reported in a Korean study 76. In 2013, FDA product labeling added a recommendation for thyroid hormone testing at baseline and at follow‐up for quetiapine 77. For olanzapine, we could find little information about thyroid effects, and for risperidone 67, 73 and aripiprazole 78, studies concluded that thyroid abnormalities did not occur with treatment, despite some case reports 79. FDA labeling also makes no mention of thyroid issues for these three drugs 80, 81, 82.\n\nOur study suggests that the relative perception of risk for lithium is overestimated by observation bias: lithium‐treated patients received thyroid tests more than twice as frequently as those on other therapies. Moreover, despite the link between hypothyroidism and BD, only 40% of patients received a thyroid test in the year before or during monotherapy. According to our study, hypothyroidism appears underdiagnosed for patients with BD in clinical settings, particularly on non‐lithium therapies, suggesting that increased testing may offer clinical benefits for this treatable disorder. Treatment of even subclinical hypothyroidism may improve outcomes among patients with BD 83. Subclinical hypothyroidism has been associated with treatment resistance and/or rapid cycling 84. Patients with abnormal TSH and/or free thyroxine index spend longer times in the acute treatment phase and have significantly higher mean Hamilton Scale for Depression scores during the maintenance phase 85. Also, elevated TSH has been identified in medication‐naïve patients with mixed mania during the first episode 86. Therefore, we recommend that all patients with BD be periodically assessed for thyroid function, independent of the medication they receive. Currently, only lithium and quetiapine carry testing recommendations in their FDA product labels 77, 87.\n\nOur results support the hypothesis that hypothyroidism occurs with increased frequency in patients with BD. Even in lithium‐naïve bipolar patients, increased hypothyroidism has been found compared to published population averages 88. Importantly, long‐term follow‐up indicates that the risk of hypothyroidism persists beyond the first year after treatment initiation, but does appear to eventually plateau for all treatments. In the case of lithium, this is consistent with a long‐term cross‐sectional study showing that patients with BD with 10–20 years of lithium exposure had the same thyroid function as patients with BD with > 20 years of exposure 89.\n\nSeveral explanations exist in the literature for the observation of hypothyroidism in patients with BD. While some researchers have proposed a causal link between lithium treatment and hypothyroidism 88, 90, 91, studies on autoimmune thyroiditis (a major cause of hypothyroidism) suggest that a compromised thyroid confers a greater risk of BD 92, and that lithium use confers no risk for autoimmune thyroiditis 27. Increased hypothyroidism in BD could have several explanations. On the one hand, imbalances of the thyroid metabolism could be linked to the pathophysiology of BD, either causally or through linked, potentially parallel mechanisms, influencing each other in a bidirectional way. On the other hand, hypothyroidism could be related to treatment, suggesting that commonly used medications for BD target a common signaling pathway shared with thyroid metabolism. The therapeutic effect of these medications could lead to thyroid abnormalities as an unintended adverse effect. A third explanation would suggest that hypothyroidism occurs independently and is not related to BD risk. It may be detected in patients with BD at a higher rate because of increased testing. Our analysis cannot distinguish between these not necessarily exclusive explanations; however, our observation clearly challenges the assumption of lithium treatment as the only cause of hypothyroidism in patients with BD.\n\nAlthough the analyses presented here diligently employed statistical methodologies to account for treatment biases and potential confounding factors, such studies face certain challenges. For example, the use of administrative claims data entails a retrospective study design in which patients were neither randomized to treatment nor examined directly during a defined observational period. Consequently, hypothyroidism could be underestimated if patient symptoms went unreported, or their provider did not perform thyroid testing. Because the reported risk estimates are calculated at the average value of the covariates, including thyroid testing, which is low in our population, our risk estimates may be low. While every attempt was made to correct for thyroid testing observation bias with our CRR model, we recognize that we could not disentangle increased thyroid testing due to treatment guidelines from that due to symptoms of hypothyroidism. Nevertheless, even when we exclude the thyroid testing rank covariate, the lithium hypothyroidism risk estimate increases only modestly to 1.54 times the lowest risk therapy, compared to a 1.39‐fold range in the model that corrects for tests. Nevertheless, our corroboration of not only lithium, but also age and sex as known risk factors for hypothyroidism in patients with BD 19, 93, 94 demonstrates that our population is representative of earlier studies of hypothyroidism in BD.\n\nResults presented here demonstrate a modest (statistically significant) effect of lithium on hypothyroidism in BD, compared to alternate therapies. Estimates on the four‐year cumulative hypothyroidism incidence for lithium ranged from 1.06‐fold higher than quetiapine up to 1.39‐fold higher than oxcarbazepine. These results differ from those of a case−control meta‐analysis suggesting a 5.78‐fold increased risk of hypothyroidism over placebo 23. However, the stark differences may be explained by the fact that only lithium treatment was the focus in those and other analyses 94, whereas our results directly compared lithium with other therapies that may also carry hypothyroidism risk. Another study comparing lithium with other therapies did not account for biases in thyroid testing 45.\n\nSince the results presented here were obtained in ‘real world’ settings, and in a sample representing much of the privately insured population of the USA, we propose that our findings are highly representative, are generalizable, and have external validity.\n\nConclusions\nThyroid abnormalities occur with high frequency in patients with BD regardless of treatment. Therefore, (i) patients should be regularly tested for clinical or subclinical thyroid abnormalities on all therapies and treated as indicated to prevent adverse effects of hormone imbalances on mood; and (ii) since hypothyroidism occurs under all treatments, we suggest that more emphasis should be placed on understanding the role of thyroid disorders in BD. It remains for future work to investigate hypothyroidism risk in untreated patients and patients on polypharmacy.\n\nAuthor contributions\nStudy concept and design: CGL, BK, AJM, NGH, DJP, NWH, SSY and RLO. Acquisition, analysis, or interpretation of data: CGL, AJM, NRL, NWH and BK. Drafting of the manuscript: CGL and BK. Critical revision of the manuscript for important intellectual content: CGL, BK, DJP, NGH, SSY, AJM, RLO, NWH, NRL and MT. Statistical analysis: CGL, NWH, NRL and SSY. Obtained funding to cover cloud computing costs: CGL and AJM. Administrative, technical, or material support: DJP.\n\nDisclosures\nMT was a full‐time employee at Lilly (1997 to 2008). He has received honoraria from, or consulted for, Abbott, Actavis, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Johnson & Johnson, Otsuka, Merck, Sunovion, Forest, Gedeon Richter, Roche, Elan, Alkermes, Allergan, Lundbeck, Teva, Pamlab, Wyeth and Wiley Publishing. His spouse was a full‐time employee at Lilly (1998–2013). CGL and AJM received funding from the Reagan‐Udall Foundation for the FDA for cloud computing costs for the project (project RUF‐IMEDS‐SA_0010). The Reagan‐Udall foundation for the FDA provided access to the data used for the study, which is licensed from third parties. They provide a computational framework and resources for methods development and analysis. The funding agency had no role in the design and conduct of the study; analysis and interpretation of the data; preparation, review, and approval of the manuscript; or decision to submit the manuscript for publication.\n\nSupporting information\n\nTable S1. Significance of lithium vs. alternate therapies without bias correction.\n\n\nTable S2. Competing risk regression (CRR) model of risk of ending monotherapy after >0 months, >3 months, and >6 months of monotherapy.\n\n\nFig. S1. Moving average of thyroid tests as a function of exposure time and treatment.\n\n\nFig. S2. Cumulative incidence of hypothyroidism confidence limits.\n\n\nFig. S3. Cumulative incidence of ending monotherapy from CRR: >0, >90, and >182 days after commencing monotherapy.\n\n\nFig. S4. Cumulative incidence of hypothyroidism by sex from CRR: >0, >90, and >182 days after commencing monotherapy.\n\n\nFig. S5. Schoenfeld‐type residuals for model covariates.\n\nClick here for additional data file.\n\n Acknowledgements\nWe would like to thank two anonymous referees for their helpful suggestions.\n==== Refs\nReferences\n1 \nAmerican Psychiatric Association \n. Diagnostic and Statistical Manual of Mental Disorders, (DSM‐5®) [Internet]. American Psychiatric Pub , 2013 Available from: http://dx.doi.org/10.1176/appi.books.9780890425596 [accessed April 2015].\n2 \n\nKessler \nRC \n, \nChiu \nWT \n, \nDemler \nO \n, \nMerikangas \nKR \n, \nWalters \nEE \n. Prevalence, severity, and comorbidity of 12‐month DSM‐IV disorders in the National Comorbidity Survey Replication . 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J Child Adolesc Psychopharmacol \n2014 ; 24 : 325 –335 .24956042 \n72 \n\nDelbello \nMP \n, \nSchwiers \nML \n, \nRosenberg \nHL \n, \nStrakowski \nSM \n. A double‐blind, randomized, placebo‐controlled study of quetiapine as adjunctive treatment for adolescent mania . J Am Acad Child Adolesc Psychiatry \n2002 ; 41 : 1216 –1223 .12364843 \n73 \n\nKelly \nDL \n, \nConley \nRR \n. Thyroid function in treatment‐resistant schizophrenia patients treated with quetiapine, risperidone, or fluphenazine . J Clin Psychiatry \n2005 ; 66 : 80 –84 .15669892 \n74 \n\nKontaxakis \nVP \n, \nKaraiskos \nD \n, \nHavaki‐Kontaxaki \nBJ \n, \nFerentinos \nP \n, \nPapadimitriou \nGN \n. Can quetiapine‐induced hypothyroidism be reversible without quetiapine discontinuation? \nClin Neuropharmacol \n2009 ; 32 : 295 –296 .19820433 \n75 \n\nSuppes \nT \n, \nVieta \nE \n, \nLiu \nS \n, \nBrecher \nM \n, \nPaulsson \nB \n; Trial 127 Investigators \n. 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Lithium‐induced subclinical hypothyroidism: review of the literature and guidelines for treatment . J Clin Psychiatry \n1999 ; 60 : 249 –255 .10221287 \n85 \n\nFagiolini \nA \n, \nKupfer \nDJ \n, \nScott \nJ \n et al. Hypothyroidism in patients with bipolar I disorder treated primarily with lithium . Epidemiol Psichiatr Soc \n2006 ; 15 : 123 –127 .16865933 \n86 \n\nZarate \nCA \n, \nTohen \nM \n, \nZarate \nSB \n. Thyroid function tests in first‐episode bipolar disorder manic and mixed types . Biol Psychiatry \n1997 ; 42 : 302 –304 .9270910 \n87 \nLithobid® \n[package insert] [Internet]. Noven Therapeutics, LLC, \n2011 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018027s056lbl.pdf [accessed January 2016].\n88 \n\nValle \nJ \n, \nAyuso‐Gutierrez \nJL \n, \nAbril \nA \n, \nAyuso‐Mateos \nJL \n. Evaluation of thyroid function in lithium‐naive bipolar patients . 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Gender differences in thyroid system function: relevance to bipolar disorder and its treatment . Bipolar Disord \n2014 ; 16 : 58 –71 .24245529 \n94 \n\nShine \nB \n, \nMcKnight \nRF \n, \nLeaver \nL \n, \nGeddes \nJR \n. Long‐term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data . Lancet \n2015 ; 386 : 461 –468 .26003379\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1398-5647",
"issue": "18(3)",
"journal": "Bipolar disorders",
"keywords": "anticonvulsants; antipsychotics; bipolar disorder; competing risks; hypothyroidism; lithium",
"medline_ta": "Bipolar Disord",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007037:Hypothyroidism; D018020:Lithium Compounds; D008297:Male; D012306:Risk; D016019:Survival Analysis",
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"pages": "247-60",
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"pubdate": "2016-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "24956042;17388706;10572366;19934393;9270910;26417756;6019331;17555817;19958039;10807488;4194439;25359625;22265699;13212414;758817;1774419;23774517;25670757;19289454;15939839;4103395;8516591;21824562;19820433;19942149;19538689;24916006;16051025;26339294;18415684;10221287;4916293;17042835;16307266;17141745;16259552;26362394;23051081;20565432;20152550;10772436;15669892;23946049;22618302;10789300;26003379;16504798;18237359;11958781;18655520;24245529;21596216;21847264;16565629;27226264;16865933;26437373;20614417;16633154;26316422;12364843;11944505;4896983;4107030;15645000;20062101;9827658;24551421;5065279;15305188;16199826;17016877",
"title": "Hypothyroidism risk compared among nine common bipolar disorder therapies in a large US cohort.",
"title_normalized": "hypothyroidism risk compared among nine common bipolar disorder therapies in a large us cohort"
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"abstract": "BACKGROUND\nPanitumumab is an EGFR inhibitor used for the treatment of metastatic colorectal cancer (mCRC), even if its use is related to skin toxicity.\n\n\nMETHODS\nWe report the development of forearm panniculitis in two women during the treatment with Panitumumab (6 mg/Kg intravenous every 2 weeks) + FOLFOX-6 (leucovorin, 5- fluorouracil, and oxaliplatin at higher dosage) for the treatment of mCRC.\n\n\nRESULTS\nIn both patients, clinical, laboratory and radiological evaluation documented the presence of a local panniculitis, probably related to panitumumab (Naranjo score: 6). Panatimumab discontinuation and antimicrobial + corticosteroid treatment induced a remission of skin manifestations.\n\n\nCONCLUSIONS\nWe reported for the first time the development of panniculitis during Panitumumab treatment, and we documented that the treatment with beta-lactams to either fluoroquinolones or oxazolidinone in the presence of corticosteroid improves clinical symptoms in young patients with mCRC, without the development of adverse drug reactions or drug-drug interactions.",
"affiliations": "Department of Medical Science, Oncology and Elderly Operative Units, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy.;Department of Medical Science, Oncology and Elderly Operative Units, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy.;Department of Medical Science, Oncology and Elderly Operative Units, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy.;Department of Medical Science, Oncology and Elderly Operative Units, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy.;Department of Medical Science, Oncology and Elderly Operative Units, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy.;Department of Medical Science, Oncology and Elderly Operative Units, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy.;Department of Experimental Medicine, University Vanvitelli of Naples, Naples, Italy.;Department of Health Sciences, Clinical Pharmacology and Pharmacovigilance Unit, MaterDomini Hospital, University of Catanzaro, Catanzaro, Italy.",
"authors": "Domenico|Ciliberto|C|;Antonella|Ierardi|I|;Benedetto|Caroleo|C|;Luigi|Scalise|S|;Antonio|Cimellaro|C|;Lidia|Colangelo|C|;Giuseppe|Spaziano|S|;Gallelli|Luca|L|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077544:Panitumumab; D002955:Leucovorin; D005472:Fluorouracil",
"country": "United Arab Emirates",
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"doi": "10.2174/1574886314666190522094713",
"fulltext": "\n==== Front\nCurr Drug SafCurr Drug SafCDSCurrent Drug Safety1574-88632212-3911Bentham Science Publishers CDS-14-23310.2174/1574886314666190522094713ArticlePanitumumab Induced Forearm Panniculitis in Two Women With Metastatic Colon Cancer Domenico Ciliberto 1Antonella Ierardi 1Benedetto Caroleo 1Luigi Scalise 1Antonio Cimellaro 1Lidia Colangelo 1Giuseppe Spaziano 2Gallelli Luca 3*1Department of Medical Science, Oncology and Elderly Operative Units, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy;\n\n\n2Department of Experimental Medicine, University Vanvitelli of Naples, Naples, Italy;\n\n\n3Department of Health Sciences, Clinical Pharmacology and Pharmacovigilance Unit, MaterDomini Hospital, University of Catanzaro, Catanzaro, Italy* Address correspondence to this author at the Department of Health Sciences, Clinical Pharmacology and Pharmacovigilance Operative Unit, MaterDomini Hospital, University of Catanzaro, Via T Campanella 115 - 88100 Catanzaro, Italy; Tel: +390961712322; Fax +390961774424; E-mail: gallelli@unicz.it11 2019 11 2019 14 3 233 237 04 3 2019 30 4 2019 01 5 2019 © 2019 Bentham Science Publishers2019 This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.Background:\nPanitumumab is an EGFR inhibitor used for the treatment of metastatic colorectal cancer (mCRC), even if its use is related to skin toxicity.\n\nCase Presentation:\nWe report the development of forearm panniculitis in two women during the treatment with Panitumumab (6 mg/Kg intravenous every 2 weeks) + FOLFOX-6 (leucovorin, 5-fluorouracil, and oxaliplatin at higher dosage) for the treatment of mCRC.\n\nResults:\nIn both patients, clinical, laboratory and radiological evaluation documented the presence of a local panniculitis, probably related to panitumumab (Naranjo score: 6). Panatimumab discontinuation and antimicrobial + corticosteroid treatment induced a remission of skin manifestations.\n\nConclusion:\nWe reported for the first time the development of panniculitis during Panitumumab treatment, and we documented that the treatment with beta-lactams to either fluoroquinolones or oxazolidinone in the presence of corticosteroid improves clinical symptoms in young patients with mCRC, without the development of adverse drug reactions or drug-drug interactions.\n\nKeywords\nPanitumumabpanniculitisadverse drug reactionEGFRmCRCFOLFOX\n==== Body\n1 INTRODUCTION\nDermatologic toxicities represent a relevant problem during each drug treatment and it significantly impact the patients’ quality of life (QoL), reducing compliance and clinical outcomes [1-3].\n\nSkin toxicities are commonly described during the treatment with the epidermal growth factor receptor (EGFR) inhibitors. Panitumumab is an EGFR inhibitor used for treatment of metastatic colorectal cancer (mCRC).\n\nIn particular, the administration of Panitumumab to FOLFOX (leucovorin 200 mg/m2 IV infusion, 5-fluorouracil 600 mg/m2 IV infusion and oxaliplatin 85 mg/m2 IV infusion) or FOLFOX4 (FOLFOX + 5-fluorouracil 400 mg/m2 bolus), or FOLFOX6 (FOLFOX4 at higher dosage) as first-line treatment for both RAS (rat sarcoma viral oncogene homolog) wild-type or KRAS (Kirsten rat sarcoma viral oncogene homolog) mCRC significantly improved overall survival compared to FOLFOX alone [4] and to FOLFOX plus bevacizumab [5]. Unfortunately, the development of skin rash, papules and pustules in the face, scalp, and trunk, typically with or without pain have been described within the first 3 weeks of treatment with EGFR inhibitors [6-8], although these adverse drug reactions could be an indicator of a biological effect [8]. Herein, we report two patients that developed severe panniculitis during panitumumab treatment successfully treated with empirical antibiotic therapy + corticosteroid.\n\n2 CASE REPORTS\n2.1 Case 1\nA 44-year-old woman, with a clinical history of descending colon cancer (stage IV) with liver and peritoneal metastases, received an anticancer treatment with FOLFOX-6 + Panitumumab (standard dosage: 6 mg/Kg intravenous every 2 weeks) from April 2017 up to November 2017 and then with 5-Fluorouracil + Panitumumab until May 2018.\n\nIn May 2018, the patient presented fever (39°C) and severe inflammation on left forearm (Fig. 1). Clinical evaluation revealed the presence of edema, rubor and sever pain (VAS score 8/10) on left forearm, while laboratory test showed a significant increase in both neutrophil cells count (25,500 cell/mmc; normal range 2,500-7,700) and procalcitonin (PCT 5.79 ng/ml; normal range < 0.5 ng/mL), while blood culture failed to detect infections in the bloodstream. Forearm ultrasound documented an area with blurred margins of thickening and with marked structural disruption of the subcutaneous adipose panniculus confirmed by Magnetic Resonance Imaging (MRI), that also showed an edema of both subcutaneous adipose matrix and fibrous septa on the whole forearm on the ulnar side without involvement of the underlying muscle (Figs. 2 and 3). A diagnosis of panniculitis was postulated and Naranjo probability scale, [9] documented a possible association between Panitumumab and panniculitis (score 6).\n\nPanitumumab was dismissed and an empirical antibiotic treatment with Linezolid (600 mg bid) and Ceftriaxone (1 gr bid) plus a corticosteroid (betamethasone, 2 mg bid) was started with an improvement of clinical symptoms in 3 days (fever 36.5°C, PCT <0.5 ng/mL). Betamethasone was dismissed and about 3 days later a new clinical and laboratory evaluation documented a neutrophilic leukocytosis (16,000 cell/mmc), therefore ceftriaxone was discontinued, meropenem (2 gr tid) was started for 10 days and then linezolid was changed to tedizolid (200 mg/day) with a complete remission of both clinical symptoms and radiological signs in about 2 months and without the development of adverse drug reactions or drug-drug interactions.\n\nAbout 1 month later, Panitumumab was added again in the treatment and a new follow-up on January 2019 did not show any further adverse drug reactions.\n\n2.2 Case 2\nA 49-year-old woman, with a clinical history of descending colon cancer (stage IV) with liver metastases, on April 2018 started a treatment with FOLFOX-6 + P and 1 month later (after the second administration of P) she developed a skin rash on the face that induced about 2 months later (fifth administration of P) the discontinuation of the biological drug (P). On June 2018, the patient developed panniculitis on the left forearm with oleocranic bursitis. Clinical evaluation revealed the absence of fever (36.5°C), while laboratory findings were in normal range (neutrophil 6,000 cell/mmc; normal range 2,500-7,700; PCT <0.5 ng/mL). Naranjo probability scale, [9] documented a possible association between Panitumumab and forearm disease (score 6), therefore an empirical antibiotic treatment with Ceftriaxone (1 gr bid) and ciprofloxacin (500 mg bid) plus a corticosteroid (methylprednisolone, 4 mg/day for 4 days) was started with a complete improvement of signs and symptoms in 2 weeks and without the development of adverse drug reactions or drug-drug interactions (Fig. 4).\n\n3 DISCUSSION\nIn this study, we reported the development of panniculitis in two women with metastatic colorectal cancer. Previously, several authors reported that many factors (e.g. drugs, allergy, bit of animals, parasites) are able to induce skin manifestations [10-14]. In our cases, clinical history suggested that probably Panitumumab could play a role in these skin manifestations.\n\nBergman et al. [15], in a retrospective study, documented that 32 of 34 patients treated with panitumumab developed a skin rash that required an antimicrobial treatment documenting an association between drug and adverse drug reaction.\n\nEven if the specific mechanism of skin toxicity related to EGFR inhibitors has not been well demonstrated, some authors suggested that it could be related to the inhibition of EGFR in the basal lamina that induces a local inflammation, with the release of chemokines and leukocyte recruitment leading to keratinocyte apoptosis and skin damage [16, 17].\n\nIn an experimental study Liu et al. [18], documented that erlotinib hydrochloride induced skin toxicity proceeding from skin irritation to scleroderma and it was related to the inhibition of dermal EGFR with the development of skin inflammation and release of secondary inflammatory mediators (e.g. IL-10, IL-2, IL-6, TNF-α, and IL12A) prompting to skin toxicity.\n\nIn agreement with our previous studies [19-22], using the Naranjo probability scale, we documented a possible association between severe panniculitis and panitumumab in two women with mCRC (Naranjo score 6) that required a treatment with corticosteroids and empirical antimicrobial drugs.\n\nUsually, the management of skin manifestations during EGFR inhibitors treatment is not fully standardized, however several recommendations based on small studies or case reports suggest a treatment with hydrocortisone 1% plus doxycycline (100 mg), twice a day, for the first 6 weeks (level II evidence) [23-25].\n\nIn contrast, in the present study considering the clinical characteristics of the patients (metastatic cancer and immune depression), we did not use tetracycline + topical corticosteroid but we preferred a more aggressive treatment with systemic corticosteroid + linezolid/ceftriaxone in a patient and systemic corticosteroid + ceftriaxone/ciprofloxacin in another patient with an improvement of symptoms.\n\nThis study has some limitations that are related to the type of the study (case report) and also the absence of skin biopsy.\n\nHowever, it confirms that the development of skin toxicity represents a relevant problem during the treatment with EGFR inhibitors and that a treatment with corticosteroid and antimicrobials is able to improve clinical symptoms. In our institution, recently, we performed a study able to identify polymorphic variants associated with erlotinib-related skin toxicity that could be used to predict this severe adverse event in patients treated with anti-EGFR agents [26].\n\nCONCLUSION\nIn conclusion, we reported for the first time the development of panniculitis during the treatment with Panitumumab and we documented that beta-lactams with fluoroquinolones or with oxazolidinone may be useful to improve symptoms in young patients with mCRC without the development of adverse drug reactions or drug interactions.\n\nACKNOWLEDGEMENTS\nAll authors looked after the patient and wrote the report.\n\nETHICS APPROVAL AND CONSENT TO PARTICIPATE\nNot Applicable.\n\nHUMAN AND ANIMAL RIGHTS\nNot applicable.\n\nCONSENT FOR PUBLICATION\nWritten informed consent was obtained from both patients for this study.\n\nSTANDARD FOR REPORTING\nThe CARE guidelines and methodologies were followed in this study.\n\nFUNDING\nNone.\n\nCONFLICT OF INTEREST\nThe authors declare no conflict of interest, financial or otherwise.\n\nFig. (1) Panniculitis in the first woman at the admission. It is possible to see the presence of a large area of erythema and lymphangitis.\n\nFig. (2) Ultrasound of the forearm: it is possible to note inhomogeneity of the sub-cutis with tissue edema and marked structural disruption of the subcutaneous adipose panniculus.\n\nFig. (3) Magnetic resonance: thickened of sub-cutis and structural disruption of the subcutaneous adipose panniculus.\n\nFig. (4) Panniculitis in the second woman at the admission. It is possible to see the large area of erythema and olecranon bursitis at admission.\n==== Refs\nREFERENCES\n1 Ra H.S. Shin S.J. Kim J.H. Lim H. Cho B.C. Roh M.R. The impact of dermatological toxicities of anti-cancer therapy on the dermatological quality of life of cancer patients. J. Eur. Acad. Dermatol. Venereol. 2013 27 1 e53 e59 22329482 \n2 Rosen A.C. Case E.C. Dusza S.W. Impact of dermatologic adverse events on quality of life in 283 cancer patients: A questionnaire study in a dermatology referral clinic. Am. J. Clin. Dermatol. 2013 14 4 327 333 23625802 \n3 Thaler J. Karthaus M. Mineur L. Skin toxicity and quality of life in patients with metastatic colorectal cancer during first-line panitumumab plus FOLFIRI treatment in a single-arm phase II study. BMC Cancer 2012 12 438 23020584 \n4 Douillard J.Y. Oliner K.S. Siena S. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N. Engl. J. Med. 2013 369 11 1023 1034 24024839 \n5 Schwartzberg L.S. Rivera F. Karthaus M. PEAK: A randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J. Clin. Oncol. 2014 32 21 2240 2247 24687833 \n6 Li T. Perez-Soler R. Skin toxicities associated with epidermal growth factor receptor inhibitors. Target. Oncol. 2009 4 2 107 119 19452131 \n7 Tan E.H. Chan A. Evidence-based treatment options for the management of skin toxicities associated with epidermal growth factor receptor inhibitors. Ann. Pharmacother. 2009 43 10 1658 1666 19755624 \n8 Perez-Soler R. Chachoua A. Hammond L.A. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J. Clin. Oncol. 2004 22 3238 3247 15310767 \n9 Naranjo C.A. Busto U. Sellers E.M. A method for estimating the probability of adverse drug reactions. Clin. Pharmacol. Ther. 1981 30 2 239 245 7249508 \n10 Mumoli L. Gambardella A. Labate A. Rosacea-like facial rash related to metformin administration in a young woman. BMC Pharmacol. Toxicol. 2014 15 3 24507578 \n11 Succurro E. Ruffo M. De Sarro G. Gallelli L. Arturi F. Bilateral lower limbs edema with “wooden” character induced by insulin glargine treatment. Acta Diabetol. 2015 52 4 809 811 25563477 \n12 Misago N. Inoue T. Narisawa Y. Delayed reaction after an octopus bite showing a giant cell-rich granulomatous dermatitis/panniculitis. J. Cutan. Pathol. 2008 35 11 1068 1072 18544063 \n13 Vasapollo P. Cione E. Luciani F. Gallelli L. Generalized intense pruritus during Canagliflozin treatment: Is it an adverse drug reaction? Curr. Drug Saf. 2018 13 1 38 40 27048192 \n14 Gallelli L. Ferraro M. Mauro G.F. De Sarro G. Generalized exfoliative dermatitis induced by interferon alfa. Ann. Pharmacother. 2004 38 12 2173 2174 15522975 \n15 Bergman H. Walton T. Del Bel R. Managing skin toxicities related to panitumumab. J. Am. Acad. Dermatol. 2014 71 4 754 759 25085331 \n16 Holcmann M. Sibilia M. Mechanisms underlying skin disorders induced by EGFR inhibitors. Mol. Cell. Oncol. 2015 2 4 e1004969 27308503 \n17 Reck M. Gutzmer R. Management of the cutaneous side effects of therapeutic epidermal growth factor receptor inhibition. Onkologie 2010 33 8-9 470 479 20838065 \n18 Liu Y. Jiang X. Gu Y. Chen Y. Preventive effect of Diallyl Trisulfide on cutaneous toxicities induced by EGFR inhibitor. Int. Immunopharmacol. 2019 69 79 87 30682720 \n19 Gallelli L. Ferreri G. Colosimo M. Retrospective analysis of adverse drug reactions to bronchodilators observed in two pulmonary divisions of Catanzaro, Italy. Pharm. Res. 2003 47 493 499 \n20 Gallelli L. Siniscalchi A. Palleria C. Adverse Drug Reactions Related to drug administration in hospitalized patients. Curr. Drug Saf. 2017 12 3 171 177 28625147 \n21 Caroleo B Staltari O Gallelli L Perticone F Reactivation of chronic hepatitis B during treatment with tenofovir disoproxil fumarate: Drug interactions or low adherence? BMJ Case Reports 2015 \n22 Gallelli L. Staltari O. Palleria C. De Sarro G. Ferraro M. Hepatotoxicity induced by methimazole in a previously health patient. Curr. Drug Saf. 2009 4 204 206 19534646 \n23 Lacouture M.E. Anadkat M.J. Bensadoun R.J. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support. Care Cancer 2011 19 8 1079 1095 21630130 \n24 Balagula Y. Garbe C. Myskowski P.L. Clinical presentation and management of dermatological toxicities of epidermal growth factor receptor inhibitors. Int. J. Dermatol. 2011 50 2 129 146 21244375 \n25 Perez-Soler R. Delord J.P. Halpern A. HER1/EGFR inhibitor-associated rash: Future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. Oncologist 2005 10 345 356 15851793 \n26 Arbitrio M. Di Martino M.T. Barbieri V. Identification of polymorphic variants associated with erlotinib-related skin toxicity in advanced non-small cell lung cancer patients by DMET microarray analysis. Cancer Chemother. Pharmacol. 2016 77 205 209 26607259\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1574-8863",
"issue": "14(3)",
"journal": "Current drug safety",
"keywords": "EGFR; FOLFOX; Panitumumab; adverse drug reaction; mCRC; panniculitis.",
"medline_ta": "Curr Drug Saf",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D044683:Colon, Descending; D003110:Colonic Neoplasms; D005260:Female; D005472:Fluorouracil; D005542:Forearm; D006801:Humans; D002955:Leucovorin; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077544:Panitumumab; D015434:Panniculitis",
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"title": "Panitumumab Induced Forearm Panniculitis in Two Women With Metastatic Colon Cancer.",
"title_normalized": "panitumumab induced forearm panniculitis in two women with metastatic colon cancer"
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"abstract": "Acute generalized exanthematous pustulosis (AGEP) is a rare, drug-related pustular eruption usually starting from folds with edema and erythema and with subsequent spreading. Clinically AGEP is characterized by the sudden appearance of dozen of sterile, non follicular, small pustules on erythematous and edematous skin. Mild non erosive mucosal involvement, mostly oral, may sometimes occur. Fever, neutrophilia and peripheral blood eosinophilia (in a third of patients) are present. Other skin signs such as facial edema, purpura, target-like lesions and blisters have been described but are not typical for AGEP. Diagnostic criteria for AGEP were established by an international committee of experts, the European Study of Severe Cutaneous Adverse Reactions (EuroSCAR). The most relevant histopathological feature is represented by the detection of non-follicular subcorneal and/or intracorneal spongiform pustules that are usually large, contiguous and tend to coalesce. After elimination of the causative drug, pustules usually spontaneously disappear in a few days with desquamation and the reaction fully resolves within 15 days. Internal organs are not usually involved and no systemic treatment is required. Withdrawal of the culprit drug is mandatory. Although AGEP is a self-limiting disease with a favourable prognosis, secondary infections are a not infrequent complication in patients in poor general medical conditions. The reported mortality is about 5%. The most severe cases are associated with drug rechallenge.",
"affiliations": "Dermatology Unit, Department of Clinical‑Surgical Diagnostic and Pediatric Sciences, University of Pavia Policlinico San Matteo IRCCS Foundation, Pavia, Italy - vassallo@yahoo.com.",
"authors": "Vassallo|C|C|;Derlino|F|F|;Brazzelli|V|V|;D'Ospina|R D|RD|;Borroni|G|G|",
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"medline_ta": "G Ital Dermatol Venereol",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000368:Aged; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D000959:Antihypertensive Agents; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies",
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"title": "Acute generalized exanthematous pustulosis: report of five cases and systematic review of clinical and histopathological findings.",
"title_normalized": "acute generalized exanthematous pustulosis report of five cases and systematic review of clinical and histopathological findings"
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"abstract": "Renal toxicity has been described with tramadol overdoses; however, it is typically associated with rhabdomyolysis, multiorgan failure and/or mortality. Our patient was a 16-year-old female who was evaluated following an intentional tramadol ingestion, estimated 27.8 to 37 mg/kg, and had a seizure prior to arriving at our health care facility. Her symptoms were consistent with a tramadol ingestion; however, she developed transient acute renal impairment (peak serum creatinine, 4.04 mg/dL), which improved over 6 days with minimal intervention. No other causes were identified to explain her acute renal impairment thus it was attributed to the tramadol overdose. Providers should be aware that transient acute renal impairment could occur with an intentional tramadol ingestion and may not require aggressive intervention.",
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"authors": "Mike|Thomas B|TB|;DeVault|Heather|H|;Blackford|Martha G|MG|",
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"keywords": "acute kidney injury; adolescent; adverse drug effect; analgesics; case report; drug overdose; tramadol",
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"title": "Acute Tramadol Ingestion With Transient Acute Kidney Injury in an Adolescent Female.",
"title_normalized": "acute tramadol ingestion with transient acute kidney injury in an adolescent female"
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"abstract": "Mycobacterium Avium Complex (MAC) is an established microbiologic cause of pulmonary disease, lymphadenitis, and disseminated disease in cases of advanced immune suppression. However, MAC manifesting as vertebral osteomyelitis is less common, and is particularly rare in the absence of Acquired Immunodeficiency Syndrome (AIDS). Prompt diagnosis of MAC vertebral osteomyelitis is challenging, but necessary to prevent serious morbidity or mortality.\n\n\n\nWe report a case of MAC osteomyelitis of the lumbar spine in a 70-year-old woman on extended duration corticosteroid therapy for systemic lupus erythematosus who presented with progressive back pain. Upon presentation, imaging revealed osteomyelitis of the lumbar spine with associated paraspinal abscess. Cultures from the surgical evacuation of the paraspinal abscess yielded no pathogen growth and she was therefore treated with empiric antibacterial therapy. Two weeks after her initial hospital discharge she represented with severe back pain and radiologic evidence of progressive disease in her lumbar spine. Two additional vertebral biopsies were required during her first 2 weeks of admission. MAC eventually grew from culture 14 days after collection. She was treated with ethambutol and rifampin and her symptoms resolved in 2 weeks, though therapy was continued for 12 months.\n\n\n\nMAC is an unusual cause of vertebral osteomyelitis in patients with AIDS, but is exceedingly rare in those without severe immune compromise. Despite its rarity, it must be considered in cases of vertebral osteomyelitis that do not respond to empiric antibiotic therapy. Multiple biopsies may be necessary to obtain a diagnosis and avoid destructive infectious complications of an untreated infection.",
"affiliations": "Division of Infectious Diseases and International Health, University of Virginia Health System, P.O. Box 801379, Charlottesville, VA, 22908-1361, USA. meg5cs@virginia.edu.;Department of Infectious Diseases, University of Pennsylvania Health System|, 3400 Spruce Street, Philadelphia, PA, 19104, USA.;Division of Infectious Diseases and International Health, University of Virginia Health System, P.O. Box 801379, Charlottesville, VA, 22908-1361, USA.",
"authors": "Gray|Megan E|ME|0000-0002-9172-6821;Liu|Peter W|PW|;Wispelwey|Brian|B|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004977:Ethambutol; D012293:Rifampin",
"country": "England",
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"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 314310.1186/s12879-018-3143-4Case ReportMycobacterium Avium complex vertebral osteomyelitis in the absence of HIV infection: a case report and review http://orcid.org/0000-0002-9172-6821Gray Megan E. (434) 942-5242meg5cs@virginia.edu 1Liu Peter W. (808)722-3975peterliu53@gmail.com 2Wispelwey Brian (434) 982-1699BW9G@hscmail.mcc.virginia.edu 11 0000 0004 1936 9932grid.412587.dDivision of Infectious Diseases and International Health, University of Virginia Health System, P.O. Box 801379, Charlottesville, VA 22908-1361 USA 2 0000 0004 0454 0768grid.412701.1Department of Infectious Diseases, University of Pennsylvania Health System|, 3400 Spruce Street, Philadelphia, PA 19104 USA 22 5 2018 22 5 2018 2018 18 2357 9 2017 10 5 2018 © The Author(s). 2018Open 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\nMycobacterium Avium Complex (MAC) is an established microbiologic cause of pulmonary disease, lymphadenitis, and disseminated disease in cases of advanced immune suppression. However, MAC manifesting as vertebral osteomyelitis is less common, and is particularly rare in the absence of Acquired Immunodeficiency Syndrome (AIDS). Prompt diagnosis of MAC vertebral osteomyelitis is challenging, but necessary to prevent serious morbidity or mortality.\n\nCase presentation\nWe report a case of MAC osteomyelitis of the lumbar spine in a 70-year-old woman on extended duration corticosteroid therapy for systemic lupus erythematosus who presented with progressive back pain. Upon presentation, imaging revealed osteomyelitis of the lumbar spine with associated paraspinal abscess. Cultures from the surgical evacuation of the paraspinal abscess yielded no pathogen growth and she was therefore treated with empiric antibacterial therapy. Two weeks after her initial hospital discharge she represented with severe back pain and radiologic evidence of progressive disease in her lumbar spine. Two additional vertebral biopsies were required during her first 2 weeks of admission. MAC eventually grew from culture 14 days after collection. She was treated with ethambutol and rifampin and her symptoms resolved in 2 weeks, though therapy was continued for 12 months.\n\nConclusions\nMAC is an unusual cause of vertebral osteomyelitis in patients with AIDS, but is exceedingly rare in those without severe immune compromise. Despite its rarity, it must be considered in cases of vertebral osteomyelitis that do not respond to empiric antibiotic therapy. Multiple biopsies may be necessary to obtain a diagnosis and avoid destructive infectious complications of an untreated infection.\n\nKeywords\nMycobacterium avium complexNon-tuberculous mycobacteriaVertebral osteomyelitisChronic corticosteroid usehttp://dx.doi.org/10.13039/100000002National Institutes of Health5T32 A1007046 - 40issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nMycobacterium Avium Complex (MAC) includes two important human pathogens, Mycobacterium avium and Mycobacterium intracellulare. MAC organisms are ubiquitous in the environment and have been identified in typical reservoirs of soil, water, and animals [1]. There are no documented cases of horizontal transmission of non-tuberculous mycobacteria (NTM) infections [2], and manifestations of human disease arise most commonly after acquisition of bacterial inoculum via inhalation or ingestion [1, 3].\n\nThe most well recognized disease manifestations of MAC are pulmonary disease, lymphadenitis, and in the case of advanced immunocompromised, disseminated disease [1, 3, 4]. Yet, of considerable importance to the clinician are also less common presentations of MAC, such as osteomyelitis. Although bacterial vertebral osteomyelitis is not difficult to diagnose, delayed recognition of MAC as the causative pathogen is likely to lead to significant adverse sequelae. Particularly vexing are difficulties with rapid microbiologic identification owing to the fastidious characteristics of MAC organisms and treatment challenges that arise from the complexity and duration of recommended therapies.\n\nVertebral osteomyelitis due to MAC is a poorly described entity. The majority of cases in the medical literature are presented in hosts affected by Human Immunodeficiency Virus (HIV) or AIDS [4–8], though there are reports of MAC osteomyelitis in HIV infected patients with immune reconstitution and CD4 T-lymphocyte counts well above the recommended threshold for maintenance of MAC prophylaxis [8]. Here we report a case of lumbar vertebral osteomyelitis due to MAC in a patient on systemic corticosteroid therapy and review the available literature regarding this rare infection.\n\nCase presentation\nA 70-year-old woman presented with 5 months of progressive low back pain. She had a complex medical history including a remote splenectomy, anti-phospholipid syndrome, autoimmune hemolytic anemia requiring previous courses of cyclophosphamide, L3 laminectomy 2 years prior, and systemic lupus erythematosus (SLE) with ongoing therapy with hydroxychloroquine and prednisone 20 mg daily. Her low back pain initially manifested in the context of a herpes zoster infection and management of presumed neuropathic pain was pursued. In ensuing months, she had progression of low back pain despite conservative management. Magnetic Resonance Imaging (MRI) of the lumbar spine showed evidence of an epidural abscess at L2–3, L3–4 with vertebral osteomyelitis at L2-L3. Admission vitals showed a heart rate of 120 beats per minute, blood pressure of 121/59 mmHg, temperature of 36.9 °C, respiratory rate 16 breaths per minute, and SpO2 of 93% on room air. She had a mild leukocytosis with a white blood cell count of 12.18 k/uL. C-reactive protein and sedimentation rate were elevated at 2.8 mg/dL and 45 mm/h respectively. She underwent surgical evacuation of the epidural abscess and wound revision of L2-L3. Intra-operative findings included dark brown fluid that egressed from her epidural site, but no purulent fluid was visualized. Intraoperative cultures of vertebral bodies and discs showed no evidence of bacterial or fungal growth. Acid-fast bacterial (AFB) stains, cultures and QuantiFERON®-TB Gold In-Tube testing were also negative. Empiric treatment with vancomycin and cefepime was initiated with plans to complete a six-week course.\n\nThree weeks after surgical intervention, she re-presented with persistent low back pain and encephalopathy. Cefepime was considered as a possible etiology of her altered mental status and therefore was replaced by aztreonam. Admission vital signs were unremarkable. C-reactive protein and sedimentation rate were 4.9 mg/dL and 36 mm/h respectively, with notable increase in C-reactive protein from 2.8 mg/dL. Lumbar spinal computed tomography (CT) demonstrated severe lytic and sclerotic destructive changes centered on the disc space of L2-L3 and the vertebral body of L4. There were also findings consistent with a large paraspinal abscess anterior to the L3 vertebral body. A biopsy of the L3 vertebral body was obtained and showed no organisms on gram stain with no growth after 7 days. This prompted a repeat bone biopsy in attempts to define the causative pathogen and direct further antimicrobial therapy. Meanwhile, empiric antibiotics to cover typical pathogens were continued. Two weeks following the initial vertebral body biopsy there was growth of acid fast bacilli from the bony specimen, which was further identified as MAC by hybridization probe. In vitro susceptibility testing indicated a favorable resistance profile with susceptibility to clofazimine, rifabutin, clarithromycin, ethambutol, and rifampin. Treatment with ethambutol and azithromycin was initiated after receiving susceptibility results. Two-drug therapy was selected due to the favorable susceptibility of the MAC isolate, in addition to efforts to mitigate potential adverse drug effects and medication interactions. She had no evidence of MAC pulmonary involvement on chest CT and the etiology of her infection was uncertain. Two months later she was seen in follow-up with resolution of her symptoms. She will continue antibiotics to complete a 12-month course.\n\nDiscussion\nThere have been 16 case reports describing MAC causing vertebral osteomyelitis in non-HIV infected individuals in the literature to date (Table 1). As discussed, HIV/AIDS is a risk factor for MAC infection as are other forms of immunosuppression related to medications or genetic defects. In patients without known immune compromise, additional factors that may heighten clinical suspicion for MAC vertebral osteomyelitis include advanced age, osteoporosis, trauma, previous spinal surgery, or known pulmonary disease [9]. Of the reported cases, including the patient discussed in this report, 53% (n = 9) had no known immunodeficiency, 47% (n = 8) were on chronic corticosteroid therapy, 18% (n = 3) had osteoporosis and 12% (n = 2) were surgically asplenic. Osteoporosis is not thought to be a risk factor due to direct pathophysiologic influence, but rather the potential for physicians to attribute patients’ symptoms and associated radiologic findings to compression fractures with resultant delay in directed therapy.Table 1 Summary of clinical details from published cases of MAC vertebral osteomyelitis in patients without a known HIV diagnosis\n\nREFERENCE\tCountry\tAge, SEX\tClinical manifestations\tUnderlying Conditions\tSite of Involvement\tAntibacterial/\nMonths of Therapy\tSurgical Intervention\tDiagnosis Method/\nWeeks to Positivity\tBiopsies\t\n9\tU.S.A.\t72, F\tMid-thoracic back pain, fevers, LE* weakness, decreased sensation\tPolymyositis, steroid use\tT11-L1 osteomyelitis, extra-dural soft tissue mass compressing anterior spinal cord\tclarithromycin, ethambutol, rifampin/NA\tNo\t(Acid fast stain lead to TB diagnosis)\nTissue culture/ NA\t1\t\n10\tU.S.A.\t62, F\tLow back pain\tNone\tParaspinal abscess at L5-S1, destructive changes of L5 and S1 vertebral bodies.\tclarithromycin, clofazamine, ethambutol/21\tYes\tTissue culture/NA\t1\t\n11\tU.S.A.\t35, M\tRight shoulder pain\tSLE, steroid use\tRight humeral head osteomyelitis, thoracolumbar infection with associated paraspinal abscess\tethambutol, isoniazid, streptomycin/24+, until death\tYes\tTissue culture/NA\t1\t\n12\tJapan\t76, F\tMAC pulmonary infection, low back pain\tNone\tT4-T5 osteomyelitis\tclarithromycin, moxifloxacin, rifampicin/NA\tYes\tTissue culture/NA\t1\t\n13\tU.S.A.\t79, M\tLow back pain, urinary incontinence\tSLE, steroid use, osteoporosis\tThoracolumbar osetomyelitis with spinal cord compression due to soft tissue paraspinal mass. 10 cm lung mass with pleural effusion.\tInitial empiric: Isoniazid, rifampin, pyrazinamide/2.25\nDefinitive: amikacin/4, clindamycin, clofazamine, ethambutol, rifampin/6 - until death\tYes\t(Acid fast stain lead to TB diagnosis) Tissue culture/9\t2\t\n17\tJapan\t38, F\tLow back pain\tSLE, steroid use\tSeptic arthritis of bilateral knees, T8-T9 paravertebral abscess and T9 osteomyelitis\tclarithromycin, ethambutol, rifampin/12\tYes\tTissue culture/NA\t1\t\n17\tJapan\t50, M\tLow back pain\tNone\tParavertebral abscess and psoas abscess at level of L4, osteodiscitis at L2-L5.\tclarithromycin, ethambutol, rifampin/+ 12\tYes\tTissue culture/5\t1\t\n18\tChina\t60, M\tLow back pain\tNone\tL2-L3 osteomyelitis with psoas abscess\tInitial empiric: ethambutol, isoniazid, pyrazinamide, rifampicin/3.\nDefinitive: amikacin/2, ethambutol, rifampicin/12\tYes\t(Pathology lead to TB diagnosis)\nTissue culture/12\t1\t\n19\tJapan\t67, M\tLow back pain, fever\tDiabetes mellitus\tT spine to L spine with psoas abscess\tclarithromycin, cycloserine, ethambutol, rifampicin, streptomycin sulfate/+ 24\tYes\tPCR* from sinus tract/8\t1\t\n20\tAustralia\t70, F\tLow back pain, paraplegia\tOsteoporosis, chronic bronchitis\tT12 osteomyelitis with spinal cord compression\tclarithromycin, ethambutol, rifampin/NA\tNo\tTissue culture/2\t2\t\n21\tU.S.A.\t60, F\tLow back pain, fevers, productive cough\tSarcoidosis, steroid use, COPD, osteoporosis, splenectomy\tT7-T9 osteomyelitis with paraspinal abscess causing cord compression at T8-T9.\tInitial empiric: clarithromycin, ethambutol, isoniazid, rifampin.\nDefinitive: clarithromycin, ethambutol, rifampin/24\tYes\t(Acid-fast stain lead to TB diagnosis)\nTissue culture/NA\t1\t\n26\tU.S.A.\t27, F\tLow back pain, fevers, LE weakness and hyporeflexia\tSLE, steroid, hydroxychloroquine use\tL5 osteomyelitis, soft tissue mass extending into spinal canal and anteriorly into retroperitoneum, 1 cm breast nodule\tcycloserine, ethambutol, rifampin, streptomycin/20 months – until death.\tYes\tTissue culture from breast/NA\t1\t\n27\tU.S.A.\t39, M\tLow back pain, paraplegia\tNone\tT6 and T7 destruction, paraspinal abscess with spinal cord impingement.\tciprofloxacin, erythromycin, ethambutol/6\tYes\tTissue culture/NA\t1\t\n28\tU.S.A.\t31, F\tBack pain, painful adenopathy\tNone\tAxillary abscess, sternal abscess, T7-T8 osteomyelitis with paraspinal abscess, metastatic osteomyelitis to proximal femurs, pelvis, sternum, and distal radius\tInitial empiric: clarithromycin, isoniazid, pyridoxine, rifampin\nDefinitive: ciprofloxacin, clarithromycin, cycloserine, ethambutol, rifampin/24\tNo\t(Acid-fast stain from abscesses lead to TB diagnosis)\nTissue culture/NA\t1\t\n29\tU.S.A.\t12, F\tLeft leg pain\tNone\tMultifocal osteomyelitis involving the tibias, right femur, pelvis, spine and orbit\tNA\tYes\tTissue culture/NA\t1\t\n30\tAustralia\t70, M\tBack pain, ataxia\tILD, steroid use\tT5-T7 osteomyelitis with vertebral destruction\tNA\tYes\tTissue culture/NA\t1\t\nF female, M male, LE lower extremity, SLE systemic lupus erythematosus, COPD chronic obstructive pulmonary disease, ILD interstitial lung disease, NA data not available, TB Mycobacterium tuberculosis, PCR polymerase chain reaction\n\n\n\nIdentifying the mode of transmission in patients with MAC infection is difficult, and there is often no discernable exposure history. Several case reports cite prior trauma as the risk factor for development of infection [10, 11], whereas others were thought to have a pulmonary MAC infection with subsequent hematogenous seeding of the spine [12, 13]. Another theory that has been proposed is that of locus minoris resistentiae, (Latin for “place of less resistance”), a longstanding medical concept that a weakened part of the body may be more susceptible to disease [10, 14]. In this case, the area of the patient’s spine that was manipulated during preceding laminectomy could have predisposed her to infection and seeding from her subsequent steroid injection. Likewise, the steroid injection may have caused local trauma leading to potential inoculation of MAC from another unknown source. Contamination of air conditioning systems, surgical tools or materials, tissue-marking agents or colonized aqueous solutions with NTM have all been observed and should be considered as potential exposures in patients who have had medical procedures or surgeries [3].\n\nEarly diagnosis of MAC infection is a challenge due to the slow growing nature of mycobacteria. Up to 6 weeks of incubation time is often required for cultures to show evidence of growth. Regardless of the causative pathogen, vertebral osteomyelitis is a diagnostic challenge. Even in patients with pyogenic osteomyelitis only 28% of cases are diagnosed within the first month of symptom onset [15]. Diagnosis of osteomyelitis can be made without image guided aspiration biopsy or open biopsy in patients with positive blood cultures for typical causative organisms, such as Staphylococcus or Brucella [16]. Generally, blood cultures are negative and a bone or soft tissue biopsy for histopathological and microbiological diagnosis is required. Bone and soft tissue cultures may also be unrevealing and repeat biopsies are recommended, but not always performed given the risks associated with invasive procedures [16]. Of the five case reports that discussed the time elapsed between biopsy and identification of the causative pathogen, the time course ranged from 2 to 12 weeks [13, 17–20]. Additionally, 18% (n = 3) of cases required more than one biopsy to establish a diagnosis [13, 19, 20].\n\nOur patient had culture negative vertebral osteomyelitis when first diagnosed. She had no risk factors for mycobacterium infection, apart from chronic corticosteroid use. The first two bone and soft tissue biopsies obtained were not immediately helpful in establishing any microbiologic diagnosis. Multidisciplinary discussion and collaboration led to a third bone biopsy, which is the recommended course of action. Due to the slow growth of MAC, it was the second bone biopsy that showed growth, 2 weeks after it was collected. This highlights the need for repeated biopsies in patients with culture negative vertebral osteomyelitis, particularly when accompanied by a poor clinical response to empiric therapy.\n\nAdditional recommended methods for diagnosing MAC vertebral osteomyelitis include histologic evaluation [16]. In mycobacterial infection, microscopic evaluation of tissue biopsies may show infiltrating histiocytes and granulomatous change, but these findings are neither sensitive nor specific [19]. Several of the reported MAC vertebral osteomyelitis cases were initially treated with empiric anti-tuberculous agents based on histopathologic findings of granulomatous inflammation, without additional positivity from histopathologic stains or cultures. Though empiric treatment of tuberculosis is recommended in cases with evidence of mycobacterial infection, in these cases it has led to increased morbidity given MAC’s inherent resistance of many anti-tuberculosis agents [9, 13, 18, 21]. As AFB stains do not differentiate between tuberculous and non-tuberculous mycobacteria, the addition of empiric therapy for NTM infections in patients with positive AFB stains should be considered [21].\n\nTherapeutic options for MAC vertebral osteomyelitis include both surgical and medical interventions. MAC vertebral osteomyelitis can often lead to abscess formation and/or fistulous tracts, likely due to delay in diagnosis and definitive treatment. Indications for surgical debridement include abscess formation, progressive destruction of vertebral bodies or neurologic compromise. There are no consensus guidelines established for the treatment of MAC skin, soft tissue or skeletal disease [2, 15]. Tailoring treatment based on in vitro susceptibility testing is recommended and is associated with a favorable clinical response [22].\n\nIt is well accepted that the macrolide is the backbone of MAC therapy, though a multidrug regimen is required as monotherapy has been shown to increase resistance [2, 23]. Clarithromycin and azithromycin have both proven to be effective in combination regimens, though clarithromycin did show more rapid clearance in patients with bacteremia [2]. Ethambutol is the generally the second recommended agent. A rifamycin is frequently added as a third agent and may have some modest benefit, though existing clinical data is limited. Rifabutin is preferred over rifampin due to superior in vitro activity against MAC. In cases of macrolide resistance, an aminoglycoside in combination with a respiratory fluoroquinolone is generally used as a replacement. Clofazimine has been associated with increased mortality in patients with disseminated MAC [24].\n\nAll pharmacotherapies have potential associated adverse effects. While macrolides are generally well-tolerated, use of ethambutol can lead to serious optic neuropathies. The rifamycins are inducers of the cytochrome P-450 oxidative enzymes and the P-glycoprotein transport system. This results in drug-drug interactions with agents such as warfarin, oral contraceptives, itraconazole, and protease inhibitors, which is often a challenge given the frequency of NTM infections in HIV infected patients [25]. Due to the limited chemotherapeutic options, the treatment regimen and duration of treatment should be tailored to each patient’s individual needs. Of the 14 case reports that discussed antimicrobial therapy, the average number of antimicrobial agents used after diagnosis of MAC was 3.4. More than three agents were often implemented in the setting of drug resistance.\n\nOur patient was treated with a two-drug regimen for 12 months with excellent clinical response. A two-drug regimen was pursued due to the high risk for harmful drug interactions with rifamycins. In pulmonary MAC infection, treatment is continued until two negative sputum cultures are obtained [2]. However, obtaining repeat tissue samples in order to evaluate for cure in patients with vertebral osteomyelitis requires an additional invasive and potentially harmful procedure, and is therefore avoided. Of the 11 case reports that discussed length of therapy, the average duration was 16.8 months [10, 11, 13, 17–19, 21, 26–30]. Treatment course for vertebral osteomyelitis is not well established given the rarity of this disease, but at least 12 months or more is likely required.\n\nConclusion\nVertebral osteomyelitis is a rare manifestation of MAC in persons with HIV or AIDS, but is even less common in persons without immunocompromising conditions. Chronic corticosteroid therapy may pose a greater risk for MAC vertebral osteomyelitis than what has previously been recognized. The diagnosis and treatment of MAC vertebral osteomyelitis is complex and challenging. Repeated attempts at tissue acquisition should be strongly considered in patients with culture negative vertebral osteomyelitis, particularly when accompanied by a poor clinical response to empiric antibiotic therapy.\n\nAbbreviations\nAIDSAcquired immunodeficiency syndrome\n\nCTComputed tomography\n\nHIVHuman immunodeficiency virus\n\nMACMycobacterium Avium Complex\n\nMRIMagnetic resonance imaging\n\nNTMNon-tuberculous mycobacteria\n\nSLESystemic lupus erythematosus\n\nAcknowledgements\nWe would like to thank the patient described in this case for allowing us to share it with the scientific community.\n\nFunding\nThis research was supported in part by Award Number 5 T32 A1007046–40 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.\n\nAuthors’ contributions\nPL composed the background section of the manuscript and contributed to editing. BW edited the manuscript. Megan Gray composed the remainder of the manuscript and is the corresponding author. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable, consent was obtained from the patient described in this report.\n\nConsent for publication\nConsent for publication was obtained from the individual patient described in this report. Written consent is available by request.\n\nCompeting interests\nThe authors have no competing interests to disclose.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Gordin F, Horsburgh CR. Mycobacterium avium complex. In: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 8 ed. Vol. 3. Philadelphia, PA: Elsevier, 2015:2832,2833–2834.\n2. Griffith DE Aksamit T Brown-Elliott BA An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases Am J Respir Crit Care Med 2007 175 367 416 10.1164/rccm.200604-571ST 17277290 \n3. Wagner D Young LS Nontuberculous mycobacterial infections: a clinical review Infection 2004 32 257 270 10.1007/s15010-004-4001-4 15624889 \n4. Inderlied CB Kemper CA Bermudez LE The mycobacterium avium complex Clin Microbiol Rev 1993 6 266 310 10.1128/CMR.6.3.266 8358707 \n5. Rotstein AH Stuckey SL Mycobacterium avium complex spinal epidural abscess in an HIV patient Australas Radiol 1999 43 554 557 10.1046/j.1440-1673.1999.00732.x 10901982 \n6. Kahlon SS East JW Sarria JC Mycobacterium-avium-intracellulare complex immune reconstitution inflammatory syndrome in HIV/AIDS presenting as osteomyelitis AIDS Read 2008 18 515 518 18975441 \n7. Aberg JA Chin-Hong PV McCutchan A Koletar SL Currier JS Localized osteomyelitis due to mycobacterium avium complex in patients with human immunodeficiency virus receiving highly active antiretroviral therapy Clin Infect Dis 2002 35 E8 E13 10.1086/340714 12060894 \n8. Wood BR Buitrago MO Patel S Hachey DH Haneuse S Harrington RD Mycobacterium avium complex osteomyelitis in persons with human immunodeficiency virus: case series and literature review Open Forum Infect Dis 2015 2 ofv090 10.1093/ofid/ofv090 26180837 \n9. Mehta JB Emery MW Girish M Byrd RP Jr Roy TM Atypical pott's disease: localized infection of the thoracic spine due to mycobacterium avium-intracellulare in a patient without human immunodeficiency virus infection South Med J 2003 96 685 688 10.1097/01.SMJ.0000054604.75361.57 12940321 \n10. Chan ED Kong PM Fennelly K Dwyer AP Iseman MD Vertebral osteomyelitis due to infection with nontuberculous mycobacterium species after blunt trauma to the back: 3 examples of the principle of locus minoris resistentiae Clin Infect Dis 2001 32 1506 1510 10.1086/320155 11317255 \n11. Zvetina JR Demos TC Rubinstein H Mycobacterium intracellulare infection of the shoulder and spine in a patient with steroid-treated systemic lupus erythematosus Skelet Radiol 1982 8 111 113 10.1007/BF00349575 \n12. Takakuwa O Oguri T Kasai D Nakamura A Sato S Ueda R A case of spinal osteomyelitis due to mycobacterium intracellulare with pulmonary mycobacterium avium complex Nihon Kokyuki Gakkai Zasshi 2010 48 759 764 21066865 \n13. Pirofsky JG Huang CT Waites KB Spinal osteomyelitis due to mycobacterium avium-intracellulare in an elderly man with steroid-induced osteoporosis Spine (Phila Pa 1976) 1993 18 1926 1929 10.1097/00007632-199310000-00036 8235886 \n14. Lo Schiavo A Ruocco E Russo T Brancaccio G Locus minoris resistentiae: an old but still valid way of thinking in medicine Clin Dermatol 2014 32 553 556 10.1016/j.clindermatol.2014.04.001 25160095 \n15. Petitjean G Fluckiger U Scharen S Laifer G Vertebral osteomyelitis caused by non-tuberculous mycobacteria Clin Microbiol Infect 2004 10 951 953 10.1111/j.1469-0691.2004.00949.x 15521995 \n16. Berbari EF Kanj SS Kowalski TJ Executive summary: 2015 infectious diseases society of america (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults Clin Infect Dis 2015 61 859 863 10.1093/cid/civ633 26316526 \n17. Shimizu H Mizuno Y Nakamura I Fukushima S Endo K Matsumoto T Vertebral osteomyelitis caused by non-tuberculous mycobacteria: case reports and review J Infect Chemother 2013 19 972 977 10.1007/s10156-013-0550-8 23338014 \n18. Wong NM Sun LK Lau PY Spinal infection caused by mycobacterium avium complex in a patient with no acquired immune deficiency syndrome: a case report J Orthop Surg (Hong Kong) 2008 16 359 363 10.1177/230949900801600319 19126907 \n19. Suzuki T Murai H Miyakoshi N Hongo M Itoi E Shimada Y Osteomyelitis of the spine caused by mycobacterium avium complex in an immunocompetent patient J Orthop Sci 2013 18 490 495 10.1007/s00776-011-0183-7 22170522 \n20. Weiner BK Love TW Fraser RD Mycobacterium avium intracellulare: Vertebral osteomyelitis J Spinal Disord 1998 11 89 91 10.1097/00002517-199802000-00015 9493777 \n21. Niazi S Batra V Zangrilli JG Atypical mycobacterial osteomyelitis in a non-AIDS patient Conn Med 2002 66 387 389 12181861 \n22. Horsburgh CR,Jr, Mason UG,3rd, Heifets LB, Southwick K, Labrecque J, Iseman MD. Response to therapy of pulmonary mycobacterium avium-intracellulare infection correlates with results of in vitro susceptibility testing. Am Rev Respir Dis, 1987; 135: 418–421.\n23. Chaisson RE Benson CA Dube MP Clarithromycin therapy for bacteremic mycobacterium avium complex disease. A randomized, double-blind, dose-ranging study in patients with AIDS. AIDS clinical trials group protocol 157 study team Ann Intern Med 1994 121 905 911 10.7326/0003-4819-121-12-199412150-00001 7978715 \n24. Chaisson RE Keiser P Pierce M Clarithromycin and ethambutol with or without clofazimine for the treatment of bacteremic mycobacterium avium complex disease in patients with HIV infection AIDS 1997 11 311 317 10.1097/00002030-199703110-00008 9147422 \n25. Baciewicz AM Chrisman CR Finch CK Self TH Update on rifampin, rifabutin, and rifapentine drug interactions Curr Med Res Opin 2013 29 1 12 10.1185/03007995.2012.747952 23136913 \n26. Brodkin H Paraspinous abscess with mycobacterium avium-intracellulare in a patient without AIDS South Med J 1991 84 1385 1386 10.1097/00007611-199111000-00025 1948230 \n27. Igram CM Petrie SG Harris MB Atypical mycobacterial vertebral osteomyelitis in an immunocompetent patient Orthopedics 1997 20 163 166 9048393 \n28. King BF Disseminated mycobacterium avium complex in an immunocompetent previously healthy woman J Am Board Fam Pract 1994 7 145 148 8184706 \n29. Mahan S Jolles PR MAI osteomyelitis. 18-year scintigraphic follow-up Clin Nucl Med 1995 20 594 598 10.1097/00003072-199507000-00005 7554659 \n30. Bhatia K Frydenberg E Steel T Ow-Yang M An anterior expandable titanium cage in mycobacterium avium vertebral osteomyelitis J Clin Neurosci 2011 18 431 434 10.1016/j.jocn.2010.07.108 21237655\n\n",
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"issue": "18(1)",
"journal": "BMC infectious diseases",
"keywords": "Chronic corticosteroid use; Mycobacterium avium complex; Non-tuberculous mycobacteria; Vertebral osteomyelitis",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000038:Abscess; D000368:Aged; D000900:Anti-Bacterial Agents; D004359:Drug Therapy, Combination; D004977:Ethambutol; D005260:Female; D006801:Humans; D008161:Lumbosacral Region; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection; D010019:Osteomyelitis; D012293:Rifampin",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D016454:Review",
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"title": "Mycobacterium Avium complex vertebral osteomyelitis in the absence of HIV infection: a case report and review.",
"title_normalized": "mycobacterium avium complex vertebral osteomyelitis in the absence of hiv infection a case report and review"
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"abstract": "OBJECTIVE\nA case of eosinophilic peritonitis (EP) with severe cardiovascular compromise in a patient receiving intraperitoneal vancomycin therapy is described.\n\n\nCONCLUSIONS\nA woman with a medical history including hypertension, end-stage renal disease, and anemia of chronic disease was hospitalized for complaints of severe abdominal pain and loss of appetite over the preceding four days; she had been undergoing peritoneal dialysis for about one year. Bacterial infection was diagnosed on the basis of peripheral blood and peritoneal fluid analyses showing highly elevated neutrophil and total nucleated cell (TNC) counts. Vancomycin was added to the peritoneal dialysis bags, with subsequent dramatic TNC and neutrophil reductions over two days, but the woman's condition continued to worsen; she developed severe hypotension and on hospital day 13 was transferred to the intensive care unit for central line placement and vasopressor support. The clinician team determined that conversion from bacterial peritonitis to EP had occurred. After the exclusion of other potential causes of EP (e.g., a reaction to dialysis equipment, antihypertensive medication use), intraperitoneal administration of vancomycin was deemed to be the probable cause. Within days of discontinuation of vancomycin use, the patient's hypotension abated, her abdominal symptoms resolved, and she was discharged home. In this case, the diagnosis of EP was complicated by the initial presentation of bacterial peritonitis (confirmed by laboratory and culture data). A literature search identified one other published report of vancomycin-induced EP.\n\n\nCONCLUSIONS\nA 37-year-old woman developed EP after receiving vancomycin intraperitoneally. The infection resolved after discontinuation of vancomycin.",
"affiliations": "Hospitalist Department, Indiana University Health Arnett, Lafayette, IN.;Pharmacy Department, Indiana University Health Arnett, Lafayette, IN. jslaven2@iuhealth.org.;Internal Medicine Department, Kingsbrook Jewish Medical Center, Brooklyn, NY.;Internal Medicine-Nephrology Department, Indiana University Health Arnett, Lafayette, IN.",
"authors": "Deweese|Ryan|R|;Slavens|Jennifer|J|;Barua|Antara|A|;Sutton|James|J|",
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"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D004802:Eosinophilia; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D010538:Peritonitis; D014640:Vancomycin",
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"title": "Vancomycin-induced eosinophilic peritonitis.",
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"abstract": "Trimethoprim-sulfamethoxazole was given to a 16-year-old boy as prophylaxis for a urinary tract infection. He developed severe cholestatic hepatitis 41 days after administration of the drug. A liver biopsy specimen showed a mixed inflammatory infiltrate in the portal triads and prominent bile stasis. The clinical course in this patient supports the concept of an indirect hypersensitivity reaction to sulfamethoxazole.",
"affiliations": null,
"authors": "Stevenson|D K|DK|;Christie|D L|DL|;Haas|J E|JE|",
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"title": "Hepatic injury in a child caused by trimethoprim-sulfamethoxazole.",
"title_normalized": "hepatic injury in a child caused by trimethoprim sulfamethoxazole"
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"abstract": "Ruxolitinib is the only approved therapy for myelofibrosis (MF). However, its use in patients with myeloproliferative neoplasms (MPN) not participating in clinical studies has been poorly described. We reviewed the medical records of 45 patients (35 MF, 10 others) treated with ruxolitinib at our center, off clinical study, during the year after its approval. Patients had advanced features and were refractory to multiple therapies. Ruxolitinib was effective in reducing splenomegaly (51% response rate) and constitutional symptoms (42% response rate). It controlled blood counts in patients with polycythemia and thrombocythemia but was not effective in patients with non-classic MPNs. Ruxolitinib was an active therapy in patients previously treated with a JAK inhibitor and was safely combined with hypomethylating agents in patients with elevated blasts. Median overall survival was 24 months; 10 patients transformed to acute leukemia. Its use in combination with other active agents should be further explored in clinical studies.",
"affiliations": "a Department of Leukemia , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.;a Department of Leukemia , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.;a Department of Leukemia , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.;a Department of Leukemia , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.;a Department of Leukemia , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.;a Department of Leukemia , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.;a Department of Leukemia , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.;a Department of Leukemia , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.",
"authors": "Naqvi|Kiran|K|;Daver|Naval|N|;Pemmaraju|Naveen|N|;Bose|Prithviraj|P|;Garcia-Manero|Guillermo|G|;Cortes|Jorge|J|;Kantarjian|Hagop M|HM|;Verstovsek|Srdan|S|",
"chemical_list": "D000970:Antineoplastic Agents; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; D053614:Janus Kinase 2",
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"abstract": "Pyridox(am)ine- 5- phosphate Oxidase deficiency (PNPO) is a rare cause of neonatal metabolic encephalopathy associated with refractory status epilepticus. We report a case of a premature neonate presenting with drug-resistant seizures beginning at 2 hours of life. The baby showed initial transient response to pyridoxine followed by recurrence. Genetic report confirmed the diagnosis of PNPO deficiency. A literature review on phenotypic variants in terms of response to pyridoxine is also presented along with a proposed algorithm to manage a case of suspected vitamin responsive epilepsy. This case highlights our limited understanding of why variation in response to treatment exists in children with PNPO deficiency.",
"affiliations": "Pediatric Neurology. Consultant, Division of Pediatric Neurology, BL Kapur Superspecialiy Hospital, Delhi, India.;Fellow Neonatology, Department of Neonatology, BLK Superspeciality Hospital, Delhi, India.;Neonatology. Consultant and NICU in Charge, Division of Neonatology, BL Kapur Superspeciality Hospital, Delhi, India.;Neonatology. Consultant NICU, Division of Neonatology, BL Kapur Superspeciality Hospital, Delhi, India.;Pediatric Neurology, Department of Pediatrics, Kalawati Saran Children's Hospital, Delhi, India.",
"authors": "Farmania|Rajni|R|;Gupta|Ankit|A|;Ankur|Kumar|K|;Chetry|Sanjeev|S|;Sharma|Suvasini|S|",
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"doi": "10.1016/j.ebr.2021.100443",
"fulltext": "\n==== Front\nEpilepsy Behav Rep\nEpilepsy Behav Rep\nEpilepsy & Behavior Reports\n2589-9864\nElsevier\n\nS2589-9864(21)00017-4\n10.1016/j.ebr.2021.100443\n100443\nArticle\nComplexities of pyridoxine response in PNPO deficiency\nFarmania Rajni rajni.farmania@gmail.com\naf⁎\nGupta Ankit bg\nAnkur Kumar ch\nChetry Sanjeev di\nSharma Suvasini ej\na Pediatric Neurology. Consultant, Division of Pediatric Neurology, BL Kapur Superspecialiy Hospital, Delhi, India\nb Fellow Neonatology, Department of Neonatology, BLK Superspeciality Hospital, Delhi, India\nc Neonatology. Consultant and NICU in Charge, Division of Neonatology, BL Kapur Superspeciality Hospital, Delhi, India\nd Neonatology. Consultant NICU, Division of Neonatology, BL Kapur Superspeciality Hospital, Delhi, India\ne Pediatric Neurology, Department of Pediatrics, Kalawati Saran Children’s Hospital, Delhi, India\nf Consultant and Incharge, Pediatric Neurology, Department of Pediatrics, BLK Superspeciality Hospital, Delhi, India\ng Fellow Neonatology, Department of Neonatology, BLK Superspeciality, Delhi, India\nh Consultant and NICU incharge, Department of Neonatology, BLK Superspeciality, Delhi, India\ni Consultant NICU, Department of Neonatology, BLK Superspecilaity, Delhi, India\nj Associate Professor, Division of Pediatric Neurology, Department of Pediatrics, BLK Superspeciality, Delhi, India\n⁎ Corresponding author at: Consultant Pediatric Neurologist, BLK Super Speciality Hospital, OPD 1, Room :26, Ground floor, BLK Super Speciality Hospital, India. rajni.farmania@gmail.com\n03 4 2021\n2021\n03 4 2021\n16 10044320 11 2020\n27 2 2021\n4 3 2021\n© 2021 The Author(s)\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/).\nHighlights\n\n• Treatment of PNPO deficiency related neonatal status epilepticus is challenging.\n\n• Pyridoxine responsiveness is seen in huge number of cases of PNPO deficiency.\n\n• Various phenotypic variants in terms of response to pyridoxine are known in PNPO disorder making the treatment complex.\n\n• Immediate complete cessation of seizures or normalization of EEG on pyridoxine or pyridoxal 5 phosphate therapy is not necessary for the diagnosis, and treatment should be continued till the genetic tests are available.\n\nPyridox(am)ine- 5- phosphate Oxidase deficiency (PNPO) is a rare cause of neonatal metabolic encephalopathy associated with refractory status epilepticus. We report a case of a premature neonate presenting with drug-resistant seizures beginning at 2 hours of life. The baby showed initial transient response to pyridoxine followed by recurrence. Genetic report confirmed the diagnosis of PNPO deficiency. A literature review on phenotypic variants in terms of response to pyridoxine is also presented along with a proposed algorithm to manage a case of suspected vitamin responsive epilepsy. This case highlights our limited understanding of why variation in response to treatment exists in children with PNPO deficiency.\n\nKeywords\n\nPyridox(am)ine −5- phosphate oxidase\nPyridoxal 5 phosphate\nPyridoxine\nNeonatal status epilepticus\nVitamin responsive epilepsy\n==== Body\nPyridox (am)ine- 5- phosphate oxidase (PNPO) deficiency is a vitamin-responsive epilepsy syndrome that poses significant challenges in management. Traditionally, pyridoxal phosphate (PLP) was considered to be the treatment of choice; however, a considerable proportion of cases respond to pyridoxine (PN) [1]. Even in these infants whose seizures respond to pyridoxine, the effect is variable and unpredictable [2], [3]. The genotype and phenotype correlation relative to a ssuccessful response to treatment is poor. Here, we describe a preterm infant with refractory status epilepticus who showed a transient response to pyridoxine therapy but no effect on addition of PLP. The infant was later diagnosed to have a novel pathogenic mutation in the PNPO gene. This case highlights our limited understanding of why variation in response to treatment exists in children with PNPO deficiency.\n\nCase report\n\nA 31-week preterm 1500 g male newborn was born to non-consanguineous parents by caesarean section due to maternal pre-eclampsia and fetal distress. Poor respiratory efforts with severe hypotonia were observed at birth with Apgar scores of 5 at 1 minute, and 7 at 5 minutes. The cord blood gas analysis was suggestive of mixed acidosis with high lactate levels (5.1 mmol/L). Surfactant was administered immediately after delivery. At 2 hours of life, he developed multifocal myoclonic jerks, eyelid twitching and facial grimacing with ictal crying. The EEG showed a burst suppression pattern; the generalized spike and sharp wave paroxysms correlating with myoclonic jerks (Fig. 1A). His seizures were resistant to phenobarbital and levetiracetam. Intravenous pyridoxine (100 mg) was given (4th hour of life), resulting in cessation of seizures. Repeat EEG after seizure cessation showed generalized suppression with no epileptiform discharges (Fig. 1B).Fig. 1 (A) Electroencephalographic (EEG) sample on day 1 (3rd hour of life) shows a burst of rhythmic spike and sharp waves with background attenuation (B) EEG sample day 2 on (30 hours later than 1A ) shows continuous low amplitude background with the absence of epileptiform discharges.\n\nInvestigations revealed normal MRI and metabolic profile (including CSF lactate, glycine, sugar, blood ammonia, lactate, acylcarnitine profile, and urine organic acids). Blood sample was sent for whole exome sequencing. Similar seizures however, recurred on the fourth day of life after 36 hours of seizure freedom. This prompted us to start trials of other vitamins namely PLP (30 mg/kg/day), biotin (10 mg/day), and folinic acid (3 mg/kg/day) together along with continuing pyridoxine. As no benefit was noted, the vitamins were stopped on day 12 of life. His seizures remained drug-resistant despite the use of multiple anti-seizure medications including phenobarbital, levetiracetam, clobazam and topiramate. He was discharged upon parental request on day 25. At discharge he was severely encephalopathic and required nasogastric feeds. He continued to have numerous daily seizures at home.\n\nThe exome sequence analysis identified a homozygous missense variation in exon 5 of the PNPO gene (c.482 g > A) that results in the amino acid substitution of Histidine for Arginine at codon 161 (p.Arg161His) on day 42. The parents did not consent for further testing. Oral PN (30 mg/kg/day) was then restarted on an outpatient basis considering PN responsive PNPO deficiency disorder. Significant seizure control was noted after seven days, but encephalopathy was still persistent. Seizures soon recurred even on therapy, and the child finally expired at 56 days of life during sleep. There was no peri-mortem fever, fast breathing, or history suggestive of aspiration. A verbal autopsy could not elicit a definite cause of death.\n\nDiscussion\n\nPNPO deficiency is a rare neurometabolic disorder with less than 100 genetically proven cases reported in literature [1]. Clinical markers include a history of infertility, miscarriages, and excessive fetal movements, and preterm birth. Many affected infants require resuscitation at birth and are profoundly encephalopathic [1], [2]. Seizures develop within hours of birth in most babies (66% on the first day; 83% within the first week) [2]. Typical seizure semiology includes multifocal myoclonia, abnormal eye movements, facial grimacing, inconsolable cry, generalized tonic, epileptic spasms [3]. Our patient had a history of excessive fetal movements, prematurity, encephalopathy at birth, and drug-resistant epilepsy, with typical seizure types commencing from the second hour of life. The clinical differentials considered were hypoxic ischemic encephalopathy, structural brain malformations, or inherited metabolic disorders like biotinidase deficiency, non-ketotic hyperglycinemia, and vitamin responsive epilepsies. The detailed workup ruled out most of the structural and metabolic etiologies. The final diagnosis was obtained by genetic analysis.\n\nPNPO plays an important role in pyridoxine metabolism pathway. Dietary pyridoxine and pyridoxamine is converted to its active form pyridoxal-5-phosphate (PLP) by this enzyme. Theoretically, PLP should be the sole treatment option for PNPO, but it responds in a substantial number of cases (44%) only to PN [1]. Response to therapy with PN is subject to the presence of residual functional enzyme activity which enables its conversion to PLP. Other possible mechanism of PN response is by virtue of its chaperone effect inhibiting the premature damage of PNPO enzyme [4].\n\nPyridoxine response is guided by certain specific mutations, notably R225H, D33V, R116Q/P as reported earlier. It involves replacement of highly sustained arginine residues as reported in pyridoxine sensitive cases [3], [5]. The current case also consists of replacing the arginine residue by histidine due to a novel mutation (c.482G > A, p.Arg161His), thus adding to existing literature. Given that cases with similar mutations are known to have the variable therapeutic response from complete to partial, other environmental parameters like prematurity, age at therapeutic trial, riboflavin status, and pyridoxine levels in mothers might be additionally contributory [4]. Since, PNPO is flavin mono nucleotide( FMN) dependent enzyme, addition of riboflavin may also be of benefit. [10].\n\nTherapeutic variants of PNPO deficiency may be classified as: prompt responders to PN, late responders to PN, partial responders to PN, worsening variant on the addition of PLP to PN, vitamin combination responders [3], [4], [5], [6], [7], [8], [9], [10] (Table 1). These variants of pyridoxine responsiveness make the treatment complex and unpredictable. Our patient was treated twice with pyridoxine. The response was prompt but short-lasting on both occasions. Partial responsiveness to pyridoxine in PNPO deficiency is well known [6], [7]. PLP was added in our case on day 4 after seizure recurrence which demonstrated no benefit and hence stopped after 7 days. Since, inconsistency in therapeutic response is often observed in this disorder, it is advisable to continue the empirical vitamin treatments (PN, PLP) if any clinical response is observed till the genetic results are available [2]. We propose an algorithm for such situations (Fig. 2).Table 1 Variants of Pyridoxine responsive PNPO deficient cases.\n\nCategory\tGenetic mutation\tReference\tTreatment given\tOutcome\tProposed hypothesis\t\nPrompt responders (within two weeks) 3,4,5,8\n(n = 9)\tc.98A > T, p.D33V\nc.347G > A, p.R116Q\nc.674G > A, p.R225 H\tMills4 et al 2014 (n = 3)\tInitial dose 18–55 mg/kg/day\nMaintenance 6–26 mg/kg/day\tMild developmental delay (3)\n\t-Partial residual PNPO enzyme activity\n-Chaperone effect of PN on PNPO preventing its damage\t\nc.674G > A, p.R225 H\nc.421C > T, p.R141\tPlecko8 et al 2014 (n = 4)\tPN (17–50 mg/kg/day] along with anti-seizure medications\t\nNormal development (3)\nSpastic paraparesis (1)\t\nc.481C > T; p.R161C\nc.674G > A, p.R225 H\tJaeger5 et al 2016 (n = 1)\nLugli3 et al 2019 (n = 1)\tInitial 100 mg stat followed by 15 mg/kg/day single dose\nInitial 100 mg IV B6 followed by 20 mg/kg/day\tNormal development (2)\t\nLate responders(two weeks upto 6 months)3,5,9 (n = 8)\tc.674G > A, p.R225 Hc.674G > A, p.R225 H\tPlecko8 et al* 2014 (n = 2)\tGradual response to B6; Status epilepticus within 12 hours of switch to PLP.\tNormal development, gait instability (1)\nGlobal delay (1)\nmild GDD\tNo clear mechanism proposed\t\n\tc.(98A > T) p.(D33V )\tMills4 et al 2014 (n = 5)\tTime taken to seizure control 6 months\tSpastic quadriplegia (1)\nMild delay (2)\nSevere delay (1)\nAsperger syndrome (1)\t\t\n\tc.674G > A, p.R225H\tLevtova9 et al 2015\tBrief treatment at D7 and between 7 month-12 month (100 mg BD)\tSeizure-free during the period on pyridoxine. Died at 14 month due to refractory status epilepticus\t\t\nPartial responders6,7 (n = 2)\tc.352G > A p.G118R,\tPearl6 et al 2012\tComplete seizure control with PN for 6 weeks followed by breakthrough seizure which responded to PLP\tSeizure-free, mild developmental delay\tLeaky mutation; Partial residual PNPO enzyme activity\t\nc.674G > A, p.R225H;\tWare7 et al 2014\tPrompt response in the neonatal period. Partial responsive to PN until 7 years with occasional seizures.\nWorsening of seizures with the sudden withdrawal of B6 along with initiation of PLP @44 mg/kg/day\tSeizure-free, Autism spectrum disorder\t\nc.482G > A, p.R161H\tCurrent case\tTransient response from day1-3; stopped at D12 due to non-response.\nRestart at day 45, seizure control over 7 days\tDied at 56 days of life due to refractory status epilepticus\t\nParadoxical worsening4,8 (n = 5)\tNot specified\tMills4 et al 2014 (3/8)\tResponse to PN was present but symptoms deteriorated with a change to PLP\tIndividual details not available\t-High dose of PLP may cause seizures-Impaired inhibition of PNPO by PLP thus increasing the risk of toxic levels of PLP\n- Build-up of Pyridoxamine phosphate that may have an adverse effect\t\nc(674G > A) p(R225 H)\tPlecko8 et al 2014*(2)\tGradual response to PN; Status epilepticus within 12 hours of switch to PLP.\nPyridoxine (150–200 mg) at age 8–9 years\tGDD, occasional seizures\t\nCombination vitamins4,10 (n = 2)\tD33V + R225C + R116Q\tMills4 et al 2014 (1)\tTime taken to control 3.5 months. Seizure control by adding a multivitamin to pyridoxine\tDyslexia/Aspergers\t-Riboflavin (FMN) act as a cofactor to PNPO hence aids in the synthesis of PLP\t\nc.352G N A p.Gly118R\tMohanlal10 et al 2020 (1)\tB6 + Riboflavin + Thiamine + 4 ASM\tDevelopmental delay/ spastic diplegia\t\nGDD: Global developmental delay, PLP: Pyridoxal 5 phosphate, PN: Pyridoxine.\n\n*Same cases had a late response and paradoxical worsening.\n\nFig. 2 Flow chart for management of refractory neonatal status epilepticus with suspected vitamin responsive epilepsy.\n\nOur patient succumbed fourteen days after final genetic diagnosis of PNPO deficiency even after restarting PN. The specific cause of death was not clearly identified, but he was a fragile, malnourished (weight at discharge was 1375 grams), encephalopathic infant and was hence at risk of sepsis, hypoglycemia, hypothermia and aspiration. Sudden unexpected death in epilepsy (SUDEP) could also be a possibility. However, this cannot be diagnosed in the absence of an autopsy and additional information. Prolonging the PLP treatment along with pyridoxine after day 12 and the addition of riboflavin might have made the difference in outcome.\n\nThough, it is considered to be a treatable disorder, the neurodevelopmental outcome is not always favourable despite seizure control. In a large series of 87 patients with PNPO deficiency, the authors reported mortality in 25%, developmental delay in 50 %, and normal development in the rest of the patients. Prematurity, early-onset seizures, and delay in treatment initiation have been associated with a bad prognosis [1].\n\nIn conclusion, our case and the accompanying review highlights the complexity of treatment with pyridoxine and PLP in conveying a favorable response in infants with PNPO deficiency. Vitamin treatment should continue until the results of molecular genetic testing are available. The need for early and continued treatment is crucial for overall survival as well as neurodevelopmental outcome in potentially treatable cases of neonatal metabolic encephalopathy.\n\nFinancial support\n\nNone\n\nDeclaration of Competing Interest\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n==== Refs\nReferences\n\n1 Alghamdi M, Bashiri FA, Abdelhakim M, Adly N, Jamjoom DZ, Sumaily KM, Alghanem B, Arold ST. Phenotypic and molecular spectrum of pyridoxamine-5 0-phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine-5 0-phosphate oxidase deficiency.\n2 Guerin A. Aziz A.S. Mutch C. Lewis J. Go C.Y. Mercimek-Mahmutoglu S. Pyridox (am) ine-5-phosphate oxidase deficiency treatable cause of neonatal epileptic encephalopathy with burst suppression: case report and review of the literature J Child Neurol 30 9 2015 1218 1225 25296925\n3 Lugli L. Bariola M.C. Ori L. Lucaccioni L. Berardi A. Ferrari F. Further Delineation of Pyridoxine-Responsive Pyridoxine Phosphate Oxidase Deficiency Epilepsy: Report of a New Case and Review of the Literature With Genotype-Phenotype Correlation J Child Neurol 34 14 2019 937 943 31397616\n4 Mills P.B. Camuzeaux S.S.M. Footitt E.J. Mills K.A. Gissen P. Fisher L. Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome Brain. 137 5 2014 1350 1360 24645144\n5 Jaeger B. Abeling N.G. Salomons G.S. Struys E.A. Simas-Mendes M. Geukers V.G. Pyridoxine responsive epilepsy caused by a novel homozygous PNPO mutation Mol Genet Metab Rep 6 2016 60 63 27014579\n6 Pearl P.L. Hyland K. Chiles J. McGavin C.L. Yu Y. Taylor D. Partial pyridoxine responsiveness in PNPO deficiency InJIMD Reports-Case and Research Reports 2012/6 2012 139 142\n7 Ware T.L. Earl J. Salomons G.S. Struys E.A. Peters H.L. Howell K.B. Typical and atypical phenotypes of PNPO deficiency with elevated CSF and plasma pyridoxamine on treatment Dev Med Child Neurol 56 5 2014 498 502 24266778\n8 Plecko B. Paul K. Mills P. Clayton P. Paschke E. Maier O. Pyridoxine responsiveness in novel mutations of the PNPO gene Neurology. 82 16 2014 1425 1433 24658933\n9 A. Levtova S. Camuzeaux A.-M. Laberge P. Allard C. Brunel-Guitton P. Diadori et al. 67 75 10.1007/8904_2015_413.\n10 Mohanlal S. Bindu P.S. Sureshbabu S. Kumar S. Variable treatment response in a patient with pyridoxal N phosphate oxidase (PNPO) deficiency-understanding the paradox Epilepsy & Behavior Reports. 14 2020 100357 10.1016/j.ebr.2020.100357 32395712\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2589-9864",
"issue": "16()",
"journal": "Epilepsy & behavior reports",
"keywords": "Neonatal status epilepticus; Pyridox(am)ine −5- phosphate oxidase; Pyridoxal 5 phosphate; Pyridoxine; Vitamin responsive epilepsy",
"medline_ta": "Epilepsy Behav Rep",
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"pubdate": "2021",
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"title": "Complexities of pyridoxine response in PNPO deficiency.",
"title_normalized": "complexities of pyridoxine response in pnpo deficiency"
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"abstract": "BACKGROUND\nGemcitabine is a potent cytotoxic agent used in the treatment of many solid tumours, sarcomas and lymphomas. Vascular toxicity and thrombotic events related to gemcitabine seem to be underreported.\n\n\nMETHODS\nWe report two cases of gemcitabine related digital ischemic events. Case 1. A 65-year-old man was given the first-line treatment with gemcitabine for the advanced adenocarcinoma of pancreas. After four weekly doses of gemcitabine (total dose 4000 mg/m(2)) he presented with Raynaud's like phenomenon and ischemic fingertips necrosis in five digits of both hands. Symptoms resolved in all but one digit after stopping chemotherapy and treatment with iloprost trometamol infusion. Case 2. A 77-year-old man, ex-smoker, was administered a combination of gemcitabine and cisplatin as the first-line treatment for the locally advanced bladder cancer. After 4 cycles of the treatment (total dose of gemcitabine 4000 mg/m(2)) the patient suffered digital ischemia and necrosis on two digits of a right leg. Arteriography revealed preexisting peripheral arterial occlusive disease (PAOD) of both legs with very good peripheral collateral circulation and absent microcirculation of affected two digits. The gemcitabine treatment was stopped and the patient was treated with iloprost trometamol infusion and percutaneous transluminal angioplasty with dilatation of the right superficial femoral artery. Digital changes resolved without consequences. Severe thrombocytosis (platelet count 1211 × 10(9)/L) might have also contributed to the ischemic digital event in the second case.\n\n\nCONCLUSIONS\nDigital ischemic events associated with gemcitabine chemotherapy seem to be more common in patients with tobacco-associated cancers, especially when used in combination with platinum salt. The treatment with gemcitabine in patients with evolving Raynaud's phenomenon and/or preexisting PAOD should be done with caution.",
"affiliations": "Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.",
"authors": "Kuhar|Cvetka Grasic|CG|;Mesti|Tanja|T|;Zakotnik|Branko|B|",
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"fulltext": "\n==== Front\nRadiol OncolRadiol OncolRADORadiology and Oncology1318-20991581-3207Versita, Warsaw 10.2478/v10019-010-0020-1rado-44-04-257Case ReportDigital ischemic events related to gemcitabine: Report of two cases and a systematic review Kuhar Cvetka Grasic Mesti Tanja Zakotnik Branko Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, SloveniaCorrespondence to: Cvetka Grasič Kuhar, MD. PhD, Department of Medical Oncology, Institute of Oncology Ljubljana, Zaloška c. 2, SI-1000 Ljubljana, Slovenia; Phone: +386 1 5879282; Fax: +386 1 5879305; E-mail: cgrasic@onko-i.siDisclosure: No potential conflicts of interest were disclosed.\n\n12 2010 03 5 2010 44 4 257 261 01 2 2010 01 3 2010 Copyright © by Association of Radiology & Oncology2010This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).Background\nGemcitabine is a potent cytotoxic agent used in the treatment of many solid tumours, sarcomas and lymphomas. Vascular toxicity and thrombotic events related to gemcitabine seem to be underreported.\n\nCase report\nWe report two cases of gemcitabine related digital ischemic events.\n\nCase 1. A 65-year-old man was given the first-line treatment with gemcitabine for the advanced adenocarcinoma of pancreas. After four weekly doses of gemcitabine (total dose 4000 mg/m2) he presented with Raynaud’s like phenomenon and ischemic fingertips necrosis in five digits of both hands. Symptoms resolved in all but one digit after stopping chemotherapy and treatment with iloprost trometamol infusion.\n\nCase 2. A 77-year-old man, ex-smoker, was administered a combination of gemcitabine and cisplatin as the first-line treatment for the locally advanced bladder cancer. After 4 cycles of the treatment (total dose of gemcitabine 4000 mg/m2) the patient suffered digital ischemia and necrosis on two digits of a right leg. Arteriography revealed preexisting peripheral arterial occlusive disease (PAOD) of both legs with very good peripheral collateral circulation and absent microcirculation of affected two digits. The gemcitabine treatment was stopped and the patient was treated with iloprost trometamol infusion and percutaneous transluminal angioplasty with dilatation of the right superficial femoral artery. Digital changes resolved without consequences. Severe thrombocytosis (platelet count 1211 × 109/L) might have also contributed to the ischemic digital event in the second case.\n\nConclusions\nDigital ischemic events associated with gemcitabine chemotherapy seem to be more common in patients with tobacco-associated cancers, especially when used in combination with platinum salt. The treatment with gemcitabine in patients with evolving Raynaud’s phenomenon and/or preexisting PAOD should be done with caution.\n\nchemotherapygemcitabine vascular toxicitydigital ischemic events\n==== Body\nIntroduction\nGemcitabine is an important contemporary chemotherapeutic agent for the treatment of both solid tumours and lymphomas.1 As a nucleoside analog structurally related to cytosine arabinoside, it interferes with the synthetic pathways of the tumour cell predominantly in the S phase of the cell cycle. It is a potent inhibitor of DNA synthesis and repair.2\n\nFirst approved in 1996 for the treatment of unresectable pancreatic cancer, today gemcitabine is most commonly used in the therapy of pancreatic, ovarian, breast, non-small cell lung and bladder cancer, some sarcomas, cutaneous and peripheral T-cell lymphomas as well as in relapsed Hodgkin’s lymphoma.1 The use of this drug enables progress in the routine management of cancer patients.3,4\n\nGemcitabine is a drug with a favourable toxicity profile with myelosuppression, a flu-like syndrome, skin rash and radiation recall dermatitis being the most common side effects.2\n\nAs indications for its use in oncology have been expanding, some reports showed the possibility of its vascular side effects. Among them thrombotic microangiopathy5, venous thrombembolism, acute arterial events (digital ischemia and necrosis, vasculitis), systemic capillary leak syndrome and reversible posterior leukoencephalopathy are reported.1\n\nDigital ischemic events are rare in cancer patients. They are most frequently related to vascular disease due to hypercholesterolemia, arterial hypertension, diabetes or exposure to tobacco. They may also occur as a complication of connective tissue diseases, i.e. vasculitis with digital ischemic events.\n\nIn the present article we report two cases of digital ischemic events during the therapy with gemcitabine alone and in combination with cisplatin and review data in the literature regarding this rare side effect.\n\nCase 1\nA 65-year-old male was presented in March 2009 with primary metastatic adenocarcinoma of pancreas (metastases in retroperitoneal and cervical nodes). He had a history of nephrolythiasis ten years ago and 5 months lasting history of hydronephrosis of the left kidney of grade III, caused by enlarged retroperitoneal lymph nodes. At presentation he was overweight with grade I renal impairment (creatinine 129 μmol/L). He complained of pain in the upper abdomen. Tumour marker CA 19-9 was elevated (> 12 000 IU); platelet count was 376 × 109/L.\n\nIn March 16 2009 he started the treatment with gemcitabine monotherapy in a weekly dose 1000 mg/m2. After 3 weekly doses he had less pain in the abdomen and tumour marker CA 19-9 halved (6163 IU). Platelet count was elevated (570 × 109/L). He complained of painful swelling in three digits of right hand and acrocyanosis. After the 4th dose of gemcitabine pain in digits increased and the patient was admitted to the local hospital. Raynaud’s syndrome was suspected. Criteria for paraneoplastic microthrombosis, which was suspected, were not met. At the beginning the patient was treated with acetylsalicylic acid. No improvement was recorded. On the control visit in our institution (May 05 2009) the patient complained of severe pain in five digits of both hands. The examination showed dry fingertips necrosis. Radial and ulnar pulses were normal. The Doppler ultrasound of both arms showed normal macrocirculation. Digital plethismography showed an absent signal on digits I, II and IV of the right and digits III and V of the left hand. Gemcitabine induced vasculitis causing ischemia was suspected and gemcitabine treatment was stopped. The patient was treated with the prolonged infusion of a prostacycline analogue iloprost trometamol (20 mg/day for three weeks) and analgesic therapy with NSARD and opioids. Digital changes in all but one of affected digits resolved at the next visit in June 24 2009. Ischemic changes of distal phalange of digit V of the left hand required the amputation. The patient died in August 2009 due to the progressive disease.\n\nCase 2\nA 77- year-old male presented in May 06 2009 with a diagnosis of locally advanced bladder cancer (T4aN2M0). He was heavy a smoker in the past and had a history of gastric perforation due to peptic ulcer ten years ago. In February 2009 he was temporary on amiodarone medication due to paroxysm of atrial fibrillation. Otherwise he was in good physical condition. In April 2009 he underwent an attempt of radical cistoprostatectomy. Due to the local extension of the tumour only Bricker neovesica and biopsy of pelvic lymphnodes was performed. In May 2009 he was presented for induction chemotherapy and definitive radiotherapy afterwards. From May to August 2009 he received four cycles of chemotherapy with cisplatin and gemcitabine (cisplatin 75 mg/m2 on day 1 and gemcitabine 1000 mg/m2 on days 1 every three weeks). None of the planned gemcitabine doses on day 8 was applied due to the infection. In August 8 2009 the patient presented with painful black spots on digits I and II of the right foot and subluxation of the thumbnail of the same foot. He underwent the ablation of the thumbnail. Ischemic changes in the thumb were suspected. In August 18 2009 the patient presented with the progressive painful fingertip necrosis on fingertips I and II of the right foot (Figure 1). The elevated platelet count was recorded (1211×109/L). He was sent to an angiologist. Doppler ultrasound showed severe peripheral arterial occlusive disease (PAOD) of both legs. Pelvic arteriography showed the occlusion of right superficial femoral artery (AFS) in the length of 5 cm and of left AFS in length of 18 cm, with very good collateral circulation on both sides and good transition of the both poplitheal arteries (Figure 2 and 3). The patient was treated with prolonged infusion of a prostacycline analogue - iloprost trometamol (20 mg/day for 7 days). A successful percutaneous transluminal angioplasty with dilatation of the right AFS was performed in September 1 2009. After this procedure the foot macrocirculation improved (warm skin of the right foot). Thereafter temporary wet necrosis and wound infection on digit II occurred, which healed until November 2 2009. The amputation of the affected digits was not required. Acetylsalicylic acid 100 mg/d was prescribed.\n\nDiscussion\nDigital ischemic events in cancer patients are rare. However, in cancer patients with a history of heavy smoking, dislypidemia, arterial hypertension or diabetes, PAOD may already be presented at cancer diagnosis and may lead to ischemic events. In systemic sclerosis the impairment of microcirculation due to vasculitis and/or vasospasm can also cause a digital arterial obstruction.6 Some anticancer agents (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone, doxorubicin, tamoxifen, cisplatin-gemcitabine combination) are implicated in thrombosis and thrombembolic events.7 Therefore, in a patient with predisposing factors for the impaired microcirculation these anticancer agents may attribute to digital ischemic events.6\n\nAmong cases in the literature, Barcelo et al.7 reported four cases of digital ischemic changes related to combination chemotherapy with gemcitabine plus cisplatin in patients treated for non-small cell lung cancer. In two of four cases a previously asymptomatic organic vascular lesion was aggravated while on chemotherapy with cisplatin and gemcitabine. Antiplatelet agent triflusal and vasoactive agent buflomedil were successful in resolving pain. One patient needed the additional leg amputation and two others thrombectomy.\n\nSimilarly, Venat-Bouvet et al.8 described a patient with the acute onset of bilateral PAOD with necrosis of fingerpads which presented after the treatment with gemcitabine and platinum salt as a first line treatment for urothelial carcinoma of the bladder. The patient had a favourable outcome after chemotherapy withdrawal and infusion of iloprost trometamol, as in our Case 2. In our Case 2 cumulative dose of gemcitabine was only 4000 mg/m2, in contrast to others (10000 mg/m2, 14390 mg).8,9\n\nBlaise et al.9 reported two cases of digital ischemia. First was a female treated with gemcitabine as the second line for lymph-node metastatic squamous cell carcinoma of unknown origin. The second patient was treated for bladder carcinoma with gemcitabine and carboplatine. Both resolved after the interruption of gemcitabine and additional medical treatment.\n\nAnother case attributed to vascular toxicity of gemcitabine is reported by Holstein et al.10 treated with platinum plus gemcitabine for advanced urothelial carcinoma. After the second cycle of chemotherapy the patient presented with digital ischemia. Digital amputation was avoided by sympathicolysis by bilateral blockade of brachial plexus and application of iloprost, heparin, corticosteroids and acetylsalicylic acid.\n\nPatients with scleroderma are at high risk for developing digital infarction because of their underlying vascular disease and associated Raynaud’s phenomenon. Clowse et al.11 presented a patient with scleroderma who developed multiple ischemic digits after receiving combination chemotherapy of carboplatin plus gemcitabine for lung cancer. D’Allesandro et al.12 reported a case with Raynaud type phenomenon, intermittent fever, digital necrosis and a fingertip gangrene after receiving two applications of gemcitabine for bladder cancer. The authors suggested caution in using such chemotherapy in subjects with autoimmune disorders (scleroderma, positive HEP-2 and cryoglobulin).11,13\n\nDigital ischemic changes resolved in most cases after stopping the application of chemotherapy and the treatment with prostacyclin antagonists (iloprost or buflomedil). A more sophisticated treatment with sympathicolysis by bilateral thoracic block was reported to be efficient in digital ischemic event in scleroderma patient, where gangrenous ulcers occurred due to vaso-occlusive disease, which is a combination of occlusive vasculitis and symphatically-mediated vasospasm.6 Sympathectomy and iloprost infusion were reported to be successful in the treatment of severe acral ischemia and necrotic lesions of several fingertips after receiving palliative chemotherapy with gemcitabine for inoperable squamous cell carcinoma of the tonsil.14\n\nIn our Case 1 the first signs of the impaired digital circulation (swollen and painful cold blue fingers) occurred after three weekly doses of gemcitabine therapy and worsened after the next weekly application of the same drug, therefore the causal relationship between gemcitabine and digital arterial ischemia seems very probable. The patient had no history or symptoms of preexsisting PAOD or connective tissue disease. The Raynaud’s phenomenon can be a paraneoplastic manifestation in disseminated pancreatic cancer, but would already be present at presentation of disease and would probably improve with the effective anticancer therapy. The occurrence of digital ischemia was probably related to vascular toxicity of gemcitabine, as indicated by resolving microcirculation in 4 of 5 affected digits after the discontinuation of gemcitabine and the intervention with vasodilating agent iloprost.\n\nIn Case 2 after the cumulative dose of gemcitabine of 4000 mg/m2 and cisplatin 300 mg/m2 arterial ischemic necrosis on two digits of the right foot occurred. After a detailed investigation of the patient, severe preexisting PAOD of both legs with the very good collateral circulation was diagnosed. Gemcitabine may also be capable to cause endothelial damage and thrombocytosis.1,2 The latter could also attribute to impaired microcirculation in our case (platelet count at 3rd cycle of chemotherapy 1211 × 109/L). At that time the patient was on fractionated heparin in prophylactic dosing. Instead of heparin, the antiagregation therapy with acetylsalicylic acid would be more appropriate in preventing digital arterial thrombosis. After the dilatation of the occluded segment of the main leg arterial vessel and vasodilatation effect of iloprost infusion both macro and microcirculation improved, respectively. Digital ischemic necroses resolved without durable consequences.\n\nIn both cases painful cold trophic skin changes were clinically suspicious of compromised arterial microcirculation, confirmed by absent plethysmographic signals. In Case 1 Doppler ultrasound showed good macrocirculation, which was severely impaired in Case 2, as already suggestive of PAOD by patient’s long smoking history. Clinically absent pedal pulses and angiologic examination with arteriography could place angioplastic intervention before the initiation of chemotherapy with gemcitabine and cisplatin. A noninvasive evaluation of the leg arterial perfusion could be done by MRI enhanced angiography15 and an invasive angiography being applied only in cases where an invasive procedure is indicated. The antiagregation therapy (acetylsalicylic acid 100 mg a day) in case of severe reactive thrombocytosis in cancer patients as well as in patients with cardiovascular factors is indicated and could prevent the development of digital ischemia in Case 2. Discontinuation of cisplatin plus gemcitabine and the intervention with iloprost prometanol have been proven helpful in resolving microcirculation in both cases as documented by control plethysmography. Additionally calcium channel blockers and other vasodilatators were shown beneficial in resolving digital ischemia.6,7,11\n\nConclusions\nDigital ischemic events associated with gemcitabine chemotherapy seem to be more common than previously thought, especially when used in combination with platinum salts and in patients with tobacco-associated cancers. In patients with known risk factors for PAOD, like dislypidemia, arterial hypertension, diabetes or tobacco smoking, and a history of intermittent claudication thorough the examination of peripheral pulses should be performed before the initiation of gemcitabine or platinum-gemcitabine doublet. In addition, if painful trophic digital changes develop while on therapy with gemcitabine, medical oncologists should refer the patient to an angiologist for the assessment of impaired micro or macrocirculation. In case of diagnosis of ischemic vascular event, discontinuation of gemcitabine and immediately therapy with prostacycline analogues should be initiated. The early diagnosis and the appropriate intervention improve not only the outcome of the ischemic vascular event but also the quality of life of the patient.\n\nFIGURE 1. Ischemic necrosis on digits I and II of right foot after 4 cycles of chemotherapy with cisplatin and gemcitabine (Case 2).\n\nFIGURE 2. Pelvic arteriography showing occlusion of right superficial femoralis artery (AFS) in the length of 5 cm and of left AFS in length of 18 cm (Case 2).\n\nFIGURE 3. Arteriography showing impaired circulation of distal part of both legs in Case 2.\n==== Refs\nReferences\n1. Dasanu CA Gemcitabine: vascular toxicity and prothrombotic potential Expert Opin Drug Saf 2008 7 703 16 18983217 \n2. Summary of Product Characteristics of Gemcitabine; date of revision 18 February 2009: http://emc.medicines.org.uk/medicine/596.\n3. Debevec L Jeric T Kovac V Bitenc M Sok M Is there any progress in routine management of lung cancer patients? A comparative analysis of an institution in 1996 and 2006 Radiol Oncol 2009 43 47 53 \n4. Kovač V Smrdel U Meta-analyses of clinical trials in patients with non-small cell lung cancer Neoplasma 2004 51 334 40 15640936 \n5. Izzedine H Isnard-Bagnis C Launay-Vacher V Mercadal L Tostivint I Rixe O Gemcitabine-induced thrombotic microangiopathy: a systematic review Nephrol Dial Transplant 2006 21 3038 45 16968717 \n6. Kyung RH Chan K Un JP Successful treatment of digital ulcers in a scleroderma patient with continuous infusion bilateral thoracic sympathetic block Pain Physician 2008 11 91 6 18196175 \n7. Barcelo R Lopez-Vivanco G Mane JM Rubio I Munoz A Fernandez R Distal ischemic changes related to combination chemotherapy with cisplatin and gemcitabine. Description of four cases Ann Oncol 2000 11 1191 4 11061617 \n8. Venat-Bouvet L Szelag JC Martin J Labourey JL Genet D Tubiana-Mathieu N Thrombotic microangiopathy and digital necrosis; two unrecognized toxicities of gemcitabine Anticancer Drugs 2003 14 829 32 14597878 \n9. Blaise S Appeltants H Carpentier PH Debru JL Digital ischemia and gemcitabine. Twoo new cases J Mal Vasc 2005 30 53 7 15924070 \n10. Holstein A Batge R Egberts EH Gemcitabine induced digital ischemia and necrosis Eur J Cancer Care (Engl) 2009 [Epub ahead of print] \n11. Clowse MEB Wigley FM Digital necrosis related to carboplatin and gemcitabine therapy in systemic sclerosis J Rheumatol 2003 30 1341 3 12784412 \n12. D’Alessandro V Errico M Varriale A Greco A De Cata A Carnevale V Case report: acro-necrosis of the upper limbs caused by gemcitabine therapy Cli Ter 2003 154 207 10 \n13. Hummers LK Wigley FM Management of Raynaud’s phenomenon and digital ischemic lesions in scleroderma Rheum Dis Clin North Am 2003 29 293 313 12841296 \n14. Buch RS Geisbüsch R Kunkel M Acral ischemia as a rare paraneoplastic syndrome in the terminal phase of mouth floor carcinoma. [German] Mund Kiefer Gesichtschir 2002 6 331 5 12448236 \n15. Aschauer MA Ebner F Stollberger R Advances in contrast-enhanced MR-angiography Radiol Oncol 2002 36 103 8\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1318-2099",
"issue": "44(4)",
"journal": "Radiology and oncology",
"keywords": "chemotherapy; digital ischemic events; gemcitabine vascular toxicity",
"medline_ta": "Radiol Oncol",
"mesh_terms": null,
"nlm_unique_id": "9317213",
"other_id": null,
"pages": "257-61",
"pmc": null,
"pmid": "22933925",
"pubdate": "2010-12",
"publication_types": "D016428:Journal Article",
"references": "14597878;15640936;15924070;12841296;12448236;12910811;18983217;12784412;18196175;16968717;11061617;19490003",
"title": "Digital ischemic events related to gemcitabine: Report of two cases and a systematic review.",
"title_normalized": "digital ischemic events related to gemcitabine report of two cases and a systematic review"
} | [
{
"companynumb": "SI-PFIZER INC-2011000270",
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"activesubstancename": "CISPLATIN"
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... |
{
"abstract": "Angiotensin converting enzyme (ACE) inhibitors and angiotensin II (AT-II)-receptor-antagonists have been demonstrated to cause fetotoxicity when administered to women during the second and third trimester of pregnancy. Although use of ACE inhibitors during the first trimester of pregnancy seems to be safe, with no associated teratogenicity, there is not sufficient information regarding the safety of first-trimester exposure to AT-II-receptor-antagonists. We report a case of exencephaly and unilateral renal agenesia in a fetus of a diabetic woman who became pregnant while taking irbesartan.",
"affiliations": "Endocrinology and Nutrition Department, Universitary General Hospital of Alicante, Alicante, Spain. ev.boixc@coma.es",
"authors": "Boix|E|E|;Zapater|P|P|;Picó|A|A|;Moreno|O|O|",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000804:Angiotensin II; D000077405:Irbesartan",
"country": "Italy",
"delete": false,
"doi": "10.1007/BF03345344",
"fulltext": null,
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"issn_linking": "0391-4097",
"issue": "28(11)",
"journal": "Journal of endocrinological investigation",
"keywords": null,
"medline_ta": "J Endocrinol Invest",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D003922:Diabetes Mellitus, Type 1; D005260:Female; D006801:Humans; D000077405:Irbesartan; D007668:Kidney; D009436:Neural Tube Defects; D011247:Pregnancy; D011248:Pregnancy Complications; D011261:Pregnancy Trimester, First; D013777:Tetrazoles",
"nlm_unique_id": "7806594",
"other_id": null,
"pages": "1029-31",
"pmc": null,
"pmid": "16483184",
"pubdate": "2005-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14592593;11386314;1771591;11211003;3917318;15329835;7502238;7778045;14632309;11386315;15577728;10694179;12055019;12925063;11485133;12032121;11480433;7699986;11386316;15544482",
"title": "Teratogenicity with angiotensin II receptor antagonists in pregnancy.",
"title_normalized": "teratogenicity with angiotensin ii receptor antagonists in pregnancy"
} | [
{
"companynumb": "BMS13334750",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
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"actiondrug": "1",
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"activesubstancename": "HYDROCHLOROTHIAZIDE"
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"... |
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"abstract": "A 17-year-old boy was referred to our institution for a re-evaluation of congenital nephrogenic diabetes insipidus. A water restriction test revealed no urine concentration or volume reduction and a subsequent pitressin test revealed a lack of an anti-diuretic response. Nephrogenic diabetes insipidus was confirmed, and the patient was treated using trichlormethiazide 4 mg, indomethacin 175 mg, and desmopressin 20 μg. His blood pressure and weight were not controlled owing to polydipsia and polyuria secondary to acquired excessive water drinking behavior. Repeated admissions for weight control were necessary and despite consultation with a psychiatrist for his obsessive water drinking behavior, he had end-stage renal failure after 30 years of treatment. Genetic testing revealed AVPR2 mutation (c. T866C: p. L289P) that had previously been reported as a pathogenic mutation. His excessive drinking behavior persisted, leading to hyponatremia even after initiation of hemodialysis. There was also difficulty in achieving body weight control, which was managed by repeated admissions with restriction of water intake, being the mainstay of management.",
"affiliations": "Department of Nephrology, Nephrology Center, Toranomon Hospital Kajigaya, Kajigaya 1-3-1, Takatsu-ku, Kawasaki, Kanagawa, 213-8587, Japan. faure@hotmail.co.jp.;Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, 113-8519, Japan.;Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, 113-8519, Japan.;Department of Nephrology, Nephrology Center, Toranomon Hospital Kajigaya, Kajigaya 1-3-1, Takatsu-ku, Kawasaki, Kanagawa, 213-8587, Japan.;Department of Nephrology, Nephrology Center, Toranomon Hospital Kajigaya, Kajigaya 1-3-1, Takatsu-ku, Kawasaki, Kanagawa, 213-8587, Japan.;Department of Nephrology, Nephrology Center, Toranomon Hospital Kajigaya, Kajigaya 1-3-1, Takatsu-ku, Kawasaki, Kanagawa, 213-8587, Japan.",
"authors": "Iijima|Takashi|T|0000-0002-9266-9080;Mori|Takayasu|T|;Sohara|Eisei|E|;Suwabe|Tatsuya|T|;Hoshino|Junichi|J|;Ubara|Yoshifumi|Y|",
"chemical_list": "D017483:Receptors, Vasopressin",
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-020-00549-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "10(2)",
"journal": "CEN case reports",
"keywords": "AVPR2; Nephrogenic diabetes insipidus; Polydipsia",
"medline_ta": "CEN Case Rep",
"mesh_terms": "D000293:Adolescent; D018500:Diabetes Insipidus, Nephrogenic; D006801:Humans; D008297:Male; D009154:Mutation; D059606:Polydipsia; D017483:Receptors, Vasopressin; D006435:Renal Dialysis",
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "226-229",
"pmc": null,
"pmid": "33125666",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "8311078;195476;2986401;28134709;8289981;10820168;2076930;16695887;19373493;7018256;25750571;26920127",
"title": "A patient with congenital nephrogenic diabetes insipidus due to AVPR2 mutation complicated by persisting polydipsia under hemodialysis treatment.",
"title_normalized": "a patient with congenital nephrogenic diabetes insipidus due to avpr2 mutation complicated by persisting polydipsia under hemodialysis treatment"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-301744",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DESMOPRESSIN"
},
"dr... |
{
"abstract": "BACKGROUND\nAlthough thromboembolic complications are common in adult patients with malignant diseases, cerebral venous sinus thrombosis has been rarely described in cancer afflicted pediatric and adolescent population.\n\n\nMETHODS\nA 16-year-old adolescent girl referred for complaints of pain and swelling on her left leg. On physical examination, a solid tibial mass was discovered. After the diagnosis of Ewing sarcoma with a tru-cut biopsy, chemotherapy protocol consisting of cisplatin, ifosfamide, adriamycine, and vincristine was started. During the first course of the treatment, the patient expressed headache, diplopia, and ptosis. Contrast-enhanced magnetic resonance (MR) images and MR angiography showed superior sagittal and transverse sinus thromboses. After anticoagulant therapy, the thromboses disappeared within 1.5 months. She received her chemotherapy protocol with the anticoagulant prophylaxis. After a follow-up period of 12 months, she is still in a good neurological recovery without any sequel.\n\n\nCONCLUSIONS\nChildren and adolescents with cancer should be monitored closely for thrombotic complications. We discuss this uncommon case to draw attention to the importance of early diagnosis and adequate treatment of intracranial thrombosis in childhood cancer, and we review the relevant literature.",
"affiliations": "Meram Faculty of Medicine, Department of Pediatrics, Selcuk University, 42080, Konya, Turkey. drekremunal@yahoo.com.tr",
"authors": "Unal|Ekrem|E|;Yazar|Abdullah|A|;Koksal|Yavuz|Y|;Caliskan|Umran|U|;Paksoy|Yahya|Y|;Kalkan|Erdal|E|",
"chemical_list": "D000925:Anticoagulants",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00381-008-0646-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0256-7040",
"issue": "24(9)",
"journal": "Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery",
"keywords": null,
"medline_ta": "Childs Nerv Syst",
"mesh_terms": "D000293:Adolescent; D000925:Anticoagulants; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D004172:Diplopia; D005260:Female; D006261:Headache; D006801:Humans; D008279:Magnetic Resonance Imaging; D012512:Sarcoma, Ewing; D012851:Sinus Thrombosis, Intracranial; D013977:Tibia; D020246:Venous Thrombosis",
"nlm_unique_id": "8503227",
"other_id": null,
"pages": "983-6",
"pmc": null,
"pmid": "18481071",
"pubdate": "2008-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16470154;15953008;18043135;16044439;16991135;16206194;15735962;15383489;12853582;15383478;16039698",
"title": "Cerebral venous sinus thrombosis in an adolescent with Ewing sarcoma.",
"title_normalized": "cerebral venous sinus thrombosis in an adolescent with ewing sarcoma"
} | [
{
"companynumb": "TR-FRESENIUS KABI-FK201700146",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "The aim of the present study was to analyze the risk factors for new-onset chronic kidney disease (CKD) in patients who have received a liver transplant. A total of 190 patients who underwent liver transplantation between March 2001 and January 2015 were followed up, and analyzed retrospectively. Sex, age, primary disease, preoperative laboratory findings (hemoglobin, albumin, creatinine and glomerular filtration rate), surgical approach, blood loss during the surgery and transfusion volume, postoperative complications, and the average levels of calcineurin inhibitors (CNIs) (from liver transplantation to the onset of CKD) were analyzed. In total, 40 patients developed new-onset CKD after transplantation. Clinical data in the new-onset CKD group were compared with the non-CKD group. A χ2 test, t-test and logistic regression analysis were performed using SPSS 17.0 software. The incidence of new-onset CKD after liver transplantation was 21.1%. Renal pathology included IgA nephropathy, hepatitis B virus-associated nephropathy, membranous proliferative glomerulonephritis, focal segmental glomerular sclerosis and cryoglobulinemia-associated renal injury. Among the CKD patients, 85.7% had tubulointerstitial damage. Univariate analysis showed that preoperative renal function, hemoglobin, intraoperative blood loss and transfusion volume, postoperative acute kidney injury, average levels of CNIs, and hypertension were risk factors for new-onset CKD after liver transplantation. Logistic regression analysis showed that preoperative glomerular filtration rate [odds ratio (OR)=0.980, P=0.041], hemoglobin (OR=0.972, P=0.034), average levels of CNIs (OR=1.364, P=0.015) and hypertension (OR=4.833, P=0.048)] were independent risk factors for new-onset CKD. The incidence of new-onset CKD in patients who received liver transplantation was high. The main risk factors were identified to be preoperative glomerular filtration rate, hemoglobin, postoperative average levels of CNIs and hypertension.",
"affiliations": "Department of Nephrology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, P.R. China.;Department of Nephrology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, P.R. China.;Department of Nephrology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, P.R. China.;Department of Nephrology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, P.R. China.",
"authors": "Li|Yuehong|Y|;Li|Binbin|B|;Wang|Wei|W|;Lv|Jiaxuan|J|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/etm.2018.5823",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-0981",
"issue": "15(4)",
"journal": "Experimental and therapeutic medicine",
"keywords": "calcineurin inhibitors; chronic kidney disease; liver transplantation; renal pathology",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "3589-3595",
"pmc": null,
"pmid": "29545888",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": "22494671;24029423;23668976;16556162;15084934;21140356;22217532;22759237;26311603;22067311;24373168;22408361;20207711;21115672;20098285;20534269;22847917;20620473",
"title": "Risk factors for new-onset chronic kidney disease in patients who have received a liver transplant.",
"title_normalized": "risk factors for new onset chronic kidney disease in patients who have received a liver transplant"
} | [
{
"companynumb": "CN-STRIDES ARCOLAB LIMITED-2018SP002870",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nThrombocytopenia, ascites, myelofibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome is a newly recognized and rare clinical subtype of Castleman disease. Renal involvement in TAFRO syndrome usually presents with mild proteinuria, microscopic hematuria, and acute renal injury requiring temporary renal replacement. There is no standard therapy available and treatment failures are common, leading to a poor prognosis. We report a case of acute renal failure caused by TAFRO syndrome, successfully managed by long-term corticosteroids combined with bortezomib and cyclophosphamide.\n\n\nMETHODS\nThe patient was a 52-year-old female who presented with fever, anasarca, oliguria, and abdominal distension at first. She progressed rapidly to anuric renal failure requiring hemodialysis. She also demonstrated thrombocytopenia, anemia, coagulopathy, and a hyperinflammatory status. Her CT scan showed severe polyserositis, splenomegaly, and lymphadenopathy. Her serum vascular epithelial growth factor level was significantly elevated. Axillary lymph node biopsy showed hyaline-vascular type Castleman disease, supporting the diagnosis of TAFRO syndrome. Her renal function recovered after high-dose steroids and supportive treatment. A weekly dosing regimen of bortezomib, cyclophosphamide, and dexamethasone combined with medium dose prednisone in between were deployed. Her blood cell count and renal function remained stable after 6 months. The inflammation was suppressed and the polyserositis resolved completely.\n\n\nCONCLUSIONS\nTAFRO syndrome is rare and has a poor prognosis due to the lack of standard treatment. Our patient might be the first TAFRO case successfully treated by bortezomib, cyclophosphamide, and corticosteroids.",
"affiliations": "Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.;Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.;Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.;Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.;Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.;Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.;Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.;Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.;Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.;Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.;Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China, chenlimeng@pumch.cn.",
"authors": "Xia|Peng|P|;Zhang|Lu|L|;Zou|Menglian|M|;Zhang|Tengyue|T|;Li|Ran|R|;Shi|Xiaoxiao|X|;Wang|Jing|J|;Qin|Yan|Y|;Li|Xuemei|X|;Li|Jian|J|;Chen|Limeng|L|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D000069286:Bortezomib; D003520:Cyclophosphamide",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000505458",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1420-4096",
"issue": "45(4)",
"journal": "Kidney & blood pressure research",
"keywords": "Acute kidney injury; Bortezomib; TAFRO syndrome",
"medline_ta": "Kidney Blood Press Res",
"mesh_terms": "D058186:Acute Kidney Injury; D000305:Adrenal Cortex Hormones; D000069286:Bortezomib; D005871:Castleman Disease; D003520:Cyclophosphamide; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged",
"nlm_unique_id": "9610505",
"other_id": null,
"pages": "623-630",
"pmc": null,
"pmid": "32492687",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acute Kidney Injury Caused by TAFRO Syndrome in a Chinese Patient: Efficacy of Long-Term Corticosteroids Combined with Bortezomib and Cyclophosphamide.",
"title_normalized": "acute kidney injury caused by tafro syndrome in a chinese patient efficacy of long term corticosteroids combined with bortezomib and cyclophosphamide"
} | [
{
"companynumb": "CN-TAKEDA-2020TUS026076",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo report our 4-year experience in Turkey, with advanced intra-ocular retinoblastoma managed primarily with intra-arterial chemotherapy (IAC).\n\n\nMETHODS\nFrom October 2011 to September 2015, 26 group D eyes of 24 treatment-naïve retinoblastoma patients managed primarily with IAC were evaluated in this prospective study.\n\n\nRESULTS\nOf 76 procedures, ophthalmic artery cannulation failed in two patients with unilateral involvement. In the remaining 22 patients (24 eyes), the mean age at diagnosis was 18 months (range, 6-55 months). Each eye received a mean of 3 IAC sessions/eye (range, 2-5 sessions). After a median follow-up of 29 months (range, 6-55 months), complete regression of the main tumour was achieved in 23 of 24 eyes. One eye with partial regression required enucleation due to ciliary body involvement by the tumour. Overall, 16 eyes (66.6%) were salvaged with primary IAC with or without additional local treatments, and eight (33.3%) required enucleation. The main IAC-related periocular complications included transient eyelid oedema (n = 13), ptosis (n = 6) and forehead hyperpigmentation (n = 3), each resolving in 2 weeks to 4 months. Intra-ocular complications included chorioretinal atrophy (n = 9), newly noted retinal detachment (n = 5) and vitreous haemorrhage (n = 1). Kaplan-Meier eye estimates of enucleation-free survival rates were 83.3% (95% CI, 68.4-98.1%), 69.1% (95% CI, 49.8-88.3%) and 62.9 (95% CI, 41.9-83.8%) at 6 months, 1 and 2 years, respectively, and stable thereafter.\n\n\nCONCLUSIONS\nOur first 4-year experience in Turkey showed that enucleation or external-beam radiotherapy could be avoided in two-thirds of eyes with advanced intra-ocular retinoblastoma managed primarily with IAC.",
"affiliations": "Istanbul Faculty of Medicine, Department of Ophthalmology, Ocular Oncology Service, Istanbul University, Istanbul, Turkey. sbtuncer@yahoo.com.;Istanbul Faculty of Medicine, Department of Radiology, Division of Interventional Neuroradiology, Istanbul University, Istanbul, Turkey.;Cerrahpasa Medical Faculty and Oncology Institute, Division of Pediatric Hematology - Oncology, Istanbul University, Istanbul, Turkey.;Istanbul Faculty of Medicine, Department of Ophthalmology, Ocular Oncology Service, Istanbul University, Istanbul, Turkey.;Istanbul Faculty of Medicine, Department of Ophthalmology, Ocular Oncology Service, Istanbul University, Istanbul, Turkey.;Istanbul Faculty of Medicine, Department of Radiology, Division of Interventional Neuroradiology, Istanbul University, Istanbul, Turkey.",
"authors": "Tuncer|Samuray|S|;Sencer|Serra|S|;Kebudi|Rejin|R|;Tanyıldız|Burak|B|;Cebeci|Zafer|Z|;Aydın|Kubilay|K|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan",
"country": "England",
"delete": false,
"doi": "10.1111/aos.13077",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1755-375X",
"issue": "94(7)",
"journal": "Acta ophthalmologica",
"keywords": "chemosurgery; intra-arterial chemotherapy; primary therapy; retinoblastoma; superselective; superselective intra-arterial chemotherapy",
"medline_ta": "Acta Ophthalmol",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D002675:Child, Preschool; D005260:Female; D005471:Fluoroscopy; D006801:Humans; D007223:Infant; D007261:Infusions, Intra-Arterial; D008297:Male; D008558:Melphalan; D009880:Ophthalmic Artery; D011446:Prospective Studies; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D016896:Treatment Outcome; D014421:Turkey",
"nlm_unique_id": "101468102",
"other_id": null,
"pages": "e644-e651",
"pmc": null,
"pmid": "27214798",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Superselective intra-arterial chemotherapy in the primary management of advanced intra-ocular retinoblastoma: first 4-year experience from a single institution in Turkey.",
"title_normalized": "superselective intra arterial chemotherapy in the primary management of advanced intra ocular retinoblastoma first 4 year experience from a single institution in turkey"
} | [
{
"companynumb": "TR-APOPHARMA USA, INC.-2016AP015399",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": nul... |
{
"abstract": "Drug-induced liver injury is a frequent cause of acute liver failure. It may cause clinical manifestations ranging from simple alteration of the common liver function tests until more severe manifestations including encephalopathy, coagulopathy, and in many cases progressive multi-organ dysfunction. The condition, therefore, may be associated with higher morbidity and mortality as well as higher consumption of economic resources. In this paper, we present the case of a 71-year-old patient treated with hemodialysis, diabetic, with ischemic cardiopathy and severe peripheral vascular disease. The patient presented a progressive clinical deterioration with the development of ascites, jaundice and significant deterioration of liver function. Diagnostic studies have ruled out viral and immunological diseases and, in agreement with the score obtained from the Maria and Victorino scale, clopidogrel was identified as the major factor responsible for the damage. After the suspension of the drug, the follow-up has led to the complete and stable recovery of liver function.",
"affiliations": null,
"authors": "Papagni|Sergio|S|;Bonifati|Carmen|C|;Dagostino|Filippo|F|;Murgo|Angelo Marco|AM|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0393-5590",
"issue": "33(1)",
"journal": "Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia",
"keywords": null,
"medline_ta": "G Ital Nefrol",
"mesh_terms": "D000368:Aged; D056486:Chemical and Drug Induced Liver Injury; D000077144:Clopidogrel; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors; D006435:Renal Dialysis; D013988:Ticlopidine",
"nlm_unique_id": "9426434",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26913747",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clopidogrel- induced hepatotoxicity in hemodialyzed patient: a case report.",
"title_normalized": "clopidogrel induced hepatotoxicity in hemodialyzed patient a case report"
} | [
{
"companynumb": "IT-SA-2016SA036122",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BISOPROLOL"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nTo identify factors predicting mucosal healing in ulcerative colitis patients treated with anti-TNFα agents with or without azathioprine.\n\n\nMETHODS\nIn a prospective, multicenter, one-year study biologic naïve patients aged 25-65 years, with corticosteroid-dependent or refractory colitis received combination treatment with anti-TNFα and azathioprine for 6 months followed by anti-TNFα monotherapy. Patients who denied combination therapy or were outside this age range received anti-TNFα monotherapy (controls). Before and at weeks 12 and 54 of treatment the total Mayo score was calculated. Mucosal healing was defined as endoscopic subscore of 0. Mucosal expression of T helper (Th) cell-lineage specific transcription factors (Tbet, Gata3, Rorc, FoxP3) before treatment was also associated with mucosal healing.\n\n\nRESULTS\nOf 67 patients, 58 (86.6%) received combination and 9 (13.4%) anti-TNFα monotherapy. Overall 29 (43.3%) patients achieved mucosal healing; rates were higher in patients receiving combination therapy vs. monotherapy (p=0.03) and in azathioprine naïve vs. exposed patients in the combination group (p=0.01). Mucosal healing was associated with lower pre-treatment mucosal expression of transcription factor Th1-Tbet (p<0.05) and higher expression of Th17-Rorc (p<0.05).\n\n\nCONCLUSIONS\nMucosal healing was associated with combination therapy, especially in biologic and azathioprine-naïve patients and pre-treatment mucosal expression of specific Th specific transcripting factors (Tbet and Rorc).",
"affiliations": "Gastroenterology Department, Evangelismos Hospital, Athens, Greece. Electronic address: nikos.viazis@gmail.com.;Gastroenterology Department, Evangelismos Hospital, Athens, Greece.;Academic Department of Gastroenterology, First Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece.;Laboratory of Infectious Diseases, First Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece.;Gastroenterology Department, Evangelismos Hospital, Athens, Greece.;Gastroenterology Department, Evangelismos Hospital, Athens, Greece.;Gastroenterology Department, Evangelismos Hospital, Athens, Greece.;Department of Gastroenterology, University Hospital of Patras, Greece.;Department of Gastroenterology, University Hospital of Patras, Greece.;Department of Gastroenterology, University Hospital of Patras, Greece.;Laboratory of Infectious Diseases, First Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece.;Academic Department of Gastroenterology, First Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece.;Gastroenterology Department, Evangelismos Hospital, Athens, Greece.;Gastroenterology Department, Evangelismos Hospital, Athens, Greece.",
"authors": "Viazis|Nikos|N|;Giakoumis|Marios|M|;Bamias|Giorgos|G|;Goukos|Dimitris|D|;Koukouratos|Theodoros|T|;Katopodi|Konstantina|K|;Karatzas|Pantelis|P|;Triantos|Christos|C|;Tsolias|Chrisostomos|C|;Theocharis|Georgios|G|;Daikos|George L|GL|;Ladas|Spyros D|SD|;Karamanolis|Dimitrios G|DG|;Mantzaris|Gerasimos J|GJ|",
"chemical_list": "D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D020825:T-Box Domain Proteins; C406820:T-box transcription factor TBX21; D014409:Tumor Necrosis Factor-alpha; C529000:golimumab; D000069285:Infliximab; D000068879:Adalimumab; D001379:Azathioprine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.dld.2016.10.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8658",
"issue": "49(1)",
"journal": "Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver",
"keywords": "Anti-TNF therapy; Mucosal healing; Ulcerative colitis",
"medline_ta": "Dig Liver Dis",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D001379:Azathioprine; D003093:Colitis, Ulcerative; D003113:Colonoscopy; D004359:Drug Therapy, Combination; D005260:Female; D006115:Greece; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D007413:Intestinal Mucosa; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011446:Prospective Studies; D012720:Severity of Illness Index; D020825:T-Box Domain Proteins; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D014945:Wound Healing",
"nlm_unique_id": "100958385",
"other_id": null,
"pages": "29-33",
"pmc": null,
"pmid": "27866814",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Predictors of tissue healing in ulcerative colitis patients treated with anti-TNF.",
"title_normalized": "predictors of tissue healing in ulcerative colitis patients treated with anti tnf"
} | [
{
"companynumb": "GR-JNJFOC-20170126553",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "Weekly rifapentine and isoniazid therapy (known as 3HP) for latent tuberculosis infection (LTBI) is increasingly used, but systemic drug reactions (SDR) remain a major concern. Methods: We prospectively recruited two LTBI cohorts who received the 3HP regimen. In the single-nucleotide polymorphism (SNP) cohort, we collected clinical information of SDRs and examined the NAT2, CYP2E1, and AADAC SNPs. In the pharmacokinetic (PK) cohort, we measured plasma drug and metabolite levels at 6 and 24 h after 3HP administration. The generalised estimating equation model was used to identify the factors associated with SDRs. Candidate SNPs predicting SDRs were validated in the PK cohort. A total of 177 participants were recruited into the SNP cohort and 129 into the PK cohort, with 14 (8%) and 13 (10%) in these two cohorts developing SDRs, respectively. In the SNP cohort, NAT2 rs1041983 (TT vs. CC+CT, odds ratio [OR] [95% CI]: 7.00 [2.03-24.1]) and CYP2E1 rs2070673 (AA vs. TT+TA, OR [95% CI]: 3.50 [1.02-12.0]) were associated with SDR development. In the PK cohort, isoniazid level 24 h after 3HP administration (OR [95% CI]: 1.61 [1.15-2.25]) was associated with SDRs. Additionally, the association between the NAT2 SNP and SDRs was validated in the PK cohort (rs1041983 TT vs. CC+CT, OR [95% CI]: 4.43 [1.30-15.1]). Conclusions: Isoniazid played a role in the development of 3HP-related SDRs. This could provide insight for further design of a more optimal regimen for latent TB infection.",
"affiliations": "Department of Internal Medicine, National Taiwan University Hospital, Hsinchu Branch, Hsinchu 30059, Taiwan. sheepman1024@gmail.com.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan. 990325kmuh@gmail.com.;School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan. shuwenlin@ntu.edu.tw.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan. cmhkmu@gmail.com.;School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan. ytljolly@gmail.com.;Institute of Biochemistry and Molecular Biology, National Taiwan University Medical College, Taipei 10051, Taiwan. vagrantlin@hotmail.com.;Institute of Biochemistry and Molecular Biology, National Taiwan University Medical College, Taipei 10051, Taiwan. bsyan@ntu.edu.tw.;School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan. kuoch@ntu.edu.tw.;Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. d830166@gmail.com.;Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan. jywang@ntu.edu.tw.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan. chong@kmu.edu.tw.",
"authors": "Lee|Meng-Rui|MR|0000-0002-7220-4833;Huang|Hung-Ling|HL|;Lin|Shu-Wen|SW|;Cheng|Meng-Hsuan|MH|;Lin|Ya-Ting|YT|;Chang|So-Yi|SY|;Yan|Bo-Shiun|BS|0000-0002-9613-4788;Kuo|Ching-Hua|CH|;Lu|Po-Liang|PL|;Wang|Jann-Yuan|JY|0000-0003-3406-366X;Chong|Inn-Wen|IW|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jcm8060812",
"fulltext": "\n==== Front\nJ Clin MedJ Clin MedjcmJournal of Clinical Medicine2077-0383MDPI 10.3390/jcm8060812jcm-08-00812ArticleIsoniazid Concentration and NAT2 Genotype Predict Risk of Systemic Drug Reactions during 3HP for LTBI https://orcid.org/0000-0002-7220-4833Lee Meng-Rui 1†Huang Hung-Ling 234†Lin Shu-Wen 5Cheng Meng-Hsuan 267Lin Ya-Ting 5Chang So-Yi 8https://orcid.org/0000-0002-9613-4788Yan Bo-Shiun 8Kuo Ching-Hua 5Lu Po-Liang 39https://orcid.org/0000-0003-3406-366XWang Jann-Yuan 10*Chong Inn-Wen 2371 Department of Internal Medicine, National Taiwan University Hospital, Hsinchu Branch, Hsinchu 30059, Taiwan; sheepman1024@gmail.com2 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan; 990325kmuh@gmail.com (H.-L.H.); cmhkmu@gmail.com (M.-H.C.); chong@kmu.edu.tw (I.-W.C.)3 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; d830166@gmail.com4 Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80145, Taiwan5 School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan; shuwenlin@ntu.edu.tw (S.-W.L.); ytljolly@gmail.com (Y.-T.L.); kuoch@ntu.edu.tw (C.-H.K.)6 School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan7 Departments of Respiratory Therapy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan8 Institute of Biochemistry and Molecular Biology, National Taiwan University Medical College, Taipei 10051, Taiwan; vagrantlin@hotmail.com (S.-Y.C.); bsyan@ntu.edu.tw (B.-S.Y.)9 Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan10 Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan* Correspondence: jywang@ntu.edu.tw; Tel.: +886-2-23562905; Fax: +886-2-23582867† Meng-Rui Lee and Hung-Ling Huang contributed equally to this manuscript.\n\n06 6 2019 6 2019 8 6 81217 5 2019 03 6 2019 © 2019 by the authors.2019Licensee 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/).Weekly rifapentine and isoniazid therapy (known as 3HP) for latent tuberculosis infection (LTBI) is increasingly used, but systemic drug reactions (SDR) remain a major concern. Methods: We prospectively recruited two LTBI cohorts who received the 3HP regimen. In the single-nucleotide polymorphism (SNP) cohort, we collected clinical information of SDRs and examined the NAT2, CYP2E1, and AADAC SNPs. In the pharmacokinetic (PK) cohort, we measured plasma drug and metabolite levels at 6 and 24 h after 3HP administration. The generalised estimating equation model was used to identify the factors associated with SDRs. Candidate SNPs predicting SDRs were validated in the PK cohort. A total of 177 participants were recruited into the SNP cohort and 129 into the PK cohort, with 14 (8%) and 13 (10%) in these two cohorts developing SDRs, respectively. In the SNP cohort, NAT2 rs1041983 (TT vs. CC+CT, odds ratio [OR] [95% CI]: 7.00 [2.03–24.1]) and CYP2E1 rs2070673 (AA vs. TT+TA, OR [95% CI]: 3.50 [1.02–12.0]) were associated with SDR development. In the PK cohort, isoniazid level 24 h after 3HP administration (OR [95% CI]: 1.61 [1.15–2.25]) was associated with SDRs. Additionally, the association between the NAT2 SNP and SDRs was validated in the PK cohort (rs1041983 TT vs. CC+CT, OR [95% CI]: 4.43 [1.30–15.1]). Conclusions: Isoniazid played a role in the development of 3HP-related SDRs. This could provide insight for further design of a more optimal regimen for latent TB infection.\n\nisoniazidN-acetyltransferase 2rifapentinelatent tuberculosis infectionsystemic drug reaction\n==== Body\n1. Introduction\nTuberculosis (TB) remains one of the deadliest infectious diseases, with an estimated 10.0 million new cases and 1.6 million deaths in 2017 [1]. The World Health Organization (WHO) has set the goal of eliminating TB as a public health problem, aiming to achieve 90% and 95% reductions in the TB incidence and number of TB deaths by 2035 [2]. Latent tuberculosis infection (LTBI), a status of persistent immune response to stimulation by Mycobacterium tuberculosis antigens without clinically manifest active TB [3], has a 10% risk of progressing to active TB [4] and has thus emerged as a critical target for improving TB control and elimination [5]. The importance of targeting LTBI toward TB control has extended from countries with low TB prevalence to TB-endemic areas [6,7]. LTBI treatment, therefore, is being advocated as a universal policy in TB control [6,7].\n\nThe effectiveness of LTBI programmes has long been limited. Real-world data published in 1999 and obtained from an inner-city population in Atlanta, Georgia in the United States revealed that only 27% of subjects who received isoniazid (INH) preventive therapy completed their treatment [8]. A 2016 meta-analysis including 748,572 subjects in 58 studies also found poor completion of LTBI programmes, with a 60% treatment completion rate [9]. With the introduction of rifapentine (RPT), a rifamycin with much longer half-life than rifampin, the duration of a modern preventive regimen termed 3HP comprising RPT and INH could be shortened to 12 doses administered weekly, with the completion rate approaching 90% [10,11,12]. Also, for the four LTBI regimens currently suggested by WHO, 3HP remained the one with the fewest total doses required [13]. Though 3HP is less hepatotoxic, 3.8% of those receiving 3HP experience systemic drug reactions (SDRs) [14], which usually, if not always, requires treatment interruption or termination. The risk of a severe adverse event (AE) and SDR are even higher among subjects > 35 years old [12,14]. \n\nTo date, little has been discovered regarding the risk factors or predictors of SDRs due to 3HP therapy. In a pharmacokinetics study of RPT treatment in 35 TB patients during once-weekly continuation phase therapy, serious AEs were not linked with a higher area under the plasma concentration–time curve (AUC0~∞) of RPT [15]. Furthermore, no studies have reported on plasma INH levels after once-weekly INH treatment or the association between plasma INH level and AE development. Therefore, we conducted this study to determine the predictors of SDRs during 3HP therapy by measuring the plasma levels of drugs and their major metabolites and by genotyping the three key drug-metabolising enzymes.\n\n2. Methods\n2.1. Study Design\nThis was a prospective, multicentre, observational study recruiting individuals in close contact with index patients who received a new diagnosis of acid-fast smear (AFS)-positive pulmonary TB between September 2016 and August 2018. The study was conducted in two medical centres—the National Taiwan University Hospital in northern Taiwan and Kaohsiung Medical University Hospital in southern Taiwan—and their four branch hospitals. The study was approved by the institutional ethics committees of both medical centres (NTUH REC 201609044RINB and KMUHIRB-G[II]-20170033). \n\n2.2. Study Population\nIndividuals were eligible for enrollment if they were (1) aged ≥12 years; (2) in close contact with patients diagnosed with AFS-positive pulmonary TB; and (3) diagnosed with LTBI using either a tuberculin skin test (TST) or QuantiFERON-TB Gold in-tube assay (QFT; Cellestis/Qiagen, Carnegie, Australia). Close contact was defined as unprotected exposure of ≥8 h in a single day or a cumulative duration of ≥40 h. A positive TST was defined as an induration of ≥10 mm read at 48–72 h according to current guidelines in Taiwan. QFT was performed according to the manufacturer’s instructions. All close contacts enrolled in this study were tested with either TST or QFT. This study excluded participants who were suspected to have active TB because of their clinical symptoms or image examinations; to be concurrently using drugs with severe drug–drug interactions; to be allergic to INH, rifampin, or RPT (https://www.micromedexsolutions.com/); or who had a life expectancy <3 years.\n\n2.3. Protocol\nAfter written informed consent was obtained, participants were enrolled into the pharmacokinetics cohort (PK cohort) if they could comply with the blood sampling schedule required in the PK study. For this cohort, a plasma sample was collected to determine the concentrations of RPT, INH, and their metabolites (25-desacetyl-rifapentine [DeAcRPT] and acetyl-isoniazid [AcINH]) at either 23–25 h (C24, preferred) or 5–7 h (C6, Tmax of RPT) or both after administration of the study drugs at weeks 4 and 8 (refer to Supplement File for laboratory methods, including Table S1 and Figure S1) [15,16], or while SDR developed. For participants not enrolled in the PK cohort, genotyping for single-nucleotide polymorphisms (SNPs) of drug-metabolising enzymes, including N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1), and arylacetamide deacetylase (AADAC), was performed at baseline (SNP cohort) (refer to Supplement File for laboratory method, including Table S2).\n\nUnder supervision, each participant received weekly RPT (900 mg for participants with body weight >50.0 kg; 750 mg for 32.1–50.0 kg; 600 mg for 25.1–32.0 kg; and 450 mg for 14.1–25.0 kg) plus INH (15 mg/kg, rounded up to nearest 150 mg; maximum 900 mg) for a total of 12 doses, constituting the 3HP regimen. The drugs were administered by government-paid supporters under the National TB Program of Taiwan. The research assistants contacted all participants every week in person or by telephone to inquire about any AEs after the treatment. The participants were followed up until treatment completion or termination.\n\n2.4. Outcome\nThe primary endpoint was development of SDRs during 3HP treatment, defined as AEs that met either of the following: (1) hypotension (systolic blood pressure < 90 mmHg), urticaria, angioedema, acute bronchospasm, or conjunctivitis; and (2) >4 of the following symptoms occurring concurrently (>1 of which had to be grade 2 or higher): weakness, fatigue, nausea, vomiting, headache, fever, aches, sweats, dizziness, shortness of breath, flushing, or chills [14]. The probability of AEs to the study drugs was determined using the Naranjo algorithm [17]. A Naranjo score of 5–8 indicates probable AEs, whereas a score of >9 indicates definite AEs. AEs were graded using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events [18].\n\n2.5. Statistical Analysis\nCollected data included age, sex, height, weight, smoking status, comorbidities, concurrent medication, laboratory test and imaging results, study drugs, AEs, and medical records. The dataset was independently sampled. For continuous variables with normal distribution and homogeneity of variance, we used independent-sample t test or one-way ANOVA for comparison of intergroup differences. Otherwise we used non-parametric methods including Mann–Whitney U test or Kruskal–Wallis test for comparison. For categorical variables, we used chi-square for intergroup comparison and in case that more than 20% of the expected cell counts for the table are less than five, we used Fisher’s exact test. Plasma drug concentration after 1 and 2 months of 3HP treatment was compared using the Wilcoxon rank-sum test. To accommodate correlation of values within subjects, generalised estimating equation (GEE) models were fitted to explore the risk factors of SDRs (binary outcome) during 3HP treatment, adjusting for age, sex, body mass index (BMI), smoking status, INH and RPT dosage (which was exactly the same), taking 3HP before or after meal, comorbidity and concomitant medications. We also performed time-dependent Cox proportional hazard model to explore SDRs risk factors with adjustment of abovementioned variables in the GEE model. For handling the issue of low extrapolated drug concentration level below limit of quantification (BLQ) (in Supplementary File), we performed two sensitivity analyses, including: 1. Assuming drug concentrations BLQ to be zero and; 2. Excluding drug concentrations BLQ. Statistical significance was set at two-sided p < 0.05. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).\n\n3. Results\n3.1. Selection of Study Participants\nDuring the study period, 177 participants were recruited to the SNP cohort and 129 to the PK cohort (Figure 1). The clinical characteristics of the two cohorts are summarised in Table 1.\n\n3.2. Clinical Characteristics of the SNP Cohort\nAmong the 177 participants in the SNP cohort, 14 (8%) developed an SDR; seven were flu-like syndrome, three were shock, three were urticaria, and the remaining SDR was conjunctivitis. The majority of the participants were young (mean age 37.1 ± 17.8 years) and had good nutritional status (mean BMI 23.2 ± 3.52). Few (n = 11, 6%) had an underlying comorbidity, and the laboratory data were generally within normal limits. Compared with the participants who developed an SDR, those who did not were younger (p = 0.038) and had superior renal function (p = 0.009). \n\n3.3. Association of SNPs with SDRs in the SNP Cohort\nIn the SNP cohort, two SNPs were significantly associated with SDR development (Table 2). In a recessive model, NAT2 rs1041983 was associated with SDR development in both univariate analysis (TT vs. CC+CT, odds ratio [OR] [95% CI]: 8.47 [2.55–28.1], p = 0.0005) and multivariate analysis (TT vs. CC+CT, OR [95% CI]: 7.00 [2.03–24.1], p = 0.002). Additionally, CYP2E1 rs2070673 was associated with SDR development in both univariate analysis (AA vs. TT+TA, OR [95% CI]: 3.51 [1.05–11.7], p = 0.041) and multivariate analysis (AA vs. TT+TA, OR [95% CI]: 3.50 [1.02–12.0], p = 0.047). The results of SNPs with nonsignificant associations with SDRs are summarised in Table S3 of the Supplementary File. \n\n3.4. Clinical Characteristics of the PK Cohort\nAmong the 129 participants in the PK cohort, 13 (10.1%) developed an SDR (shock: two; flu-like syndrome: eight; both: three) (Table 1). The treatment completion rate was 83% (107/129). A total of 52 participants with 84 C6 blood samples were available, of which four samples were collected while they were experiencing an SDR. In C24 blood sampling, 144 samples from 83 participants were available; 11 samples were collected during an SDR. Among the 13 cases experiencing SDRs, ten (77%) occurred in the 3rd dose, 11 (85%) had the onset of SDRs less than 6 h after 3HP administration, and ten (77%) completely recovered within 2 days after onset (Table 3). \n\nAmong the C6 blood samples, 50 samples were collected in the first month, whereas 34 were collected in the second month. Three SDRs developed among the participants who supplied 50 first-month C6 blood samples, whereas one SDR developed among the participants who supplied the 34 s-month blood samples (6% vs. 3%, p = 0.644). Among the C24 blood samples, 80 samples were collected in the first month, whereas 64 were collected in the second month. Seven SDRs developed among the participants who supplied the 80 first-month C24 blood samples, whereas four SDRs developed among the participants who supplied the 64 s-month blood samples (9% vs. 6%, p = 0.755). The correlations between plasma concentrations of drugs and metabolites are illustrated in Figure 2.\n\n3.5. Pharmacodynamical Results of the PK Cohort\nRegarding C6 drug concentrations, no differences were discovered between the participants with and without an SDR in INH, AcINH, RPT, or DeAcRPT (INH: 3.2 [2.4–3.9] vs. 2.0 [1.2–3.5] µg/mL, p = 0.663; RPT: 22.2 [18.8–27.8] vs. 20.7 [16.7–31.9] µg/mL, p = 0.832; Figure 3). Regarding C24 drug concentrations, INH level was significantly higher in the participants with an SDR compared with those without (0.25 [0.06–0.53] vs. 0.06 [0.05–0.15] µg/mL, p = 0.024). RPT level was not significantly different between the SDR and SDR-free participants (p = 0.184) in the C24 samples.\n\nIn C24 blood sampling, plasma INH level was higher among age >50 compared with age 30–50 and age <30. C24 RPT level, C6 INH level, and C6 RPT level, however, were not different between different age groups (Table S4 in Supplement File).\n\nThe C6 drug concentrations of AcINH and C24 drug concentrations of INH, AcINH, RPT, and DeAcRPT were significantly different between participants with differing renal function, being the highest in those with eGFR < 60 (Table S5 in Supplement File). \n\nThe plasma levels of INH, RPT and their metabolites were not significantly altered by taking 3HP before or after meal, except that the C6 RPT level was significantly higher in participants taking 3HP after meal (p = 0.038) (Figure S2 in Supplement File).\n\nComparing PK results for the first-month and second-month C6 blood samples (n = 32), the concentrations of INH, AcINH, RPT, and DeAcRPT were not significantly different (Table S6 in Supplement File). \n\n3.6. Sex-Based Discrepancy in PK Results\nThe drug dosage of INH and RPT was higher in the women than in the men (p < 0.0001; Figure 4).\n\nIn the C24 blood samples from 83 participants (44 male and 39 female), RPT level was higher in the women than in the men (p < 0.0001), whereas INH level was not (p = 0.536) (Figure 4). In C6 blood samples from 52 participants (21 male and 31 female), RPT level was again higher in the women than in the men (p = 0.018), whereas INH level was not (p = 0.549).\n\n3.7. GEE Model in the PK Cohort\nIn the GEE model constructed for analysis of the C24 data, plasma INH level was associated with a higher risk of SDR development (OR [95% CI]: 1.61 [1.15–2.25], p = 0.006). By contrast, plasma RPT level was not associated with a higher risk of SDR development (OR [95% CI]: 1.01 [1.00–1.02], p = 0.218). In analysis assuming drug concentrations BLQ to be zero (OR [95% CI]: 1.52 [1.13–2.05], p = 0.006) and excluding drug concentration BLQ (OR [95% CI]: 1.94 [1.32–2.87], p = 0.001), the association of INH and SDRs remains. \n\nIn analysis of the C6 data, no factors were significantly associated with SDR development in the GEE model (INH, OR [95% CI]: 1.00 [0.98–1.02], p = 0.990; RPT, OR [95% CI]: 1.00 [0.99–1.01], p = 0.996). \n\n3.8. Time-Dependent Cox Proportional Hazard Model in the PK Cohort\nIn the time-dependent Cox regression model for C24 data analysis in the PK cohort, plasma INH level remained associated with a higher risk of SDR development (HR [95% CI]: 39.2 [1.19–1291.4], p = 0.040). Plasma RPT level was not associated with a higher risk of SDR development (OR [95% CI]: 1.08 [0.86–1.36], p = 0.513).\n\nIn analysis of the C6 data, no factors were significantly associated with SDR development in the time-dependent Cox regression model. \n\n3.9. Validation for Predicting SDR Using SNPs\nThe NAT2/CYP2E1 SNPs were validated in the PK cohort (Table 4). In a recessive model, NAT2 rs1041983 was associated with SDR development in both univariate analysis (TT vs. CC+CT, OR [95% CI]: 4.23 [1.30–13.8], p = 0.017) and multivariate analysis (TT vs. CC+CT, OR [95% CI]: 4.43 [1.30–15.1], p = 0.017). CYP2E1 rs2070673 was not associated with SDR development in either univariate analysis (AA vs. TT+TA, OR [95% CI]: 1.84 [0.46–7.41], p = 0.392) or multivariate analysis (AA vs. TT+TA, OR [95% CI]: 1.90 [0.46–7.80], p = 0.375). \n\n4. Discussion\nThis is the first prospective study investigating the effects of plasma INH and RPT levels and the SNPs of their metabolising enzymes on the risk of SDRs during 3HP therapy. We discovered that NAT2 and probably CYP2E1, but not AADAC, gene SNPs were associated with the development of SDRs among individuals receiving the 3HP regimen. Interestingly, the plasma INH level, but not RPT level, was associated with SDR development in the PK study. \n\nThe 3HP regimen is among the four regimens for LTBI that is recommended by the WHO and is also probably the most promising regimen because of its convenience, with only 12 doses required [19]. With its effectiveness well established, the major remaining concern regarding this latest LTBI regimen may be its AEs. Studies have estimated that 4.9% to 9.1% of those in close contact with patients with TB and who received 3HP failed to complete the regimen because of the side effects [10,12]. SDRs while on the 3HP regimen have generally been linked with RPT, which has a well-known side effect: flu-like syndrome (Table S7 in Supplement File) [14,20,21,22]. Additionally, RPT is a newer agent, making it a possible contributor to SDRs given that a higher SDR rate was observed compared with other INH-containing regimens. Some scholars, however, have argued against this point. First, one study using the 3HP regimen demonstrated that rechallenge with RPT did not necessarily lead to SDRs [14]. In the same study, rifapentine was better tolerated than isoniazid upon rechallenge [14]. In another study involving 1200 mg of RPT once weekly as continuation therapy for active TB, no SDRs were linked with RPT [23]. Finally, in a study of 162 pulmonary TB patients receiving RPT with a dosage of more than 15 mg/kg daily, no patients developed SDRs [24]. In our systematic review, we discovered that among reports describing an association between RPT and flu-like symptoms, RPT was commonly coadministered with INH (Table S7 in Supplement File). Furthermore, in cases describing an association between INH and flu-like symptoms, the associations were all proven with rechallenge (Table S8 in Supplement File) [25,26].\n\nAlthough a less well-known effect than that of RPT, INH can also lead to flu-like syndrome (Table S8 in Supplement File) [25,26]. Of the patients with active TB who were receiving INH, usually with a dose of 300 mg/day, 1–9.8% developed flu-like syndrome. In the 3HP regimen, INH dosage is 900 mg/week, and no data exist regarding the proportion of cases developing SDRs under a single INH dosage higher than this.\n\nThe association between the high INH dose and SDR during 3HP therapy may be explained through some hypotheses. First, since INH could bind to key enzymes in cytokine pathways, such as peroxidase [27], a high plasma level of INH may activate pathways which are not activated under normal dose of INH due to low binding affinity. Second, the high plasma INH level may interfere with or interact with rifapentine metabolite, leading to SDR. Interestingly, a study investigating drug–drug interactions between dolutegravir and once weekly INH/RPT also revealed a higher INH area under concentration curve among those who develop toxicities and a higher INH level among two cases experiencing severe flu-like syndrome [28].\n\nNAT2 protein metabolises INH into AcINH, which is later hydrolysed into acetylhydrazine. Acetylhydrazine is then oxidised by CYP2E1 to form a hepatotoxic substance, causing damage to hepatocytes [29]. Additionally, AADAC is the enzyme responsible for the deacetylation of rifamycins, and it affects the metabolism of rifamycins [30]. In our study, several points support the association between INH and SDR development. First, the NAT2 SNP, which is known to affect INH metabolism, rather than the AADAC SNPs, which are involved in RPT metabolism, was associated with SDR development. Second, INH drug level, rather than RPT drug level, was discovered to be associated with SDR development. Third, the short duration and rapid resolution of symptoms in some cases may indicate that a rapidly metabolised drug was the causative agent. \n\nIn our study, there was a sex-based discrepancy in the RPT plasma level but not in INH level. Sex differences in pharmacokinetics and pharmacodynamics for many drugs have been documented before and were commonly attributed to the endogenous hormone influence on cytochrome P450 activity [31]. Our study observed a higher RPT level in female and this phenomenon was not observed for INH. This may be explained that INH level was more significantly modulated and determined by acetylation rate [29]. In previous study, the proportion of fast, slow and intermediate acetylators was not different between male and female [32]. \n\nFor practical clinical application of our study findings, one may consider testing NAT2 genotype before LTBI treatment. If our described SNPs are identified, LTBI cases may be suggested to receive preventive regimens other than 3HP, such as four-month rifampin, to avoid SDR [33]. Also, for developing better drug combination therapy for LTBI, tailoring isoniazid dosage by avoiding single large isoniazid dose may be a reasonable approach. In the recently published Brief TB trial comparing one-month isoniazid and rifapentine with nine-month INH for preventive therapy, the isoniazid dosage was reduced to 300 mg daily and SDRs seemed to be less observed [34].\n\nOur study also had limitations. First, the sample size was relatively small. Therefore, we may not have been able to identify all the SNPs associated with SDRs. Second, this study was conducted in the Taiwanese population. In our previous study, the proportion of NAT2 slow-acetylators was 22.8% (n = 82) among 360 TB patients [35]. Whether our findings can be extrapolated to other ethnicities remains unknown.\n\n5. Conclusions\nResults of this study suggest that INH plays a more critical role than is generally perceived in 3HP-related SDRs. By designing a more optimal LTBI regimen, this study highlights the importance of INH in causing SDRs. Also, NAT2 SNP could also be used for risk stratification among TB contacts receiving 3HP regimen.\n\nAcknowledgments\nThe authors thank the staff of the Centers of Genomic Medicine and Precision Medicine at National Taiwan University for measuring serum drug concentrations and genotyping drug-metabolising enzymes.\n\nSupplementary Materials\nThe following are available online at https://www.mdpi.com/2077-0383/8/6/812/s1, Figure S1: The multiple reaction monitoring chromatogram of isoniazid, rifapentine and their metabolites standard spiked plasma, Figure S2: Boxplot showing the plasma concentration of isoniazid (INH), acetyl-isoniazid (AcINH), rifapentine (RPT), and desacetyl-rifapentine (DeAcRPT) at 6 (C6) and 24 (C24) hours after dosing, stratified by the timing of taking medication, either before (AC) or after meal (PC) (p value calculated using the Mann–Whitney U test), Table S1: Retention time (Rt) and mass parameters of four target compounds and their isotopes internal standards, Table S2: Primer sequences, Table S3: Association of NAT2/CYP2E1/AADAC single nucleotide polymorphism (those with p value > 0.05) and systemic drug reaction, Table S4: Plasma concentration of isoniazid (INH) and rifapentine (RPT) stratified by age **, Table S5: Plasma concentration of isoniazid (INH), acetyl-isoniazid (AcINH), rifapentine (RPT), and desacetyl-rifapentine (DeAcRPT) stratified by estimated glomerular filtration rate (eGFR) *, Table S6: Comparison of plasma concentration of isoniazid (INH), acetyl-isoniazid (AcINH), rifapentine (RPT), and desacetyl-rifapentine (DeAcRPT) for first and second months, Table S7: Literature review of original reports (S7A) and case reports (S7B) for flu-like syndrome suspected due to a rifamycin, Table S8: Literature review of original reports (S8A) and case reports (S8B) for flu-like syndrome due to isoniazid (INH) proven by re-challenge.\n\nClick here for additional data file.\n\n Author Contributions\nConceptualization, M.-R.L., H.-L.H., J.-Y.W. and I.-W.C.; Data curation, M.-R.L., H.-L.H., Y-T.L., B.-S.Y., and C.-H.K.; Formal analysis, M.-R.L., M.-H.C., B.-S.Y., P.-L.L., and J.-Y.W.; Funding acquisition, H.-L.H., J.-Y.W., and I.-W.C.; Investigation, M.-R.L., H.-L.H., S.-W.L., Y.-T.L., C.-H.K., and P.-L.L.; Methodology, S.-W.L., Y.-T.L., S.-Y.C., B.-S.Y., C.-H.K., P.-L.L., and J.-Y.W.; Project administration, H.-L.H., Y.-T.L., S.-Y.C., B.-S.Y., and J.-Y.W.; Resources, S.-W.L., and S.-Y.C.; Supervision, S.-W.L., J.-Y.W., and I.-W.C.; Validation, H.-L.H., and M.-H.C.; Visualization, M.-H.C., S.-Y.C., and I.-W.C.; Writing—original draft, M.-R.L., H.-L.H., S.-Y.C., P.-L.L., and J.-Y.W.; Writing—review & editing, S.-W.L., M.-H.C., Y.-T.L., B.-S.Y., C.-H.K., J.-Y.W., and I.-W.C.\n\nFunding\nThe study was supported by grants from the Ministry of Health and Welfare (MOHW106-CDC-C-11400104 and MOHW107-CDC-C-114-000105) and the Ministry of Science and Technology (MOST106-2314-B-002-055, MOST107-2314-B-002-191 and MOST107-2314-B-037-106-MY3). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nConflicts of Interest\nThe authors have no conflicts of interest to declare.\n\nFigure 1 Case enrollment (PK: pharmacokinetic; SNP: single-nucleotide polymorphism).\n\nFigure 2 XY plot showing the correlations between plasma concentration of isoniazid (INH) and acetyl-isoniazid (AcINH) (upper panels), and plasma concentration of rifapentine (RPT) and desacetyl-rifapentine (DeAcPRT) (lower panels) at 6 (C6, left column) and 24 (C24, right column) hours after drug administration, with cases who experienced a systemic drug reaction (SDR) marked in red.\n\nFigure 3 Boxplot showing the concentration of isoniazid (INH), acetyl-isoniazid (AcINH), rifapentine (RPT), and desacetyl-rifapentine (DeAcRPT) at 6 (C6) and 24 (C24) hours after dosing, stratified by the development of systemic drug reactions (SDRs) (p value calculated using the Mann–Whitney U test).\n\nFigure 4 Boxplot showing drug dosage per kg body weight (middle panel) and plasma concentration of INH, acetyl-isoniazid (AcINH), rifapentine (RPT), and desacetyl-rifapentine (DeAcRPT) in male and female participants at 6 (C6, left panel) and 24 (C24, right panel) hours after dosing (p value calculated using the Mann–Whitney U test).\n\njcm-08-00812-t001_Table 1Table 1 Clinical characteristics and laboratory data.\n\n\n\tSNP Group\n(n = 177)\tSDR\n(n = 14)\tNo SDR\n(n = 163)\tp Value\tPK Group\n(n = 129)\tSDR\n(n = 13)\tNo SDR\n(n = 116)\tp Value\t\nAge (year)\t37.1 ± 17.8\t46.6 ± 14.5\t36.3 ± 17.9\t0.038\t48.8 ± 17.2\t51.6 ± 12.7\t48.5 ± 17.6\t0.533\t\n≤35\t94 (53%)\t2 (14%)\t92 (56%)\t0.002\t30 (23%)\t2 (15%)\t28 (24%)\t0.868\t\n35–55\t44 (25%)\t8 (57%)\t36 (22%)\t\n\t46 (36%)\t5 (38%)\t41 (35%)\t\n\t\n>55\t39 (22%)\t4 (29%)\t35 (21%)\t\n\t53 (41%)\t6 (46%)\t47 (41%)\t\n\t\nFemale sex\t83 (47%)\t6 (43%)\t77 (47%)\t0.753\t67 (52%)\t6 (46%)\t61 (53%)\t0.660\t\nHousehold contact\t38 (21%)\t2 (13%)\t36 (22%)\t0.737\t53 (41%)\t5 (38%)\t48 (41%)\t>0.999\t\nHeight (cm)\t165.8 ± 8.3\t165.1 ± 8.8\t165.9 ± 8.2\t0.729\t164.3 ± 9.0\t163.7 ± 7.5\t164.4 ± 9.1\t0.788\t\nWeight (kg)\t64.0 ± 11.9\t65.7 ± 12.0\t63.8 ± 10.9\t0.568\t65.5 ± 12.1\t63.1 ± 9.4\t65.8 ± 12.4\t0.444\t\nBody-mass index (kg/m2) \t23.2 ± 3.52\t24.1 ± 3.22\t23.1 ± 3.55\t0.334\t24.2 ± 3.36\t23.45 ± 2.23\t24.26 ± 3.46\t0.413\t\nCurrent smoker\t20 (11%)\t4 (29%)\t16 (80%)\t0.057\t28 (22%)\t5 (38%)\t23 (20%)\t0.154\t\neGFR (mL/min/1.73 m2)\t\n\t\n\t\n\t0.005\t\n\t\n\t\n\t0.670\t\n<60\t14 (8%)\t0\t14 (9%)\t\n\t6 (5%)\t1 (8%)\t5 (4%)\t\n\t\n60–90\t54 (31%)\t10 (71%)\t44 (27%)\t\n\t47 (36%)\t4 (31%)\t43 (37%)\t\n\t\n≥90\t109 (62%)\t4 (29%)\t105 (66%)\t\n\t77 (59%)\t8 (62%)\t68 (59%)\t\n\t\nComorbidity\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\nHBV infection\t3 (2%)\t0\t3 (2%)\t>0.999\t7 (5%)\t1 (8%)\t6 (5%)\t0.534\t\nHCV infection\t2 (1%)\t0\t2 (1%)\t>0.999\t3 (2%)\t0\t3 (3%)\t>0.999\t\nDiabetes mellitus\t3 (2%)\t0\t3 (2%)\t>0.999\t11 (9%)\t2 (15%)\t9 (8%)\t0.306\t\nMalignancy\t1 (1%)\t1 (7%)\t0\t0.079\t6 (5%)\t2 (15%)\t4 (3%)\t0.112\t\nAutoimmune\t1 (1%)\t0\t1 (1%)\t>0.999\t1 (1%)\t1 (8%)\t0\t0.100\t\nAsthma\t0\t0\t0\t\n\t1 (1%)\t0\t1 (1%)\t>0.999\t\nHypertension\t5 (3%)\t2 (14%)\t3 (2%)\t0.051\t25 (19%)\t5 (38%)\t20 (17%)\t0.130\t\nAnti-hypertensive medication\t5 (3%)\t2 (14%)\t3 (2%)\t0.051\t19 (15%)\t4 (31%)\t15 (13%)\t0.101\t\nIsoniazid dose (mg/kg)\t14.2 ± 2.1\t13.8 ± 2.0\t14.3 ± 2.1\t0.483\t14.0 ± 2.2\t14.3 ± 1.9\t13.9 ± 2.2\t0.512\t\nRifapentine dose (mg/kg)\t14.2 ± 2.1 \t13.8 ± 2.0\t14.3 ± 2.1\t0.454\t14.0 ± 2.2\t14.3 ± 1.9\t13.9 ± 2.2\t0.512\t\nHemoglobin (g/dL)\t14.0 ± 1.6\t14.2 ± 1.5\t14.0 ± 1.6\t0.643\t14.0 ± 1.5\t13.8 ± 1.6\t14.1 ± 1.5\t0.560\t\nLeukocyte (K/µL)\t6.44 ± 1.77\t6.78 ± 1.42\t6.41 ± 1.80\t0.448\t6.81 ± 1.85\t6.98 ± 1.44\t6.78 ± 1.90\t0.732\t\nPlatelet (K/µL)\t258 ± 56\t253 ± 57\t259 ± 56\t0.705\t270 ± 58\t280 ± 45\t269 ± 59\t0.511\t\nAST (U/L)\t23.4 ± 17.0\t28.0 ± 19.6\t23.0 ± 16.8\t0.291\t23.3 ± 10.0\t25.5 ± 5.6\t23.0 ± 10.4\t0.201\t\nALT (U/L)\t23.0 ± 28.0\t27.6 ± 30.8\t22.6 ± 27.9\t0.526\t23.7 ± 18.9\t27.2 ± 11.1\t23.3 ± 19.6\t0.290\t\nTotal bilirubin (mg/dL)\t0.65 ± 0.28\t0.63 ± 0.38\t0.66 ± 0.27\t0.823\t0.63 ± 0.22\t0.70 ± 0.25\t0.62 ± 0.22\t0.215\t\nCreatinine (mg/dL)\t0.82 ± 0.20\t0.83 ± 0.16\t0.82 ± 0.20\t0.754\t0.84 ± 0.29\t0.83 ± 0.18\t0.84 ± 0.30\t0.876\t\nTreatment completion\t159 (90%)\t4 (29%)\t155 (95%)\t<0.0001\t107 (83%)\t4 (31%)\t103 (89%)\t<0.0001\t\nALT: alanine transaminase; AST: aspartate transaminase; eGFR: estimated glomerular filtration rate; PK: pharmacokinetic; SDR: systemic drug reaction; SNP: single nucleotide polymorphism. Data are number (percentage) or mean ± standard deviation.\n\njcm-08-00812-t002_Table 2Table 2 Association of NAT2/CYP2E1 single-nucleotide polymorphisms (SNPs) with systemic drug reactions.\n\n\n\t\n\tUnadjusted OR (95% CI)\tp Value\tAdjusted OR (95% CI) *\tp Value\t\n\nAdditive model\n\t\n\t\n\t\n\t\n\t\n\t\nNAT2 rs1041983\tCC\tRef\t\n\tRef\t\n\t\nCT\t0.85 (0.14–5.29)\t0.101\t0.87 (0.14–5.46)\t0.132\t\nTT\t7.67 (1.51–39.0)\t0.0006\t5.82 (1.08–35.1)\t0.003\t\nCYP2E1 rs2070673\tTT\tRef\t\n\tRef\t\n\t\nTA\t0.84 (0.20–3.52)\t0.815\t0.89 (0.21–3.80)\t0.871\t\nAA\t3.21 (0.79–15.0)\t0.103\t3.28 (0.78–13.9)\t0.106\t\n\nDominant model\n\t\n\t\n\t\n\t\n\t\n\t\nNAT2 rs1041983\tCC\tRef\t\n\tRef\t\n\t\nCT+TT\t2.41 (0.51–11.3)\t0.265\t2.01 (0.41–9.96)\t0.394\t\nCYP2E1 rs2070673\tTT\tRef\t\n\tRef\t\n\t\nTA+AA\t1.43 (0.42–4.84)\t0.568\t1.49 (0.43–5.20)\t0.532\t\n\nRecessive model\n\t\n\t\n\t\n\t\n\t\n\t\nNAT2 rs1041983\tCC+CT\tRef\t\n\tRef\t\n\t\nTT\t8.47 (2.55–28.1)\t0.0005\t7.00 (2.03–24.1)\t0.002\t\nCYP2E1 rs2070673\tTT+TA\tRef\t\n\tRef\t\n\t\nAA\t3.51 (1.05–11.7)\t0.041\t3.50 (1.02–12.0)\t0.047\t\n* Adjusted for age, sex and estimated glomerular filtration rate.\n\njcm-08-00812-t003_Table 3Table 3 Detailed information of the participants experiencing systemic drug reaction during 3HP therapy in the pharmacokinetic (PK) cohort.\n\nAge/Sex\tBW (kg)/BH (cm)\tAdverse Reactions\tSeverity (Grade)\tComorbidity & Medication\tRisk Allele in NAT2/CYP2E1 *\tINH/RPT Conc. # [Sampling Week]\tOnset (Week)\tTime of Onset/Duration (h)\tOutcome of 3HP\t\n66.3/F\t50.0/149\tfever, chills, malaise, myalgia, headache\t2\tLung adenocarcinoma under gefitinib\t1/2\tC24: 0.11/18.5 [3]\t3\t7/29\tStop\t\n64.4/M\t62.5/170\tfever, myalgia, chills, weakness, sweating\t2\tHTN under amlodipine & olmesartan\t2/1\tC6: 5.61/21.3 [4]\t3\t6/18\tStop\t\n59.8/F\t59.5/154\tfever, chills, dyspnea, angioedema, malaise\t3\tBreast cancer, cured\t2/2\tC24: 0.51/16.7 [3]\t3\t4/>100\tStop\t\n56.7/M\t73.0/175\tshock (BP 90/60 mmHg), fever, flush, myalgia, dyspnea, rash\t3\tHTN under lercanidipine\t2/2\tC24: 1.04/8.9 [3]\t3\t5/47\tStop\t\n53.4/F\t63.0/160\tfever, chills, dizziness, myalgia, dizziness\t2\tNil\t1/1\tC6: 2.98/11.4 [4]\t3\t9/15\tStop\t\n51.4/M\t74.0/167\tshock (BP 85/67 mmHg), dizziness, vomiting\t2\tDM, HTN \t2/1\tC24: 0.80/8.9 [3]\t3\t3/47\tStop\t\n50.5/M\t72.0/168\tshock (BP 88/63 mmHg), fever, nausea, vomiting, dizziness, sweating\t2\tHTN under bisoprolol & olmesartan\t2/0\tC24: 0.25/6.9 [7]\t7\t1/8\tStop\t\n33.9/F\t47.0/158\tshock (BP 82/57 mmHg), fever, headache, nausea, vomiting, malaise\t3\tNil\t2/0\tC24: 0.43/15.4 [3]\t3\t1/88\tStop\t\n20.6/F\t53.0/162\tshock, fever, chills, headache, myalgia, nausea\t3\tNil\t1/1\tC6: 3.36/42.3 [4] C24: 0.06/18.4 [4]\t3\t2/30\tStop\t\n60.9/M\t62.0/161\tfever, myalgia, nausea, vomiting dizziness\t2\tDM, HTN amlodipine & valsartan\t0/1\tC24: 0.06/11.0 [3]\t3\t6/28\tComplete\t\n55.9/F\t60.0/163\tfever, chills, myalgia, malaise, headache\t3\tAS under celecoxib\t0/0\tC24: 0.04/14.3 [4]\t3\t5/76\tComplete\t\n53.7/M\t76.5/174\tfever, chills, dizziness, malaise, nausea\t2\tHBV carrier not Tx\t2/1\tC24: 0.55/14.9 [6]\t6\t3/16\tComplete\t\n43.8/M\t67.5/167\tfever, myalgia, dizziness, tachypnea, malaise\t2\tNil\t1/0\tC6: 0.70/23.0 [4]\t4\t1/27\tComplete\t\nAS, ankylosing spondylitis; BP, blood pressure; CYP2E1, cytochrome P450 2E1; DM, diabetes mellitus; HTN, hypertension; INH, isoniazid; NAT2, N-acetyltransferase 2, RPT, rifapentine; Tx, treatment; * Number of T allele at NAT2 rs1041983/number of A allele at CYP2E1 rs2070673; # Drug levels that were higher than the median of all tested data at the same timing (C6 of INH: 2.07 µg/mL; C6 of RPT: 20.9 µg/mL; C24 of INH: 0.06 µg/mL; C24 of RPT: 11.4 µg/mL) were shown in bold.\n\njcm-08-00812-t004_Table 4Table 4 Validation of N-acetyltransferase 2 (NAT2)/Cytochrome P450 2E1 (CYP2E1) single nucleotide polymorphisms (SNPs) with systemic drug reactions in pharmacokinetic (PK) cohort.\n\n\n\t\n\tUnadjusted OR (95% CI)\tp Value\tAdjusted OR (95% CI) *\tp Value\t\n\nAdditive model\n\t\n\t\n\t\n\t\n\t\n\t\nNAT2 rs1041983\tCC\tRef\t\n\tRef\t\n\t\nCT\t1.09 (0.19–6.28)\t0.925\t1.06 (0.18–6.34)\t0.948\t\nTT\t4.52 (0.86–23.8)\t\n0.075\n\t4.61 (0.82–25.8)\t0.082\t\nCYP2E1 rs2070673\tTT\tRef\t\n\tRef\t\n\t\nTA\t1.84 (0.49–6.94)\t0.807\t2.10 (0.54–8.20)\t0.285\t\nAA\t2.53 (0.51–12.5)\t0.383\t2.80 (0.55–14.3)\t0.216\t\n\nDominant model\n\t\n\t\n\t\n\t\n\t\n\t\nNAT2 rs1041983\tCC\tRef\t\n\tRef\t\n\t\nCT+TT\t2.13 (0.45–10.2)\t0.343\t2.04 (0.41–10.1)\t0.384\t\nCYP2E1 rs2070673\tTT\tRef\t\n\tRef\t\n\t\nTA+AA\t2.03 (0.59–6.96)\t0.262\t2.30 (0.65–8.15)\t0.199\t\n\nRecessive model\n\t\n\t\n\t\n\t\n\t\n\t\nNAT2 rs1041983\tCC+CT\tRef\t\n\tRef\t\n\t\nTT\t4.23 (1.30–13.8)\t\n0.017\n\t4.43 (1.30–15.1)\t\n0.017\n\t\nCYP2E1 rs2070673\tTT+TA\tRef\t\n\tRef\t\n\t\nAA\t1.84 (0.46–7.41)\t0.392\t1.90 (0.46–7.80)\t0.375\t\n* Adjusted for age, sex and estimated glomerular filtration rate.\n==== Refs\nReferences\n1. 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Engle M. Bliven E. Prihoda T.J. Gelfond J.A. Scott N.A. Rifapentine pharmacokinetics and tolerability in children and adults treated once weekly with rifapentine and isoniazid for latent tuberculosis infection J. Pediatric Infect. Dis. Soc. 2014 3 132 145 10.1093/jpids/pit077 26625366 \n17. Naranjo C.A. Busto U. Sellers E.M. Sandor P. Ruiz I. Roberts E.A. Janecek E. Domecq C. Greenblatt D.J. A method for estimating the probability of adverse drug reactions Clin. Pharmacol. Ther. 1981 30 239 245 10.1038/clpt.1981.154 7249508 \n18. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 NCI, NIH, DHHS Washington, DC, USA 2009 \n19. Borisov A.S. Bamrah Morris S. Njie G.J. Winston C.A. Burton D. Goldberg S. Yelk Woodruff R. Allen L. LoBue P. Vernon A. Update of recommendations for use of once-weekly isoniazid-rifapentine regimen to treat latent mycobacterium tuberculosis Infection MMWR. Morb. Mortal. Wkly. Rep. 2018 67 723 726 10.15585/mmwr.mm6725a5 29953429 \n20. Singapore Tuberculosis Service/British Medical Reseach Council Controlled trial of intermittent regimens of rifampicin plus isoniazid for pulmonary tuberculosis in Singapore Lancet 1975 2 1105 1109 53598 \n21. Hong Kong Tuberculosis Treatment Services/Brompton Hospital/British Medical Research Council Reseach Council A controlled trial of daily and intermittent rifampicin plus ethambutol in the retreatment of patients with pulmonary tuberculosis: Results up to 30 months Tubercle 1975 56 179 189 10.1016/0041-3879(75)90050-1 766340 \n22. Dickinson J.M. Mitchison D.A. Lee S.K. Ong Y.Y. O’Mahoney M.G. Girling D.J. Nunn A.J. Serum rifampicin concentration related to dose size and to the incidence of the ‘flu’ syndrome during intermittent rifampicin administration J. Antimicrob. Chemother. 1977 3 445 452 10.1093/jac/3.5.445 903325 \n23. Jindani A. Harrison T.S. Nunn A.J. Phillips P.P. Churchyard G.J. Charalambous S. Hatherill M. Geldenhuys H. McIlleron H.M. Zvada S.P. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis N. Engl. J. Med. 2014 371 1599 1608 10.1056/NEJMoa1314210 25337749 \n24. Dorman S.E. Savic R.M. Goldberg S. Stout J.E. Schluger N. Muzanyi G. Johnson J.L. Nahid P. Hecker E.J. Heilig C.M. Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial Am. J. Respir. Crit. Care Med. 2015 191 333 343 10.1164/rccm.201410-1843OC 25489785 \n25. Dutt A.K. Moers D. Stead W.W. Undesirable side effects of isoniazid and rifampin in largely twice-weekly short-course chemotherapy for tuberculosis Am. Rev. Respir. Dis. 1983 128 419 424 10.1164/arrd.1983.128.3.419 6614636 \n26. Eule H. Werner E. Winsel K. Iwainsky H. Intermittent chemotherapy of pulmonary tuberculosis using rifampicin and isoniazid for primary treatment: The influence of various factors on the frequency of side-effects Tubercle 1974 55 81 89 10.1016/0041-3879(74)90069-5 \n27. Metcalfe C. Macdonald I.K. Murphy E.J. Brown K.A. Raven E.L. Moody P.C. The tuberculosis prodrug isoniazid bound to activating peroxidases J. Biol. Chem. 2008 283 6193 6200 10.1074/jbc.M707412200 18056997 \n28. Brooks K.M. George J.M. Pau A.K. Rupert A. Mehaffy C. De P. Dobos K.M. Kellogg A. McLaughlin M. McManus M. Cytokine-mediated systemic adverse drug reactions in a drug-drug interaction study of dolutegravir with once-weekly isoniazid and rifapentine Clin. Infect. Dis. 2018 67 193 201 10.1093/cid/ciy082 29415190 \n29. Singla N. Gupta D. Birbian N. Singh J. Association of NAT2, GST and CYP2E1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity Tuberculosis 2014 94 293 298 10.1016/j.tube.2014.02.003 24637014 \n30. Nakajima A. Fukami T. Kobayashi Y. Watanabe A. Nakajima M. Yokoi T. Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: Rifampicin, rifabutin, and rifapentine Biochem. Pharmacol. 2011 82 1747 1756 10.1016/j.bcp.2011.08.003 21856291 \n31. Soldin O.P. Mattison D.R. Sex differences in pharmacokinetics and pharmacodynamics Clin. Pharmacokinet. 2009 48 143 157 10.2165/00003088-200948030-00001 19385708 \n32. Azuma J. Ohno M. Kubota R. Yokota S. Nagai T. Tsuyuguchi K. Okuda Y. Takashima T. Kamimura S. Fujio Y. NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy Eur. J. Clin. Pharmacol. 2013 69 1091 1101 10.1007/s00228-012-1429-9 23150149 \n33. Menzies D. Adjobimey M. Ruslami R. Trajman A. Sow O. Kim H. Obeng Baah J. Marks G.B. Long R. Hoeppner V. Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults N. Engl. J. Med. 2018 379 440 453 10.1056/NEJMoa1714283 30067931 \n34. Swindells S. Ramchandani R. Gupta A. Benson C.A. Leon-Cruz J. Mwelase N. Jean Juste M.A. Lama J.R. Valencia J. Omoz-Oarhe A. One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis N. Engl. J. Med. 2019 380 1001 1011 10.1056/NEJMoa1806808 30865794 \n35. Wang J.Y. Liu C.H. Hu F.C. Chang H.C. Liu J.L. Chen J.M. Yu C.J. Lee L.N. Kao J.H. Yang P.C. Risk factors of hepatitis during anti-tuberculous treatment and implications of hepatitis virus load J. Infect. 2011 62 448 455 10.1016/j.jinf.2011.04.005 21570123\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "8(6)",
"journal": "Journal of clinical medicine",
"keywords": "N-acetyltransferase 2; isoniazid; latent tuberculosis infection; rifapentine; systemic drug reaction",
"medline_ta": "J Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101606588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31174321",
"pubdate": "2019-06-06",
"publication_types": "D016428:Journal Article",
"references": "14962821;18056997;19385708;21570123;21756513;21856291;22150035;23150149;24637014;25337749;25489785;25580725;25904367;26017823;26625366;27522233;28495525;29415190;29953429;30029896;30067931;30865794;31013273;4620295;4810628;53598;6614636;7249508;766340;903325;9872853",
"title": "Isoniazid Concentration and NAT2 Genotype Predict Risk of Systemic Drug Reactions during 3HP for LTBI.",
"title_normalized": "isoniazid concentration and nat2 genotype predict risk of systemic drug reactions during 3hp for ltbi"
} | [
{
"companynumb": "TW-SA-2018SA329370",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIFAPENTINE"
},
"drugadditional": "1",
"dr... |
{
"abstract": "Laryngospasm is a rare cause of upper-airway obstruction in adults. It most commonly occurs during light anesthesia. We report a case of severe laryngospasm following rapid sequence induction in an adult requiring an emergency neurosurgical procedure. Laryngospasm occurred despite deep anesthesia with ketamine and neuromuscular blockade with succinylcholine. Several intubation attempts failed. Therefore, 2 hypotheses are considered: succinylcholine resistance and ketamine-induced laryngospasm. To our knowledge, this is the first description of laryngospasm occurring despite deep anesthesia and neuromuscular blockade. An idiosyncratic effect of ketamine may be involved, although this phenomenon has not yet been studied.",
"affiliations": "From the Department of Anesthesiology, Liège University Hospital, Sart Tilman, Liège, Belgium.;Department of Anesthesiology, Pasteur II Hospital, Nice University Hospital, Cedex 1, France.",
"authors": "Maqueda|Bastien|B|;Rousseau|Ludovic|L|",
"chemical_list": "D007649:Ketamine; D013390:Succinylcholine",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000001489",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "15(7)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000328:Adult; D006801:Humans; D007649:Ketamine; D007826:Laryngismus; D000079603:Rapid Sequence Induction and Intubation; D013390:Succinylcholine",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "e01489",
"pmc": null,
"pmid": "34166265",
"pubdate": "2021-06-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Refractory Severe Laryngospam During Rapid Sequence Induction: A Case Report.",
"title_normalized": "refractory severe laryngospam during rapid sequence induction a case report"
} | [
{
"companynumb": "FR-RENAUDINFR-2021000307",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "REMIFENTANIL"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nThere is still controversy regarding thrombo-prophylaxis for the reduction of thromboembolic disease in major orthopedic surgery.\n\n\nOBJECTIVE\nTo answer the following question: is there a difference in the effectiveness and safety in the antithrombotic management of patients with a traditional regimen of enoxaparin against acetyl salicylic acid?\n\n\nMETHODS\nThe surgeries were performed by 3 surgeons; the sample was randomized and the patients were subjected to the study criteria. We evaluated efficacy and safety as well as the need for readmission and secondary variables such as infection, acute myocardial infarction (AMI), cerebral vascular disease and death with a follow-up of 90 days.\n\n\nRESULTS\nThe total sample was 402 patients; 214 in the enoxaparin group and 188 in the aspirin group. There were 5 cases (1.24%) with thromboembolic disease, 3 (1.4%) enoxaparin and 2 (1.06%) aspirin without significant difference (p = 0.23). In terms of safety, major bleeding was zero in both groups, with minor bleeding in 7 patients (1.74%), 4 (1.86%) were from the enoxaparin group and 3 (1.59%) from the aspirin group without significant differences (p = 0.82). Secondary outcomes showed 5 (1.24%) superficial surgical wound infections and one AMI in the first 30 days of the procedure in the enoxaparin group.\n\n\nCONCLUSIONS\nAspirin as monotherapy is safe, effective in antithrombotic prophylaxis in patients operated on total knee arthroplasty.",
"affiliations": "Centro Médico (ISSEMyM) Instituto de Seguridad Social del Estado de México y Municipios, Toluca, Estado de México. México.;Centro Médico (ISSEMyM) Instituto de Seguridad Social del Estado de México y Municipios, Toluca, Estado de México. México.;Centro Médico (ISSEMyM) Instituto de Seguridad Social del Estado de México y Municipios, Toluca, Estado de México. México.;Centro Médico (ISSEMyM) Instituto de Seguridad Social del Estado de México y Municipios, Toluca, Estado de México. México.;Centro Médico (ISSEMyM) Instituto de Seguridad Social del Estado de México y Municipios, Toluca, Estado de México. México.",
"authors": "Cortes-De la Fuente|A A|AA|;Villalobos-Campuzano|C|C|;Bucio-Paticio|B|B|;Valencia-Martínez|G|G|;Martínez-Montiel|O|O|",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin; D005343:Fibrinolytic Agents; D020156:Salicylic Acid; D001241:Aspirin",
"country": "Mexico",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2306-4102",
"issue": "35(2)",
"journal": "Acta ortopedica mexicana",
"keywords": "Prophylaxis; acetylsalicylic acid; antithrombotic; knee; prosthesis; surgery",
"medline_ta": "Acta Ortop Mex",
"mesh_terms": "D000925:Anticoagulants; D019644:Arthroplasty, Replacement, Hip; D019645:Arthroplasty, Replacement, Knee; D001241:Aspirin; D017984:Enoxaparin; D005343:Fibrinolytic Agents; D006801:Humans; D011183:Postoperative Complications; D020156:Salicylic Acid",
"nlm_unique_id": "101190312",
"other_id": null,
"pages": "163-168",
"pmc": null,
"pmid": "34731917",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Comparative study between enoxaparin and salicylic acetyl acid in antithrombotic prophylaxis for patients undergoing total knee arthroplasty.",
"title_normalized": "comparative study between enoxaparin and salicylic acetyl acid in antithrombotic prophylaxis for patients undergoing total knee arthroplasty"
} | [
{
"companynumb": "MX-SA-2021SA354354",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENOXAPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "We report the safety data from the first multicenter phase 1 trial investigating the use of hypofractionated proton therapy with concurrent chemotherapy for patients with stage II or III non-small cell lung cancer.\n\n\n\nFrom 2013 through 2018, patients with newly diagnosed stage II or III non-small cell lung cancer were enrolled in a multicenter phase 1 clinical trial evaluating concurrent chemotherapy with increasing dose-per-fraction proton therapy. This was a stepwise 5 + 2 dose-intensification protocol with the following dose arms: (1) 2.5 GyRBE per fraction to 60 GyRBE; (2) 3.0 GyRBE per fraction to 60 GyRBE; (3) 3.53 GyRBE per fraction to 60.01 GyRBE; and (4) 4.0 GyRBE per fraction to 60 GyRBE. A dose arm was considered tolerable if no radiation therapy-attributable severe adverse event (SAE) occurred within 90 days of treatment among 5 patients enrolled on the arm or if 1 SAE occurred among 7 patients enrolled. Dose constraints to the heart, brachial plexus, and spinal cord were more conservative at higher doses per fraction.\n\n\n\nThe study closed early because of slow accrual and competing enrollment in NRG 1308 before accrual was met, with no maximum tolerated dose identified. Eighteen patients were treated, including 5 patients on arms 1 and 2, 7 patients on arm 3, and 1 patient on arm 4. Two SAEs occurred among 7 patients treated at 3.53 GyRBE per fraction; however, per outside expert review, both were attributed to chemotherapy and unrelated to radiation therapy.\n\n\n\nHypofractionated proton therapy delivered at 2.5 to 3.53 GyRBE per fraction to a dose of 60 GyRBE with concurrent chemotherapy has an acceptable toxicity profile. Further exploration of this regimen is warranted on a phase 2 clinical trial.",
"affiliations": "Department of Radiation Oncology, Mayo Clinic, Jacksonville, Florida. Electronic address: Hoppe.Bradford@mayo.edu.;Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, Florida.;Department of Radiation Oncology, Emory Winship Cancer Institute, Atlanta, Georgia.;Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, Florida.;Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, Florida.;Department of Medical Oncology, University of Florida College of Medicine, Jacksonville, Florida.;Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland.;Department of Radiation Oncology, Northwestern Medicine, Chicago, Illinois.;Department of Radiation Oncology, Northwestern Medicine, Chicago, Illinois.;ProCure Proton Therapy Center, New Jersey, Somerset, New Jersey.;New York Proton Center, New York, New York.",
"authors": "Hoppe|Bradford S|BS|;Nichols|Romaine C|RC|;Flampouri|Stella|S|;Li|Zuofeng|Z|;Morris|Christopher G|CG|;Pham|Dat C|DC|;Mohindra|Pranshu|P|;Hartsell|William|W|;Mohammed|Nasiruddin|N|;Chon|Brian H|BH|;Simone|Charles B|CB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ijrobp.2020.03.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0360-3016",
"issue": "107(3)",
"journal": "International journal of radiation oncology, biology, physics",
"keywords": null,
"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung; D059248:Chemoradiotherapy; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D061766:Proton Therapy; D012449:Safety",
"nlm_unique_id": "7603616",
"other_id": null,
"pages": "455-461",
"pmc": null,
"pmid": "32251754",
"pubdate": "2020-07-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hypofractionated Proton Therapy with Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Phase 1 Trial from the University of Florida and Proton Collaborative Group.",
"title_normalized": "hypofractionated proton therapy with concurrent chemotherapy for locally advanced non small cell lung cancer a phase 1 trial from the university of florida and proton collaborative group"
} | [
{
"companynumb": "US-GLAND PHARMA LIMITED-2089456",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DURVALUMAB"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which originated in Wuhan, China, in late 2019 and has led to an ongoing pandemic. COVID-19 typically affects the respiratory tract and mucous membranes, leading to pathological involvement of various organ systems. Although patients usually present with fever, cough, and fatigue, less common manifestations have been reported including symptoms arising from thrombosis and thromboembolism. A spectrum of dermatologic changes is becoming recognized in patients with COVID-19 who initially present with respiratory symptoms. The mechanism behind these manifestations remains unclear. This report presents the case of a 47-year-old Hispanic man who developed cutaneous vasculitic lesions and gangrene of the toes following admission to hospital with COVID-19 pneumonia. CASE REPORT COVID-19 has been associated with cardiovascular disease entities including stroke, acute coronary syndrome, venous thromboembolism, and peripheral vascular disease. We present a case in which a 47-year-old Hispanic man arrived at the Emergency Department with COVID-19 and was admitted for respiratory failure. Despite anticoagulation initiated on admission in the presence of an elevated D-dimer, the patient developed gangrene of all his toes, which required bilateral transmetatarsal amputation. CONCLUSIONS This case shows that dermatologic manifestations may develop in patients who initially present with COVID-19 pneumonia. These symptoms may be due to venous thrombosis following SARS-CoV-2 vasculitis, leading to challenging decisions regarding anticoagulation therapy. Randomized controlled trials are needed to evaluate the efficacy of anticoagulation, to choose appropriate anticoagulants and dosing, and to assess bleeding risk.",
"affiliations": "Department of Internal Medicine, Long Island Community Hospital, Patchogue, NY, USA.;Department of Internal Medicine, Long Island Community Hospital, Patchogue, NY, USA.;Department of Internal Medicine, Long Island Community Hospital, Patchogue, NY, USA.;Department of Critical Care, Long Island Community Hospital, Patchogue, NY, USA.;Department of Internal Medicine, Long Island Community Hospital, Patchogue, NY, USA.",
"authors": "Adekiigbe|Riliwan|R|;Ugbode|Franklin|F|;Seoparson|Sunil|S|;Katriyar|Neeraj|N|;Fetterman|Alan|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.926886",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32999267\n10.12659/AJCR.926886\n926886\nArticles\nA 47-Year-Old Hispanic Man Who Developed Cutaneous Vasculitic Lesions and Gangrene of the Toes Following Admission to Hospital with COVID-19 Pneumonia\nAdekiigbe Riliwan EF1 Ugbode Franklin EF1 Seoparson Sunil F1 Katriyar Neeraj F2 Fetterman Alan F1 \n1 Department of Internal Medicine, Long Island Community Hospital, Patchogue, NY, U.S.A.\n\n2 Department of Critical Care, Long Island Community Hospital, Patchogue, NY, U.S.A.\nCorresponding Author: Riliwan Adekiigbe, e-mail: ra347@cornell.edu; radekiigbe@licommunityhospital.orgAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n01 10 2020 \n21 e926886-1 e926886-5\n08 6 2020 09 9 2020 18 9 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 47-year-old\n\nFinal Diagnosis: Acute respiratory distress syndrome (ARDS) • COVID-19\n\nSymptoms: Chills • dyspnea • fever • respiratory distress\n\nMedication: —\n\nClinical Procedure: Central venous catheterization • endotracheal Intubation\n\nSpecialty: Critical Care Medicine\n\nObjective:\nUnusual clinical course\n\nBackground:\nCoronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), which originated in Wuhan, China, in late 2019 and has led to an ongoing pandemic. COVID-19 typically affects the respiratory tract and mucous membranes, leading to pathological involvement of various organ systems. Although patients usually present with fever, cough, and fatigue, less common manifestations have been reported including symptoms arising from thrombosis and thromboembolism. A spectrum of dermato-logic changes is becoming recognized in patients with COVID-19 who initially present with respiratory symptoms. The mechanism behind these manifestations remains unclear. This report presents the case of a 47-year-old Hispanic man who developed cutaneous vasculitic lesions and gangrene of the toes following admission to hospital with COVID-19 pneumonia.\n\nCase Report:\nCOVID-19 has been associated with cardiovascular disease entities including stroke, acute coronary syndrome, venous thromboembolism, and peripheral vascular disease. We present a case in which a 47-year-old Hispanic man arrived at the Emergency Department with COVID-19 and was admitted for respiratory failure. Despite anticoagulation initiated on admission in the presence of an elevated D-dimer, the patient developed gangrene of all his toes, which required bilateral transmetatarsal amputation.\n\nConclusions:\nThis case shows that dermatologic manifestations may develop in patients who initially present with COVID-19 pneumonia. These symptoms may be due to venous thrombosis following SARS-CoV-2 vasculitis, leading to challenging decisions regarding anticoagulation therapy. Randomized controlled trials are needed to evaluate the efficacy of anticoagulation, to choose appropriate anticoagulants and dosing, and to assess bleeding risk.\n\nMeSH Keywords:\nAnticoagulantsGangreneMicrovesselsThrombophiliaVenous Thrombosis\n==== Body\nBackground\nCoronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first identified in Wuhan, China, in late 2019 and has led to an ongoing global pandemic. According to the Johns Hopkins University of Medicine Coronavirus Resource Center, as of July 31, 2020, there have been 17 516 264 confirmed cases of COVID-19 and 678 226 deaths worldwide [1]. The virus affects all age groups, but disease severity increases with advancing age and in individuals with underlying medical conditions such as hypertension, diabetes, heart disease, lung disease, and cancer. SARS-CoV-2 is usually spread via droplets or contact with surfaces that have been contaminated. The virus typically invades the respiratory tract and mucous membranes, leading to pathological involvement of different organ systems. Patients usually present with fever, cough, and fatigue, but less common manifestations have been reported, including focal neurological deficits as a result of strokes arising from thrombosis and thromboembolism. Cutaneous manifestations with an array of morphologies have also been documented, which are suggestive of immune or inflammatory pathways in the patho-physiology of COVID-19 [2–4]. Chilblain-like lesions have been observed in patients with COVID-19. Chilblains are cold-induced lesions resulting in redness, pruritis, and inflammation of the toes due to damage of skin capillary beds; however, the mechanism of such lesions with COVID-19 remains unclear. This report presents the case of a 47-year-old Hispanic man who developed cutaneous vasculitic lesions and gangrene of the toes following admission to hospital with COVID-19 pneumonia.\n\nCase Report\nA 47-year-old Hispanic nonsmoking man with a medical history of diabetes mellitus and chronic back pain presented to the Emergency Department with progressive dyspnea associated with fever, chills, and a productive cough with rusty brown sputum for 10 days. He also reported fatigue, myalgia, and diffuse headache; he denied sick contacts, nausea, chest pain, leg pain, leg swelling, recent travel, exposure to cold, or history of toe abnormalities. He received the influenza vaccine for the current season and reported not taking any medications. On physical examination, he had an oral temperature of 40.1°C (104.1°F), blood pressure of 148/80 mmHg, heart rate of 135 beats per minute, respiratory rate of 38 cycles per minute, and an oxygen saturation of 60% on ambient air and 70% on 6 L of oxygen by nasal cannula. His weight was 86 kg, his height was 177.8 cm, and his body mass index was 27.2 kg/m2. The patient was alert and oriented to person, place, time, and situation. Cardiovascular exam revealed tachycardia, regular rhythm, no heart murmurs, no jugular venous distension, and normal peripheral pulses. Auscultation of the lungs demonstrated diffusely diminished breath sound bilaterally, and there was no lower extremity edema. Abdominal examination was benign. The patient was anicteric and had moist oral mucosa, and his feet had no skin abnormalities.\n\nLaboratory values at admission revealed white blood cell count of 18×109/L; lactic acid, 3.0 mmol/L; C-reactive protein, 171 mg/L; D-dimer, >4.3 mg/L; and ferritin, 567 ng/mL. Creatinine and troponin values were normal. Basic natriuretic peptide, platelets, liver function transaminases, and the coagulation profile were within normal limits. An influenza test was negative, and he was tested for COVID-19 as well. An arterial blood gas demonstrated respiratory acidosis with an abnormal alveolar-arterial gradient. Electrocardiogram showed sinus tachycardia with no ST-T wave changes and a QTc interval of 483 ms. A chest X-ray revealed diffuse bilateral infiltrates, while a lower extremity venous Doppler revealed an extensive deep venous thrombosis (DVT) in the right leg, extending from the superficial femoral vein through the posterior tibial vein, and a left-sided popliteal DVT. The patient was admitted to the Intensive Care Unit with an initial diagnosis of acute hypoxic respiratory failure due to community-acquired pneumonia suggestive of COVID-19 pneumonia. He was placed on mechanical ventilation and started on azithromycin at 500 mg daily; ceftriaxone, 1 g daily; weight-based, full-dose enoxaparin, 80 mg every 12 h; hydroxychloroquine, 400 mg every 12 h for 2 doses (followed by 200 mg every 12 h for 4 days); vitamin C, 500 mg twice daily; zinc sulfate, 220 mg daily; and methylprednisolone, 40 mg every 12 h.\n\nOver the next few days, the patient had a waxing and waning course; on the third day of hospitalization, positive results for SAR-CoV-2 infection were received for the patient’s reverse transcription-polymerase chain reaction (RT-PCR) test from a nasopharyngeal swab using the Abbott RealTime SARS-CoV-2 assay. On the fourth day of hospitalization, he developed a painless bluish-purple discoloration of his toes bilaterally (Figures 1, 2). His feet were warm to the touch and nontender and had 3+ palpable dorsalis pedis pulses bilaterally; there were no sensory deficits of the toes or lower extremities. A computed tomography (CT) angiogram of the aorta and lower extremity arteries bilaterally revealed patent arteries in the lower extremities. The initial purplish-discoloration of his toes continued to worsen as the toes became progressively gangrenous and stone-like; D-dimer remained elevated and the coagulation profile remained unremarkable during the time he was on full-dose anticoagulation.\n\nThe patient’s respiratory condition improved; he was extubated on day 9 of hospitalization and gradually required less supplemental oxygen over the subsequent days. He was also managed for the pain of the toes with oxycodone 20 mg every 12 h as needed. Results from RT-PCR testing from a nasopharyngeal swab using the Abbott RealTime SARS-CoV-2 assay were negative for SAR-CoV-2 infection twice (on day 20 and 22). His anticoagulation was transitioned from enoxaparin to apixaban 5 mg twice a day. However, his toes continued to be gangrenous; on day 26 of hospitalization, he underwent a bilateral transmetatarsal amputation after there was demarcation of the gangrene. He performed well postoperatively and was subsequently discharged to a subacute rehabilitation facility.\n\nDiscussion\nCOVID-19 is a rapidly evolving disease, and the incidence and epidemiology of complications such as COVID toes remain uncertain at the time of this writing. Several proposed mechanisms may account for the dermatological and vascular changes seen in the toes of a subset of patients with COVID-19. In one study, findings supported endothelial destruction induced by viral particles [5]. Affected patients in that study had negative test results for COVD-19 based on throats swabs and measurements for circulating antibodies; however, SARS-CoV-2 virus was present in the skin’s blood vessel endothelial cells of patients with symptoms of COVID toes. Such vascular damage could explain the findings seen in the patient discussed in our case.\n\nOutside direct viral endothelial damage in COVID-19, there is a state of severe inflammation with high plasma levels of pro-inflammatory cytokines including interleukin (IL)-2, IL-6, and IL-7 [6]. Another hypothesis is that this inflammatory process leads to endotheliitis and hence endothelial injury [7]. Evidence for elevated D-dimer and thrombocytopenia in COVID-19 patients supports this hypothesis [6,8,9], suggesting a coagulopathic process. Because these factors play a key role in the Virchow’s triad, it is reasonable to assume that this process can lead to small vessel thrombosis, as described in postmortem findings in COVID-19 patients [7]. Diffuse microthrombosis in the digits, which possess end arterioles, may lead to ischemia and finally gangrene of distal tissues (Figure 3). Although various authors have described the use of D-dimers in evaluating for the presence of coagulopathy, no randomized controlled trials have shown that it influences the course of COVID-19.\n\nAnother theory regarding the development of COVID toes and the progression to gangrene involves venous thrombosis and its rare association with venous gangrene. Based on data from the National Hospital Discharge Survey from 1979 to 2006, only 0.43% of patients had gangrene from deep vein thrombosis [10]. This phenomenon was implicated mainly in patients with an underlying malignancy. Considering the above clinical evidence, we believe that the pathophysiology underlying the gangrenous toes in our patient was either microvascular thrombosis (from system inflammation or direct viral endothelial damage) or related to a rare complication of venous thrombosis manifesting as venous gangrene. However, knowledge of COVID-19 pathophysiology is only based on small series and limited data.\n\nRisk factors for COVID toes presumably include elements of a patient’s clinical profile that would elevate components of Virchow’s triad, as well as complications of chronic conditions that result in peripheral vasculopathy, such as diabetes mellitus. Although the patient had diabetes, which is associated with microvascular complications [11], it cannot solely explain the rapid progression of gangrene of his toes. Because COVID toes developed within 4 days of presentation and progressed to gangrene within 10 days, it is unlikely that diabetes alone could have played a role the rapid progression.\n\nThe clinical presentation of COVID toes is progressive. Usually, mild discoloration occurs early in the course and evolves to gangrene within a relatively short timeframe, depending on the severity of the disease. The dermatological changes of the toes are often associated with pain, given that damage is likely mainly vascular and not neuronal as in diabetics. Some cases present with pruritis as well as vesicular lesions. Laboratory tests typically demonstrate elevated D-dimer and acute phase reactants, mainly secondary to the systemic hyperinflammatory state.\n\nGiven the potential for coagulopathy in COVID-19 and the evidence of benefits from anticoagulation in a prior observational study on influenza H1N1 disease [12], several clinicians recommend the use of intermediate or full-dose anticoagulation therapy for the routine care of hospitalized COVID-19 patients. This recommendation is based on a hypothesis that the therapy can alter the course of microvascular thrombosis in these patients [13]. The observational study on influenza H1N1 disease involved critically ill patients with acute respiratory distress syndrome and risk factors for venous thromboembolism (VTE) [12]. It showed that empirical anticoagulation therapy reduced VTE incidence without increased risk of hemorrhage. In a recently published observational study, the use of anticoagulation was associated with better outcomes in severely ill patients with COVID-19 who had elevated D-dimer [14]. Unfractionated-heparin has been suggested as a better choice for anticoagulation compared with low-molecular-weight heparin [15]. Our patient was placed on full-dose, weight-based enoxaparin on day 1 of hospitalization after testing revealed an elevated D-dimer level. Although there have been reports of severe arterial thrombosis associated with COVID-19, notwithstanding anticoagulation or antiplatelet therapy [16], throughout the course of our patient’s hospitalization, he was found to have sufficient lower extremity macrovascular circulation as evidenced by palpable peripheral pulses and a CT angiogram that did not find any macrovascular occlusion.\n\nOverall prognosis of COVID toes is variable and is highly dependent on the extent of the underlying systemic inflammation and any concurrent venous thrombosis. Failure of anticoagulation leads to higher morbidity and eventual demarcation of the gangrenous toes leading to amputation, and it is also associated with higher mortality.\n\nThis case demonstrates that dermatologic manifestations may develop in patients who initially present with COVID-19 pneumonia. These symptoms can be due to venous thrombosis following SARS-CoV-2 vasculitis, resulting in challenging decisions regarding anticoagulation therapy. Randomized controlled clinical trials are needed to evaluate the efficacy of anticoagulation to enable choosing appropriate anticoagulants and dosing, as well as assessing bleeding risk.\n\nConclusions\nClinicians should monitor patients with pneumonia secondary to COVID-19 for cutaneous vasculitic lesions, such as COVID toes, and should initiate anticoagulation promptly.\n\nDepartment and Institution where work was done\n\nCritical Care Department/Long Island Community Hospital (formerly Brookhaven Memorial Hospital), Patchogue, NY, U.S.A.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Dermatologic manifestations on the dorsal aspect of the patient’s feet on day 11 of hospitalization in the setting of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2.\n\nFigure 2. Dermatologic manifestations on the plantar aspect of the patient’s feet on day 11 of hospitalization in the setting of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2.\n\nFigure 3. Graphical abstract displaying the proposed vasculopathic sequence of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulting in gangrenous toes. IL – interleukin; TNFα – tumor necrosis factor α.\n==== Refs\nReferences:\n1. World Health Organization (WHO) Coronavirus disease 2019 (COVID-19) Situation report – 46 Geneva WHO 2020 https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200306-sitrep-46-covid-19.pdf?sfvrsn=96b04adf_4 \n2. Noakes A Majoe S Understanding the role that ‘COVID toe’ has in recognizing the potential extent of COVID-19 infections: A case study Pathog Glob Health 2020 114 6 283 84 32576095 \n3. El Hachem M Diociaiuti A Concato C A clinical, histopathological and laboratory study of 19 consecutive Italian paediatric patients with chilblain-like lesions: Lights and shadows on the relationship with COVID-19 infection J Eur Acad Dermatol Venereol 2020 [Online ahead of print] \n4. Freeman EE McMahon DE Lipoff JB The spectrum of COVID-19-associated dermatologic manifestations: An international registry of 716 patients from 31 countries J Am Acad Dermatol 2020 83 4 1118 29 32622888 \n5. Colmenero I Santonja C Alonso-Riaño M SARS-CoV-2 endothelial infection causes COVID-19 chilblains: Histopathological, immunohistochemical and ultrastructural study of seven paediatric cases Br J Dermatol 2020 [Online ahead of print] \n6. Zhang T Sun LX Feng RE [Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019] Zhonghua Jie He He Hu Xi Za Zhi 2020 43 6 496 502 [in Chinese] 32241072 \n7. Oudkerk M Büller HR Kuijpers D Diagnosis, prevention, and treatment of thromboembolic complications in COVID-19: Report of the National Institute for Public Health of the Netherlands Radiology 2020 [Online ahead of print] \n8. Bikdeli B Madhavan MV Jimenez D COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review J Am Coll Cardiol 2020 75 23 2950 73 32311448 \n9. Lippi G Favaloro EJ D-dimer is associated with severity of coronavirus disease 2019: A pooled analysis Thromb Haemost 2020 120 5 876 78 32246450 \n10. Musani MH Musani MA Verardi MA Venous gangrene a rare but dreadful complication of deep venous thrombosis Clin Appl Thromb Hemost 2011 17 6 E1 3 20699257 \n11. Lippi G Franchini M Targher G Epidemiological association between fasting plasma glucose and shortened APTT Clin Biochem 2009 42 118 20 19014926 \n12. Obi AT Tignanelli CJ Jacobs BN Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients J Vasc Surg Venous Lymphat Disord 2019 7 317 24 30477976 \n13. Klok FA Kruip MJHA van der Meer NJM Incidence of thrombotic complications in critically ill ICU patients with COVID-19 Thromb Res 2020 191 145 47 32291094 \n14. Tang N Bai H Chen X Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy J Thromb Haemost 2020 18 5 1094 99 32220112 \n15. Turshudzhyan A Anticoagulation options for coronavirus disease 2019 (COVID-19)-induced coagulopathy Cureus 2020 12 5 e8150 32550069 \n16. Kashi M Jacquin A Dakhil B Severe arterial thrombosis associated with Covid-19 infection Thromb Res 2020 192 75 77 32425264\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000671:Amputation; D000086382:COVID-19; D018352:Coronavirus Infections; D004636:Emergency Service, Hospital; D005500:Follow-Up Studies; D005734:Gangrene; D006630:Hispanic or Latino; D006801:Humans; D008297:Male; D008682:Metatarsal Bones; D008875:Middle Aged; D000076322:Multimorbidity; D058873:Pandemics; D010343:Patient Admission; D011024:Pneumonia, Viral; D012131:Respiratory Insufficiency; D018570:Risk Assessment; D045169:Severe Acute Respiratory Syndrome; D014034:Toes; D016896:Treatment Outcome; D014657:Vasculitis",
"nlm_unique_id": "101489566",
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"pages": "e926886",
"pmc": null,
"pmid": "32999267",
"pubdate": "2020-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19014926;32241072;30477976;32291094;32220112;32562567;32425264;32246450;32550069;20699257;32622888;32474947;32576095;32311448",
"title": "A 47-Year-Old Hispanic Man Who Developed Cutaneous Vasculitic Lesions and Gangrene of the Toes Following Admission to Hospital with COVID-19 Pneumonia.",
"title_normalized": "a 47 year old hispanic man who developed cutaneous vasculitic lesions and gangrene of the toes following admission to hospital with covid 19 pneumonia"
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"abstract": "Although efficacy of 36 months isoniazid preventive therapy (IPT) among HIV-positive individuals has been proven in trial settings, outcome, tolerance, and adherence have rarely been evaluated in real-life settings.This is a prospective observational cohort study conducted in 2 primary care rural clinics in Swaziland.After negative tuberculosis symptom screening, patients either with the positive tuberculin skin test (TST) or after tuberculosis treatment were initiated on IPT for 144 weeks. In addition to routine clinic visits, adherence was assessed every semester.Of 288 eligible patients, 2 patients never started IPT (1 refusal, 1 contraindication), and 253 (87.8%), 234 (81.3%), and 228 (79.2%) were still on IPT after 48, 96, and 144 weeks, respectively (chiP = .01). Of 41 patients who interrupted IPT before 144 weeks, 21 defaulted (of which 17 also defaulted HIV care); 16 stopped because of adverse drug reactions; 2 were discontinued by clinicians' mistake and 1 because of TB symptoms. Five patients (1.7%) died of causes not related to IPT, 5 (1.7%) developed TB of which 2 were isoniazid-resistant, and 9 (3.1%) were transferred to another clinic. As an indicator of adherence, isoniazid could be detected in the urine during 86.3% (302/350) and 73.6% (248/337) of patient visits in the 2 clinics, respectively (chiP < .001).The routine implementation of IPT 36 months was feasible and good patient outcomes were achieved, with low TB incidence, good tolerance, and sustained adherence.",
"affiliations": "Epicentre, Paris, France Médecins Sans Frontières, Geneva, Switzerland National Tuberculosis Control Program Swaziland National Aids Program, Ministry of Health, Swaziland IRD UMI 233 TransVIHMI-UM-INSERM U1175, Montpellier, France.",
"authors": "Mueller|Yolanda|Y|;Mpala|Qhubekani|Q|;Kerschberger|Bernhard|B|;Rusch|Barbara|B|;Mchunu|Gugu|G|;Mazibuko|Sikhathele|S|;Bonnet|Maryline|M|",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid",
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"doi": "10.1097/MD.0000000000007740",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 28858089MD-D-17-0064210.1097/MD.0000000000007740077404850Research ArticleObservational StudyAdherence, tolerability, and outcome after 36 months of isoniazid-preventive therapy in 2 rural clinics of Swaziland A prospective observational feasibility studyMueller Yolanda MD, MIHa∗Mpala Qhubekani MScbKerschberger Bernhard MD, MPHbRusch Barbara MIHbMchunu Gugu MPHcMazibuko Sikhathele MDdBonnet Maryline MD, PhDaeLin. Wenyu a Epicentre, Paris, Franceb Médecins Sans Frontières, Geneva, Switzerlandc National Tuberculosis Control Programd Swaziland National Aids Program, Ministry of Health, Swazilande IRD UMI 233 TransVIHMI-UM—INSERM U1175, Montpellier, France.∗ Correspondence: Yolanda Mueller, Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland (e-mail: yolanda.mueller@hospvd.ch).9 2017 01 9 2017 96 35 e77401 2 2017 26 6 2017 13 7 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This 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\nAlthough efficacy of 36 months isoniazid preventive therapy (IPT) among HIV-positive individuals has been proven in trial settings, outcome, tolerance, and adherence have rarely been evaluated in real-life settings.\n\nThis is a prospective observational cohort study conducted in 2 primary care rural clinics in Swaziland.\n\nAfter negative tuberculosis symptom screening, patients either with the positive tuberculin skin test (TST) or after tuberculosis treatment were initiated on IPT for 144 weeks. In addition to routine clinic visits, adherence was assessed every semester.\n\nOf 288 eligible patients, 2 patients never started IPT (1 refusal, 1 contraindication), and 253 (87.8%), 234 (81.3%), and 228 (79.2%) were still on IPT after 48, 96, and 144 weeks, respectively (chi2P = .01). Of 41 patients who interrupted IPT before 144 weeks, 21 defaulted (of which 17 also defaulted HIV care); 16 stopped because of adverse drug reactions; 2 were discontinued by clinicians’ mistake and 1 because of TB symptoms. Five patients (1.7%) died of causes not related to IPT, 5 (1.7%) developed TB of which 2 were isoniazid-resistant, and 9 (3.1%) were transferred to another clinic. As an indicator of adherence, isoniazid could be detected in the urine during 86.3% (302/350) and 73.6% (248/337) of patient visits in the 2 clinics, respectively (chi2P < .001).\n\nThe routine implementation of IPT 36 months was feasible and good patient outcomes were achieved, with low TB incidence, good tolerance, and sustained adherence.\n\nKeywords\nadherenceisoniazid preventive therapyTB-HIVOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nIn settings with high tuberculosis (TB) burden, isoniazid (INH) Preventive Therapy (IPT) is recommended for prevention of active tuberculosis in people living with HIV (PLHIV), particularly in individuals who are tuberculin skin test (TST)-positive.[1–3] In addition to antiretroviral therapy (ART), IPT reduces the incidence of active TB[4] and was initially recommended for 6 months.[3] However, effectiveness of IPT has been shown to diminish 6 to 18 months after completion of such a regimen,[5–7] suggesting that IPT should be provided for longer. Indeed, a trial conducted in Botswana showed that TB incidence among TST-positive PLHIV was reduced by a further 43% if IPT was given for 36 months as compared to 6 months,[8] although the reduction was not significant in PLHIV with negative or unknown TST results.\n\nDespite these results, uptake of 36 months’ IPT has been slow in many countries.[9–11] Main concerns about long-term IPT were risk of side-effects, patient adherence, development of active TB while on IPT, and increased risk of INH-resistance. For example, in South Africa, up to 28% of cases suffered from a grade 3 or 4 transaminase elevation, after a median of one-and-a-half year on IPT and only 60% were retained on IPT at 3 years.[12] Besides, although benefits of IPT are greatest in TST-positive patients, the introduction of widespread TST in resource-limited settings is limited by operational constraints such as cold chain requirements and the extra-visit required for TST reading. Although clinical trials have been essential to inform recommendations about 36 months IPT, there have been no observational studies documenting actual implementation. Confirming results from clinical trials in routine settings can help to convince decision-makers about the added value of 36 months IPT.\n\nEven though TB incidence has decreased in recent years, Swaziland is still the country with the highest TB and HIV burden reported in the world.[13] National TB control has focused on early detection and treatment of TB, in parallel with rapid scaling up and integration of ART. Although IPT was recommended for 6 months, its implementation remained challenging in 2011, and extending IPT duration to 36 months seemed unfeasible. There was also the concern that adherence and outcomes under routine conditions would be less favorable than those reported in clinical trials. Therefore, the objective of this study was to assess the feasibility of TST-based 36 months IPT strategy in HIV-infected patients in programmatic conditions in 2 rural clinics of the Shiselweni region in Swaziland, in order to inform policy-makers in the country and in similar settings. This paper focuses on adherence, tolerability, and outcomes after 48, 96, and 144 weeks of follow-up. The results of this study on initial patient screening, implementation of tuberculin-skin test, and initiation of IPT have been published previously.[14]\n\n2 Methods\nThis prospective observational cohort included PLHIV eligible for IPT followed in 2 rural nurse-led primary care clinics in the Shiselweni region, Kingdom of Swaziland (OLOS clinic in the Hlatikulu zone and New Haven clinic in the Matsanjeni zone). The study was undertaken in compliance with the Declaration of Helsinki and was approved by the Social Welfare Scientific Ethical Committee of Swaziland and the Médecins Sans Frontières Ethical Review Board. Written informed consent was obtained from all study participants.\n\nDetails of study setting and screening process can be found elsewhere.[14] Briefly, both clinics served an active ART cohort of about 700 patients. Nurses were in charge of providing HIV-TB care, which was fully integrated into general outpatient care. Expert clients (PLHIV trained to provide patient support education and counseling) assisted the nurses in managing patient files and clinic registers, as well as adherence support. Medical doctors visited the clinic once per week or every 2 weeks, according to needs, to attend to complicated cases and offer technical support.\n\nThe sample size was calculated to estimate the proportion of positive TST.[14] The IPT study population, derived from the proportion of positive TST, consisted of all at-least-16-years-old PLHIV enrolled for HIV care at 1 of the 2 study clinics who were eligible for 36 months’ IPT based on either a positive TST (≥5 mm induration) or for secondary prophylaxis (after TB treatment[2]). Exclusion criteria were kept to a minimum to be as close as possible to the routine program conditions. According to national recommendations for IPT provision, patients did not receive IPT when they were on TB treatment, where TB was suspected, or when INH was clinically contraindicated (e.g. hepatitis and allergy). Informed consent was obtained before TST screening.[14]\n\nIntensified TB case-finding was implemented at every contact between a PLHIV and the health facility, based on symptom screening (cough, night sweats, fever, weight loss, or chest pain) as per national recommendations.[15,16] Diagnosis of TB was initially based on auramine-stained microscopical examination and XpertMTB/RIF (Cepheid, Sun Valley) testing performed at health-center level (secondary level), and later only on XpertMTB/RIF as per national recommendations.[17] Samples from smear- or Xpert-positive patients were sent to reference laboratories at regional or national level for mycobacterial culture and drug susceptibility testing.\n\nPatients were seen after 1 month after starting IPT. Subsequently, appointments followed the usual visit schedule for ART or cotrimoxazole refill, that is, every 1, 2, or 3 months depending on patient, clinic, and drug stocks. Laboratory monitoring followed the general recommendations for patients under HIV care in Swaziland, namely 6-monthly CD4, and quarterly liver function test. In 2012, viral-load testing was added to routine monitoring as per the national VL algorithm. Expert clients traced patients on HIV care by phone when clinical appointments were missed by 3 days. A renewed attempt was made by phone in cases where patients did not present at the clinic over a period of 90 days. IPT outcome definitions were adapted from the national standard definitions used to monitor 6 months’ IPT:[16] “default” was defined as a patient who had taken INH for at least 1 month, then interrupted for 60 consecutive days or more; “failure” was defined as someone developing active TB disease while on IPT; “treatment discontinuation” was used for someone whose IPT had been discontinued by a health care worker due to adverse effects or any other reason; “transfer out” was used for someone who transferred to another ART site or region to continue treatment; “death” were those on IPT who were reported to have died of any cause during the course of treatment; “completed IPT” was defined as a full course of 36 times 4 weeks (total 144 weeks) of INH.\n\nPill count was systematically recorded at every patient contact. In addition, for all patients on IPT for 36 months, an in-depth evaluation was conducted twice yearly, consisting of a urine sample and a short questionnaire. Adherence was assessed through a combination of 4 parameters: pill count (i.e., the number of INH tablets remaining in the INH blister when coming for drug refill, including refill for antiretroviral or other concomitant drug), the self-reported number of days of no INH intake in the past 14 days, the Morisky scale, and isoniazid testing in the urine. For this, isoniazid strip tests (BD TAXO INH Test) were performed on urine samples following the manufacturer's instructions. This test is mostly reliable for the presence of isoniazid in the urine if the drug was taken in the last 24 hours.[18] The Morisky scale[19] combines 4 questions related to different aspects of drug intake by patients on chronic treatment (1. Do you ever forget to take your medicine? 2. Are you careless at times about taking your medicine? 3. When you feel better do you sometimes stop taking your medicine? 4. Sometimes if you feel worse when you take the medicine, do you stop taking it?). One point is attributed for every positive answer. Adherence is judged high, intermediate, or low for scores of 0, 1 to 2, and 3 to 4, respectively.[19]\n\nData were collected by the clinic staff on regular patient files during the routine follow-up visits, before extraction on study-specific case report forms by a study nurse. Occurrence of adverse drug reactions (ADR) was recorded in the patient file by the clinic nurse. Adverse drug reactions were defined as: “a response to a medicine which is noxious and unintended, and which occurs at doses normally used in man.” Additional information was requested in case of ADR, death, active TB, or treatment discontinuation. In addition, during adherence counseling, expert clients asked about side-effects experienced by the patients, without further precision on the definition of side-effect.\n\nData were entered on site weekly using Epi-Data 3.0 software (The EpiData Association, Odense Denmark), initially by a data entry clerk and later by the study nurse. Data were analyzed in Stata 12.1 software (College Station, TX). No imputation was done in the case of missing variables, apart from the date of death which was chosen randomly between date of last visit and date of information about deaths, in the absence of other information. Main outcome was described by the proportions that completed treatment, failed (developed TB), died, defaulted, discontinued, or transferred. The nonparametric test for trend across ordered groups was used to assess changes on adherence indicators over time. In the survival analysis of retention on IPT, death, TB, default and discontinuation were failures and transfers were censored. Predefined baseline characteristics that could represent risk factors for discontinuation (potential confounding factors), such as clinic, age, sex, ART status, initial baseline CD4 count at IPT initiation, and occurrence of adverse events, were tested in a non-parametric survival model, and rates of interruption per person-years were calculated. Variables associated with retention on IPT, defined as a log rank test <0.20, were further included in a multivariate Cox model in addition to age as a potential confounder.\n\n3 Results\n3.1 Patient characteristics\nThe study profile has been previously published.[14] Patient characteristics are detailed in Table 1. Overall 288 patients initiated IPT for the following reasons: 217 tested positive at the first TST, 47 tested positive at the second repeated TST at 6 months after first TST, and 24 had completed TB treatment less than 6 months ago. Median age was 38 years (interquartile range [IQR] 31–47). The median time from HIV diagnosis to inclusion was 2.8 years (IQR: 1.4–4.8), with 252 patients (87.5%) already on ART. Median CD4 count at inclusion was 477 cell/microL (IQR 344 – 616). A total of 102 (35.9%) had been treated for tuberculosis previously, and 109 (38.5%) had previously received IPT for 6 months.\n\nTable 1 Characteristics of patients started on isoniazid preventive therapy, Swaziland, 2012–2015.\n\n3.2 Outcomes\nOut of a total of 288, 286 (99.3%) actually initiated IPT (1 refusal, 1 contraindication not previously recognized) and 253 (87.8%), 234 (81.3%), and 228 (79.2%) were still on IPT after 48, 96, and 144 weeks, respectively (chi2P = .01, Table 2). Of the 40 patients who did not complete IPT, 21 defaulted (of which 17 also defaulted HIV care), 16 discontinued IPT because of adverse drug reactions (detailed below), and 2 because of a mistake of the clinician, who stopped IPT after 6 months instead of 36 months. Nine patients (3.1%) were transferred to another clinic, and 5 (1.7%) started TB treatment (described in detail below). Finally, 5 patients (1.7%) died while on IPT, corresponding to a death rate was 0.7/100 person-years (5 deaths/702 person-years of follow-up; 95%CI 0.3–1.7%). Of those 5 deaths, there was 1 road traffic accident, 2 deaths of unknown cause, and 2 possibly due to TB (1 patient with symptoms compatible with TB meningitis, and 1 with important weight loss); none was judged possibly or probably related to IPT by the physician in charge.\n\nTable 2 Cumulative outcomes after 48, 96, and 144 weeks on isoniazid preventive therapy, Swaziland, 2012–2015.\n\nFive patients were diagnosed with TB over 702 person-years of follow-up, corresponding to an annual incidence rate of 0.7/100 person-years (95%CI 0.3–1.7/100PY). Among them, there were 2 new pulmonary drug-sensitive cases, 1 extrapulmonary case (TB of the spine diagnosed by radiography), and 2 patients infected with INH-resistant mycobacteria.\n\nPatients were followed up for a median of 149 weeks (IQR 146–163 weeks) after IPT start, for a total of 702 person-years (Fig. 1). In the adjusted non-parametric analysis (Table 3), gender and ART treatment were not associated with retention on IPT, while age, a high CD4 count at IPT initiation, absence of adverse event and clinic were associated with better retention. In a multivariate Cox model, occurrence of at least 1 adverse event was the strongest predictor of treatment interruption, whereas increasing age and higher initial CD4 level were associated with retention under IPT (P < .001 for goodness-of-fit test). The proportional hazards assumption was not violated (global test P = .325).\n\nFigure 1 Kaplan–Meier curve of retention under IPT, by clinic.\n\nTable 3 Univariate and multivariate Cox analyses of predictors of isoniazid preventive therapy interruption, Swaziland, 2012–2015.\n\n3.3 Tolerance\nAdverse drug reactions were mentioned during consultations by 5.6% (15/286), 2.0% (5/253), and 0.9% (1/234) patients during the first, second, and third year of follow-up, respectively. Three cases of hepatotoxicity were recorded (1.0%), of which 2 were severe (1 with ALT 5–10x, 1 admitted for jaundice) and 1 mild. All patients recovered. Other patients mentioned symptoms which may have been due to hepatotoxicity, such as abdominal pain (3 patients), or nausea and vomiting (2 patients, including 1 pregnant women). Unfortunately, IPT was often stopped without liver tests to confirm the diagnosis. The other reported adverse reactions were 2 cases of rash, 1 of itching, 2 cases of neuropathy, 3 cases of nonspecific weight loss, 1 psychotic decompensation, and 1 case of vertigo and nystagmus.\n\nTreatment was discontinued for 16/22 patients reporting adverse-drug reactions. Of the 16 patients that discontinued IPT, 1 was found dead at home 2 months after IPT discontinuation, and 1 pregnancy resulted in stillbirth. The 2 patients with neuropathy recovered only partially. The remaining 13 patients were seen at a later appointment with no complaints raised.\n\nSide-effects reported to the expert client during the adherence assessments decreased from 19.0% (16/79) and 50.0% (25/52) at 6 months in OLOS and New Haven, respectively, to less than 1% after 30 months. These side-effects were mostly itching, symptoms of neuropathy (tingling in hands or feet), nonspecific pain (joint pains), and other complaints (abdominal pain). None led to temporary treatment interruptions. Although the nurses reported few cases of neuropathy (1.4%), up to 4.9% (14/288) were reported during the interviews with the expert clients.\n\n3.4 Adherence\nAdherence was assessed at least once in 252 patients (87.5%), with a median of 3 assessments per patient (IQR 2–4). Urine was collected between 1 and 30 hours after reported INH intake (median 13 hours in OLOS and 5 hours in New Haven, ranksum test P < .001). Not all urine samples were actually tested, mainly because of the lack of available urine strips or of the staff either collecting the urine or performing the test. Of all assessments combined, the proportion of positive urine tests for isoniazid (INH) was 80.1% (95%CI 76.9–82.9%). Of the 17 patients who had the urine tested more than 24 hours after last INH intake, 14 (82.4%) were still positive. By contrast, out of the 141 negative urine tests, there were only 11 patients admitting no INH intake in the past 24 hours.\n\nAlthough objective assessments such as the proportion of positive urine tests or pill count showed decreasing adherence over time (test for trend P = .04 and .12, respectively, Table 4), interview-based adherence indicators, such as the Morisky scale, or reported days of no intake seemed to improve over time. The main reason given for missed drug intake was not having the drug with them, or forgetting to take it. More rarely, patients cited lack of food, not feeling well, and running out of drugs before the appointment date.\n\nTable 4 Adherence to isoniazid preventive therapy at M6, M12, M18, M24, M30, and M36, by pill count, intake in past 14 days, Morisky scale, and urine tests, Swaziland, 2012–2015.\n\n4 Discussion\nTo our knowledge, this is the first study to document feasibility of 36 months’ IPT in the real life conditions of a high HIV/TB burden setting. In this setting, patient outcomes were similar or even more favorable than results obtained in African clinical trials that compared 36 months’ isoniazid with other IPT regimens.[8,12] In particular, the incidence of TB in patients on IPT was comparable with other studies, even though Swaziland carries a high TB burden. However, most patients on IPT were already on ART for some time, had high CD4 counts, and therefore were at lower risk of TB than ART-naive patients. Two TB cases were due to isoniazid-resistant mycobacteria, which is not surprising in a setting were where 13.2% of new cases and 45.2% of previously treated cases harbor INH resistance.[20] Interestingly, both age and a high initial CD4 count favored good retention on IPT, whereas the occurrence of adverse drug reactions led to treatment interruption.\n\nOccurrence of adverse drug reactions, particularly hepatotoxicity, was comparable with findings from the Botswana trial.[21] By contrast, there were more hepatotoxic events recorded in the clinical trial in South Africa[12] than found in our study, maybe related to a higher prevalence of underlying hepatitis B and alcohol use. Also, liver tests were performed systematically in clinical trials, in contrast to our setting where, despite existing recommendations, systematic laboratory testing is rare. In our study, hepatotoxicity was more frequent during the first year on INH. In these cases, extending IPT from 6 to 36 months did not much increase the risk of hepatotoxicity. However, we cannot exclude substantial underreporting of adverse events in our study, considering that almost all adverse events reported led to treatment discontinuation. This may imply that some side-effects remained unreported.\n\nIndeed, few cases of neuropathy were reported by the nurses given the number of reported instances of tingling, burning sensation, or pain in the hands and feet to the expert clients. Moreover, management of neuropathy was far from ideal, INH being often stopped instead of increasing vitamin B6. Training on these aspects should not be neglected during implementation of INH.\n\nAdherence to INH was good, based on the results of the urine test, even if it slightly decreasing over time. However, some selection bias in adherence estimates is possible, as the patients who missed their appointment, and therefore urine testing, may also be the least adherent. Nonadherent patients were probably also more likely to have the drug discontinued because of vague side-effects, whereas the adherent patients were continuing on treatment. Still, our findings show that patients can be maintained on INH in routine conditions with good adherence. The main reason given by patients for missing a dose was not having the drug with them. This suggests that aspects of drug management while on travel should be reinforced during counseling. Also, differences in packaging between IPT and ART make dispensing a difficult task for health center staff. Coformulation with cotrimoxazole would certainly simplify IPT prescription.[22]\n\nIn the context of an observational cohort conducted in routine conditions, our study suffers from some limitations. First, we cannot exclude some selection in the study population because of nonexhaustive screening and/or TST refusal. Second, the study was conducted in only 2 clinics, which may not be fully representative of all the clinics in the country. Also, most patients were already ART-experienced, and results may not be generalized to contexts with many ART-naive patients. Third, we did not aim to compare outcomes of 36 months to 6 months or non-IPT provision, because the efficacy of IPT has been established by other studies.[8,12] Also, the benefits and harms of short- and long-term IPT have been described previously and therefore were not evaluated.[12,21,22] Finally, the quality of the information obtained for TB cases or adverse reactions was limited by the fact that many patients were not assessed, or only partly, by medical doctors. On the other hand, 1 strength was the limited number of missing data, considering the simple study set-up.\n\nThis feasibility study which was conducted in the public sector in a resource constrained setting shows that implementation of 36 months’ IPT under routine conditions leads to similar outcomes as have been demonstrated previously in clinical trials. Indeed, IPT given for 36 months was well tolerated, with a limited incidence of TB cases. IPT can easily be integrated into routine follow-up of HIV-positive patients. Furthermore, adherence can be maintained in the long run. These findings support the 2015 updated WHO recommendation of giving at least 36 months IPT to adults and adolescents living with HIV, who have an unknown or positive tuberculin skin test (TST) status, in resource-constrained settings with high TB incidence and transmission.\n\nAcknowledgments\nThe authors would like to thank the patients who participated in this study, the staff, and expert clients working in the clinics, and the entire MSF teams working in Swaziland. Special acknowledgment to Mathieu Bastard for statistical advice, to Clothilde Rambaud-Althaus for support in quality monitoring, and to Béatrice Vasquez and Calorine Mekiedje for help in data cleaning and project supervision.\n\nAbbreviations: ADR = adverse drug reaction, ART = antiretroviral therapy, HIV = human immunodeficiency virus, INH = isoniazid, IPT = isoniazid preventive therapy, IQR = interquartile range, PLHIV = people living with HIV, PY = person-years, TB = tuberculosis, TST = tuberculin skin test, WHO = World Health Organization.\n\nFunding: This study was funded by Médecins Sans Frontières (MSF). MSF was involved in all stages of the study conduct and analysis.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] World Health Organization . Interim Policy on Collaborative TB/HIV Activities . Geneva, Switzerland : WHO ; 2004 .\n[2] World Health Organization . Guidelines for Intensified Tuberculosis Case-Finding and Isoniazid Preventive Therapy for People Living with HIV in Resource-Constrained Settings . Geneva, Switzerland : WHO ; 2011 .\n[3] World Health Organization, UNAIDS . Policy Statement on Preventive Therapy Against Tuberculosis in People Living with HIV . Geneva, Switzerland : WHO ; 1998 .\n[4] Group TAS Danel C Moh R \nA trial of early antiretrovirals and isoniazid preventive therapy in Africa . N Engl J Med \n2015 ;373 :808 –22 .26193126 \n[5] Johnson JL Okwera A Hom DL \nDuration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults . AIDS \n2001 ;15 :2137 –47 .11684933 \n[6] Quigley MA Mwinga A Hosp M \nLong-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults . AIDS \n2001 ;15 :215 –22 .11216930 \n[7] Den Boon S Matteelli A Ford N \nContinuous isoniazid for the treatment of latent tuberculosis infection in people living with HIV . AIDS \n2016 ;30 :797 –801 .26730567 \n[8] Samandari T Agizew TB Nyirenda S \n6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial . Lancet \n2011 ;377 :1588 –98 .21492926 \n[9] Charles MK Lindegren ML Wester CW \nImplementation of tuberculosis intensive case finding, isoniazid preventive therapy, and infection control (“three I's”) and HIV-tuberculosis service integration in lower income countries . PloS One \n2016 ;11 :e0153243 .27073928 \n[10] Getahun H Granich R Sculier D \nImplementation of isoniazid preventive therapy for people living with HIV worldwide: barriers and solutions . AIDS \n2010 ;24 (suppl 5) :S57 –65 .21079430 \n[11] Gupta S Granich R Date A \nReview of policy and status of implementation of collaborative HIV-TB activities in 23 high-burden countries . Int J Tuberc Lung Dis \n2014 ;18 :1149 –58 .25216827 \n[12] Martinson NA Barnes GL Moulton LH \nNew regimens to prevent tuberculosis in adults with HIV infection . N Engl J Med \n2011 ;365 :11 –20 .21732833 \n[13] Haumba S Dlamini T Calnan M \nDeclining tuberculosis notification trend associated with strengthened TB and expanded HIV care in Swaziland . Public Health Action \n2015 ;5 :103 –5 .26400378 \n[14] Huerga H Mueller Y Ferlazzo G \nImplementation and operational research: feasibility of using tuberculin skin test screening for initiation of 36-month isoniazid preventive therapy in HIV-infected patients in resource-constrained settings . J Acquir Immune Defic Syndr \n2016 ;71 :e89 –95 .26910386 \n[15] Getahun H Kittikraisak W Heilig CM \nDevelopment of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies . PLoS Med \n2011 ;8 :e1000391 .21267059 \n[16] Ministry of Health, Kingdom of Swaziland . National Guidelines for Implementing the “Three I's” of Tuberculosis Control . 2012 .\n[17] Sikhondze W Dlamini T Khumalo D \nCountrywide roll-out of Xpert® MTB/RIF in Swaziland: the first three years of implementation . Public Health Action \n2015 ;5 :140 –6 .26400386 \n[18] Elizaga J Friedland JS \nMonitoring compliance with antituberculous treatment by detection of isoniazid in urine . Lancet \n1997 ;350 :1225 –6 .\n[19] Morisky DE Green LW Levine DM \nConcurrent and predictive validity of a self-reported measure of medication adherence . Med Care \n1986 ;24 :67 –74 .3945130 \n[20] Sanchez-Padilla E Dlamini T Ascorra A \nHigh prevalence of multidrug-resistant tuberculosis, Swaziland, 2009–2010 . Emerg Infect Dis \n2012 ;18 :29 –37 .22260950 \n[21] Tedla Z Nyirenda S Peeler C \nIsoniazid-associated hepatitis and antiretroviral drugs during tuberculosis prophylaxis in HIV-infected adults in Botswana . Am J Respir Crit Care Med \n2010 ;182 :278 –85 .20378730 \n[22] Harries AD Lawn SD Suthar AB \nBenefits of combined preventive therapy with co-trimoxazole and isoniazid in adults living with HIV: time to consider a fixed-dose, single tablet coformulation . Lancet Infect Dis \n2015 ;15 :1492 –6 .26515525\n\n",
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"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D015331:Cohort Studies; D004334:Drug Administration Schedule; D013541:Eswatini; D005240:Feasibility Studies; D005260:Female; D015658:HIV Infections; D006801:Humans; D007538:Isoniazid; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D011446:Prospective Studies; D019035:Rural Health Services; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary",
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"references": "14746111;26515525;26400386;11684933;25216827;22260950;21267059;21492926;20378730;9652571;26400378;11216930;26910386;27073928;21079430;26193126;3945130;26730567;21732833",
"title": "Adherence, tolerability, and outcome after 36 months of isoniazid-preventive therapy in 2 rural clinics of Swaziland: A prospective observational feasibility study.",
"title_normalized": "adherence tolerability and outcome after 36 months of isoniazid preventive therapy in 2 rural clinics of swaziland a prospective observational feasibility study"
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"abstract": "Kaposi sarcoma (KS) was first described by Moritz Kaposi as a vascular tumor that mainly involves the skin but can affect any organ system. It is typically an acquired immunodeficiency syndrome defining illness but has emerged as a neoplasm also seen in patients on immunosuppressive therapy. Few KS cases have been reported in the literature associated with inflammatory bowel diseases. We report the case of a 39-year-old male with well-controlled human immunodeficiency virus (HIV) and ulcerative colitis (UC) who presented to the hospital with new skin lesions shortly after the initiation of vedolizumab to treat his refractory UC. Immunohistochemistry of the skin lesions was consistent with Kaposi's sarcoma secondary to human herpesvirus-8. This is a rare case of iatrogenic KS in a well-controlled HIV patient secondary to immunosuppressive therapy.",
"affiliations": "Department of Internal Medicine, St. Michael's Medical Center, New York Medical College, Newark, NJ, USA.;Department of Internal Medicine, St. Michael's Medical Center, New York Medical College, Newark, NJ, USA.;Department of Internal Medicine, St. Michael's Medical Center, New York Medical College, Newark, NJ, USA.",
"authors": "Ajao|Susanne O|SO|;Jayasingam|Rajasingam|R|;Shaaban|Hamid|H|",
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"doi": "10.4103/IJCIIS.IJCIIS_92_20",
"fulltext": "\n==== Front\nInt J Crit Illn Inj Sci\nInt J Crit Illn Inj Sci\nIJCIIS\nInternational Journal of Critical Illness and Injury Science\n2229-5151\n2231-5004\nWolters Kluwer - Medknow India\n\nIJCIIS-11-177\n10.4103/IJCIIS.IJCIIS_92_20\nCase Report\nIatrogenic Kaposi's sarcoma unmasked by Vedolizumab in a patient with ulcerative colitis and well-controlled human immunodeficiency virus: A case report\nAjao Susanne O. 1\nJayasingam Rajasingam 12\nShaaban Hamid 13\n1 Department of Internal Medicine, St. Michael's Medical Center, New York Medical College, Newark, NJ, USA\n2 Department of Infectious Disease, St. Michael's Medical Center, New York Medical College, Newark, NJ, USA\n3 Medical Oncology, St. Michael's Medical Center, New York Medical College, Newark, NJ, USA\nAddress for correspondence: Dr. Hamid Shaaban, 111 Central Avenue, Newark, NJ 07102, USA. E-mail: hamidshaaban@gmail.com\nJul-Sep 2021\n25 9 2021\n11 3 177180\n19 6 2020\n04 9 2020\n17 12 2020\nCopyright: © 2021 International Journal of Critical Illness and Injury Science\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nKaposi sarcoma (KS) was first described by Moritz Kaposi as a vascular tumor that mainly involves the skin but can affect any organ system. It is typically an acquired immunodeficiency syndrome defining illness but has emerged as a neoplasm also seen in patients on immunosuppressive therapy. Few KS cases have been reported in the literature associated with inflammatory bowel diseases. We report the case of a 39-year-old male with well-controlled human immunodeficiency virus (HIV) and ulcerative colitis (UC) who presented to the hospital with new skin lesions shortly after the initiation of vedolizumab to treat his refractory UC. Immunohistochemistry of the skin lesions was consistent with Kaposi's sarcoma secondary to human herpesvirus-8. This is a rare case of iatrogenic KS in a well-controlled HIV patient secondary to immunosuppressive therapy.\n\nKey Words:\n\nCase report\nhuman immunodeficiency virus\nKaposi's sarcoma\nulcerative colitis\nvedolizumab\n==== Body\npmcINTRODUCTION\n\nKaposi's sarcoma (KS) is a vascular neoplasm caused by human herpesvirus-8 infection (HHV-8). It was first described in 1872 by Moritz Kaposi as a vascular tumor that mainly involves the skin but can affect any organ system.[1] The KS skin lesions go through stages. It starts as a macule in the patch stage, which then progresses into plaques in the plaque stage. It finally ends as a nodule in the tumor stage. There are four different clinical forms of KS which include classical or sporadic, endemic, human immunodeficiency virus (HIV) associated, and the iatrogenic form.[2] Iatrogenic KS was previously commonly seen after solid organ transplant but increasing cases of this form of KS have been reported in patients on immunosuppressive therapy.[12] Patients with refractory inflammatory bowel diseases (IBD) are usually treated with immunosuppressive agents including steroids and more recently biologic agents, which directly target the inflammatory response pathway.[3] We report a case of a controlled HIV patient with refractory ulcerative colitis (UC) who was diagnosed with KS following initiation of vedolizumab therapy.\n\nCASE REPORT\n\nA 39-year-old homosexual African-American male with a past medical history of UC diagnosed 6 years earlier, condyloma acuminata, proctitis, Hodgkin's lymphoma in remission, and HIV presented to our tertiary care hospital with complaints of abdominal pain, rectal pain, and chronic bloody diarrhea. He described new tender lesions on his left medial foot which was absent at his previous admission a month ago. The lesions started as macules and later progressed tender lesions.\n\nMesalamine and long-term oral corticosteroids were prescribed previously for his recurrent UC flares without symptomatic relief and hence, he was also started on vedolizumab 2 months before this presentation. On physical examination, vital signs were normal. On abdominal examination, he had localized tenderness in the left lower quadrant. He also had tender cervical and inguinal lymphadenopathy. Digital rectal examination revealed bloody mucoid stool. Dermatologic examination revealed dark macules on the sole of both feet and a darkened hyperkeratotic purple-colored plaque on his left medial foot [Figures 1 and 2]. Laboratory investigation showed a white blood cell count of 12,600/mm3, erythrocyte sedimentation rate of 132 mm/h, and C-reactive protein of 4.6 mg/dL. His most recent CD4 was 873 cells/mm3 and viral load was 50 copies/mL. Colonoscopy showed severe proctitis with deep ulcerations in a continuous and circumferential pattern in the rectum with a normal sigmoid colon. Condyloma acuminata in a background of severe chronic active inflammation was also found at the anorectal junction. Histology showed severe chronic active inflammation with microabscess suggesting active UC with no evidence of spindle cells. Immunohistochemical analysis of the anal biopsy was positive for human papillomavirus (HPV) 16/18 and HPV 31/33 but negative for herpes simplex virus 1/2 and cytomegalovirus (CMV). He was managed with suppository hydrocortisone with symptomatic improvement in diarrhea and abdominal pain. Cervical lymph node biopsy was done which showed a polymorphous population of lymphocytes and was negative for malignant cells. A 4 mm punch biopsy of the left foot lesion showed atypical intradermal vascular and spindle cell proliferation. On immunohistochemistry, the spindle cells were positive for vascular markers (CD31 and CD34) and HHV-8 [Figure 3a and b]. Serology was also positive for HHV-8 polymerase chain reaction with high viral titers of 74 copies/mL. The results were consistent with the diagnosis of cutaneous iatrogenic KS. The patient declined surgical treatment for his refractory UC and was continued on suppository hydrocortisone in addition to vedolizumab on discharge. Follow-up colonoscopy showed improving proctitis. The patient was also started on liposomal doxorubicin to treat KS with an improvement of his foot lesion a month later following treatment [Figure 4]. He is currently doing well.\n\nFigure 1 Medial foot with a hyperkeratotic purple-colored plaque consistent with Kaposi's sarcoma\n\nFigure 2 Macules on the sole of both feet\n\nFigure 3 Foot skin biopsy consisting of spindle cells. (a) Spindle cells with irregular small vessel proliferation and erythrocyte extravasation between tumor cells. (b) Immunohistochemical stain showing human herpesvirus-8 expression of spindle cells\n\nFigure 4 Improved lesion a month later on the medial foot\n\nDISCUSSION\n\nThe patient in this report represents a case of cutaneous iatrogenic KS associated with HHV-8 in a well-controlled HIV patient with UC. KS is a rare diagnosis and is usually typically diagnosed when classic skin lesions are present. Although KS can occur at any time, it commonly occurs in patients with HIV with CD4 cells <200 cell/mm3, unlike in this patient.[4] KS developed in this patient, despite not having acquired immunodeficiency syndrome (AIDS), after immunosuppressive therapy to treat his underlying UC suggesting that his KS is iatrogenic. IBD is a chronic inflammation of the gastrointestinal tract and nearly 3 million males and 3.9 million females are living with IBD worldwide.[5]\n\nVedolizumab was approved for the treatment of both Crohn's disease (CD) and UC in 2018. It has shown efficacy and safety in patients with refractory CD and UC.[6] It is a monoclonal antibody that prevents the recruitment of lymphocytes to the inflamed tissue by blocking 4b7 integrin on the lymphocyte surface from interacting with cell adhesion molecule (MAdCAM-1) on the intestinal endothelium.[7] The 4b7 integrin is primarily expressed on a subset of memory T helper lymphocytes, and in doing so, vedolizumab inhibits lymphocyte adhesion to MAdCAM-1 which is expressed on gut endothelial cells. This reduces inflammation in gastrointestinal tissues in patients with CD and UC.[89] Biologic agents have resulted in an improved quality of life and increased control of disease activity for patients with IBD. As a result of the immunosuppressive nature of these agents, they are associated with an increased risk of opportunistic infections. Majority of trials have reported a favorable safety profile of vedolizumab with a low rate of opportunistic infections or malignancies, and only few patients required discontinuation.[10] Clinical trials have infrequently reported clostridial infections, tuberculosis, and CMV infections in patients on vedolizumab for IBD.[11] Malignancies reported in patients receiving vedolizumab therapy were gastrointestinal malignancies such as colorectal cancer, hepatic cancer, appendiceal carcinoid, and peritoneal metastases.[12]\n\nAn iatrogenic form of KS has been documented in posttransplant patients and patients with a variety of diseases treated with immunosuppressive agents. Most cases of iatrogenic KS reported in the literature are in HIV negative patients.[1] Similar to our patient, there have been reported cases of cutaneous KS in patients receiving golimumab, infliximab, and adalimumab therapy.[13141516171819] Gastrointestinal involvement of KS has also been reported in a patient with UC exposed to Infliximab.[20]\n\nThe patient in this report received multiple immunosuppressive therapies in the form of vedolizumab and steroids. Although a number of cases suggesting the correlation between steroid and KS have been documented, our theory is that vedolizumab likely unmasked KS caused by HHV-8 in this well-controlled HIV patient with no evidence of AIDS.[1] This patient was only recently started on vedolizumab therapy, and the rapid onset of the skin lesions following initiation of therapy supports a causal relationship between the two.\n\nPathological diagnosis is the gold standard of diagnosis of KS. Most KS biopsies showing spindle cells are infected by HHV-8.[21] First-line treatment for iatrogenic KS consists of withdrawal or reducing immunosuppressive therapy to restore immune defenses and improve KS lesions.[22] In this patient, this mode of approach was difficult as the patient refused surgical treatment for his refractory UC. Despite the complication of KS, his UC appeared to be improving with vedolizumab on follow-up colonoscopies. Treatment of KS lesions includes chemotherapy such as liposomal doxorubicin, which was used in this patient, and paclitaxel as a second-line agent.[21]\n\nCONCLUSION\n\nThe iatrogenic form of KS occurs in patients on immunosuppressive therapy, as this patient. Patients with IBD on immunosuppressive drugs should be followed up closely and screened for latent viral infections before initiating therapy. This is the first report of KS unmasked by vedolizumab in a patient with well-controlled HIV disease. The case highlights that HHV-8 should be recognized as a likely underlying opportunistic infection in patients with IBD on immunosuppressive therapy. Withdrawal of immunosuppressive agents or the use of chemotherapy may be considered curative.\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal the identity, but anonymity cannot be guaranteed.\n\nResearch quality and ethics statement\n\nThis case report did not require approval by the Institutional Review Board / Ethics Committee. The authors followed applicable EQUATOR Network (http://www.equator-network.org/) guidelines, specifically the CARE guideline, during the conduct of this research project.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 Chtourou L Ayedi L Rejab H Boudabous M Mnif L Grati A Iatrogenic colorectal Kaposi's sarcoma complicating a refractory ulcerative colitis in a human immunodeficiency negative-virus patient Pathologica 2017 109 371 4 29449725\n2 Martin W III Hood AF Farmer ER Kaposi sarcoma Medicine 1993 72 245 61 8341141\n3 Stasi E De Santis S Cavalcanti E Armentano R Iatrogenic Kaposi sarcoma of the terminal ileum following short-term treatment with immunomodulators for Crohn disease: A case report Medicine (Baltimore) 2019 98 e15714 31096523\n4 Temelkova I Tronnier M Terziev I Wollina U Lozev I Goldust M A series of patients with kaposi sarcoma (mediterranean/classical type): Case presentations and short update on pathogenesis and treatment Open Access Maced J Med Sci 2018 6 1688 93 30337990\n5 GBD 2017 Inflammatory Bowel Disease Collaborators. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017 Lancet Gastroenterol Hepatol 2020 5 17 30 31648971\n6 Christensen B Colman RJ Micic D Gibson PR Goeppinger SR Yarur A Vedolizumab as induction and maintenance for inflammatory bowel disease: 12-month effectiveness and safety Inflamm Bowel Dis 2018 24 849 60 29562271\n7 Navaneethan U Edminister T Zhu X Kommaraju K Glover S Vedolizumab is safe and effective in elderly patients with inflammatory bowel disease Inflamm Bowel Dis 2017 23 E17 28296827\n8 Pijls PA Gilissen LP Vedolizumab is an effective alternative in inflammatory bowel disease patients with anti-TNF-alpha therapy-induced dermatological side effects Dig Liver Dis 2016 48 1391 3 27639825\n9 Fleisher M Marsal J Lee SD Frado LE Parian A Korelitz BI Effects of vedolizumab therapy on extraintestinal manifestations in inflammatory bowel disease Dig Dis Sci 2018 63 825 33 29484571\n10 Colombel JF Sands BE Rutgeerts P Sandborn W Danese S D'Haens G The safety of vedolizumab for ulcerative colitis and Crohn's disease Gut 2017 66 839 51 26893500\n11 Ng SC Hilmi IN Blake A Bhayat F Adsul S Khan QR Low frequency of opportunistic infections in patients receiving vedolizumab in clinical trials and post-marketing setting Inflamm Bowel Dis 2018 24 2431 41 30312414\n12 Bye WA Jairath V Travis SPL Systematic review: the safety of vedolizumab for the treatment of inflammatory bowel disease Aliment Pharmacol Ther 2017 46 3 15 28449273\n13 Vural S Gündoğdu M Akay BN Korkmaz P Şanli H Heper AO Aggressive kaposi's sarcoma associated with golimumab therapy Arch Rheumatol 2018 33 384 6 30632542\n14 Cohen CD Horster S Sander CA Bogner JR Kaposi's sarcoma associated with tumour necrosis factor alpha neutralising therapy Ann Rheum Dis 2003 62 684 12810439\n15 Francesco U Saverio N Valerio M Francesco S Rosa Daniela G Kaposi's sarcoma in a psoriatic arthritis patient treated with infliximab Int Immunopharmacol 2010 10 827 20433950\n16 Martínez-Martínez ML Pérez-García LJ Escario-Travesedo E Ribera-Vaquerizo PA Kaposi sarcoma associated with infliximab treatment Actas Dermosifiliogr 2010 101 462 4 20525496\n17 Amadu V Satta R Montesu MA Cottoni F Kaposi's sarcoma associated with treatment with adalimumab Dermatol Ther 2012 25 619 20 23210762\n18 Bret J Hernandez J Aquilina C Zabraniecki L Fournie B Kaposi's disease in a patient on adalimumab for rheumatoid arthritis Joint Bone Spine 2009 76 721 2 19945327\n19 Hamzaoui L Kilani H Bouassida M Mahmoudi M Chalbi E Siai K Iatrogenic colorectal Kaposi sarcoma complicating a refractory ulcerative colitis in a human immunodeficiency negative-virus patient Pan Afr Med J 2013 15 154 24396560\n20 Schneider JW Dittmer DP Diagnosis and treatment of kaposi sarcoma Am J Clin Dermatol 2017 18 529 39 28324233\n21 Antman K Chang Y Kaposi's sarcoma N Engl J Med 2000 342 1027 38 10749966\n22 Rios A Kaposi sarcoma: a fresh look AIDS 2021 35 515 6 33507008\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2229-5151",
"issue": "11(3)",
"journal": "International journal of critical illness and injury science",
"keywords": "Case report; Kaposi's sarcoma; human immunodeficiency virus; ulcerative colitis; vedolizumab",
"medline_ta": "Int J Crit Illn Inj Sci",
"mesh_terms": null,
"nlm_unique_id": "101571136",
"other_id": null,
"pages": "177-180",
"pmc": null,
"pmid": "34760665",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "29449725;10749966;24396560;23210762;8341141;20433950;31096523;28324233;30312414;33507008;29484571;28449273;12810439;29562271;26893500;28296827;27639825;30337990;30632542;19945327;20525496;31648971",
"title": "Iatrogenic Kaposi's sarcoma unmasked by Vedolizumab in a patient with ulcerative colitis and well-controlled human immunodeficiency virus: A case report.",
"title_normalized": "iatrogenic kaposi s sarcoma unmasked by vedolizumab in a patient with ulcerative colitis and well controlled human immunodeficiency virus a case report"
} | [
{
"companynumb": "US-TAKEDA-2021TUS074480",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VEDOLIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Our prospective study is among the first attempts to examine the health of prenatally buprenorphine-exposed children after neonatal age and to determine the types of child maltreatment in this patient group. The study population included 102 children (61/41 Caucasian males/females) who had a positive urine screen for buprenorphine as a newborn. In addition to buprenorphine, the children were also prenatally exposed to other substances. The data were collected by pediatricians in follow-up visits until 3 years of age and from medical records. Ten prenatally buprenorphine-exposed children (10 %) had some birth defect. The study children had slightly more major anomalies than newborns on average in Finland (3.4 %). Eye disorders (nystagmus, opticus atrophy, and strabismus) occurred in 11 % of children. One child was diagnosed with hepatitis C transmission. One female died of sudden infant death syndrome (SIDS), and one male died of congenital heart disease. Pediatricians submitted altogether 70 reports to child welfare services of suspected maltreatment. Of these reports, 45 (64 %) involved medical neglect. Physical abuse was suspected in four reports.\n\n\nCONCLUSIONS\nWe suggest that prenatally buprenorphine-exposed children have several types of problems with their health at toddler age and that they are susceptible to child maltreatment, especially to medical neglect.",
"affiliations": "Social Pediatrics Outpatient Clinic, Hospital for Children and Adolescents, Helsinki University Central Hospital, HUS, P.O. Box 280, FI-00029, Helsinki, Finland. kaisa.kivisto@helsinki.fi.;Social Pediatrics Outpatient Clinic, Hospital for Children and Adolescents, Helsinki University Central Hospital, HUS, P.O. Box 280, FI-00029, Helsinki, Finland. sarimari.tupola@hus.fi.;Social Pediatrics Outpatient Clinic, Hospital for Children and Adolescents, Helsinki University Central Hospital, HUS, P.O. Box 280, FI-00029, Helsinki, Finland. satu.kivitie-kallio@hus.fi.",
"authors": "Kivistö|Kaisa|K|;Tupola|Sarimari|S|;Kivitie-Kallio|Satu|S|",
"chemical_list": "D000701:Analgesics, Opioid; D002047:Buprenorphine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00431-015-2562-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-6199",
"issue": "174(11)",
"journal": "European journal of pediatrics",
"keywords": "Birth defects; Buprenorphine; Child maltreatment; Health; Prenatal opioid exposure; Preschool child",
"medline_ta": "Eur J Pediatr",
"mesh_terms": "D000701:Analgesics, Opioid; D002047:Buprenorphine; D002648:Child; D002649:Child Abuse; D002675:Child, Preschool; D005260:Female; D005387:Finland; D006304:Health Status; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011446:Prospective Studies",
"nlm_unique_id": "7603873",
"other_id": null,
"pages": "1525-33",
"pmc": null,
"pmid": "26003659",
"pubdate": "2015-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12738353;1163358;22430445;15333268;17473105;17728081;7945039;18055690;9346984;11700691;11673580;11665823;86983;23432078;18972589;17556395;21747128;12874495;9430746;24972693;22835477;22553083;21345403;16257138;22356664;9233978;24500948;8734549;11182872;17166896;19056114;18608605;12725555;6178811;20338975;15223541;3812384;18474065;3762846;18559440;1116890;18480306;12411361;9776530;8528813;21683173;9200364;15679749;7943475;17850394;15266192;22211517;18185492;17364281;24132830;20410537;19056119;20945525;6653911;4834596",
"title": "Prenatally buprenorphine-exposed children: health to 3 years of age.",
"title_normalized": "prenatally buprenorphine exposed children health to 3 years of age"
} | [
{
"companynumb": "FI-RECKITT BENCKISER PHARMACEUTICAL, INC-RB-080107-2015",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE"
},
... |
{
"abstract": "BACKGROUND\nUstekinumab is a new biologic therapy targeting interleukin-12 and interleukin -23. It is currently approved for the treatment of psoriasis, but clinical trials have shown that it can induce and maintain remission in Crohn's disease (CD). We aim to evaluate effectiveness of ustekinumab in the treatment of CD.\n\n\nMETHODS\nA retrospective chart review was performed including patients (pts) from 2 academic medical centers with complicated, refractory CD started on ustekinumab between June 2011 and June 2014. Pts were treated based on a novel subcutaneous dosing schedule designed to simulate the intravenous load used in clinical trials.\n\n\nRESULTS\nForty-five pts were treated with ustekinumab during this study period. Of the pts who had clinical parameters available before and after medication start, 46% achieved clinical response (Harvey-Bradshaw index decrease ≥ 3) and 35% achieved clinical remission (Harvey-Bradshaw index ≤ 3). Short inflammatory bowel disease questionnaire scores increased significantly (46 [20, 68] to 55 [32, 70], P < 0.05). Erythrocyte sedimentation rate decreased significantly (20 [3, 54] to 12 [0, 42] mm/h, P < 0.05). C-reactive protein decreased significantly (4.9 [0.3, 111] to 3.3 [0.2, 226] mg/L, P < 0.05). Seventy-six percent of patients demonstrated an endoscopic response and 24% achieved complete endoscopic remission. Twelve patients (26%) were hospitalized for IBD-related issues. Four pts had infection-related complications. Six pts (13%) underwent surgery for IBD-related issues. Three pts stopped ustekinumab, 1 for pt preference and 2 for the lack of response.\n\n\nCONCLUSIONS\nUsing a novel subcutaneous dosing schedule, ustekinumab was successful in improving clinical, laboratory, and endoscopic markers of disease activity in patients with severe, refractory CD.",
"affiliations": "*Department of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee; †Department of Medicine, University of Maryland School of Medicine, Baltimore, MD; and ‡Department of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD.",
"authors": "Harris|Kimberly A|KA|;Horst|Sara|S|;Gadani|Akash|A|;Nohl|Anne|A|;Annis|Kim|K|;Duley|Caroline|C|;Beaulieu|Dawn|D|;Ghazi|Leyla|L|;Schwartz|David A|DA|",
"chemical_list": "D003879:Dermatologic Agents; D000069549:Ustekinumab",
"country": "England",
"delete": false,
"doi": "10.1097/MIB.0000000000000624",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0998",
"issue": "22(2)",
"journal": "Inflammatory bowel diseases",
"keywords": null,
"medline_ta": "Inflamm Bowel Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D003424:Crohn Disease; D003879:Dermatologic Agents; D004351:Drug Resistance; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D000069549:Ustekinumab; D055815:Young Adult",
"nlm_unique_id": "9508162",
"other_id": null,
"pages": "397-401",
"pmc": null,
"pmid": "26752468",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Patients with Refractory Crohn's Disease Successfully Treated with Ustekinumab.",
"title_normalized": "patients with refractory crohn s disease successfully treated with ustekinumab"
} | [
{
"companynumb": "US-JNJFOC-20150209072",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThere has been a recent surge in the literature highlighting the association of fentanyl as precipitating serotonin syndrome in patients on a serotonergic agent.\n\n\nOBJECTIVE\nThe purpose of our study was to understand the incidence of serotonin syndrome in patients who receive fentanyl while on serotonergic agents.\n\n\nMETHODS\nThis retrospective analysis was conducted from 2012 to 2013 after approval from the Institutional Review Board. We searched for all patients that had received a serotonergic agent and were admitted to the hospital during the study period. Next, we split these patients into 2 groups by placing all patients who had received fentanyl and a serotonergic agent into one group. We then searched for any of the Hunter Serotonin Toxicity Criteria in the records of patients that had received both fentanyl and a serotonergic agent. Further, we searched for all patients with serotonin syndrome mentioned in their records.\n\n\nMETHODS\nThis study was conducted at a 900 bed tertiary care academic center.\n\n\nRESULTS\nOver the 2 year study period, 112,045 patients were on a serotonergic agent, and 4,538 of these patients were treated with both fentanyl and a serotonergic agent. A search for Hunter's Criteria through the records of the patients receiving both fentanyl and a serotonergic agent revealed 23 patients had been documented with some of these symptoms. On detailed chart review, only 4 [95% CI 1 - 10] of these patients truly met Hunter's Criteria for serotonin syndrome. We then searched all admissions for a diagnosis code of serotonin syndrome during the study period. Five additional cases of serotonin syndrome were found, but none of these patients were treated with fentanyl.\n\n\nCONCLUSIONS\nSome of the limitations of our study include that it represents a single institution, although it is a large academic center. An inherent limitation may be the under diagnosis of serotonin syndrome.\n\n\nCONCLUSIONS\nThe incidence of serotonin syndrome in patients who receive both fentanyl and a serotonergic agent is low.",
"affiliations": "Massachusetts General Hospital, Boston, MA.",
"authors": "Koury|Katharine M|KM|;Tsui|Becky|B|;Gulur|Padma|P|",
"chemical_list": "D000701:Analgesics, Opioid; D018490:Serotonin Agents; D005283:Fentanyl",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-3159",
"issue": "18(1)",
"journal": "Pain physician",
"keywords": null,
"medline_ta": "Pain Physician",
"mesh_terms": "D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid; D004359:Drug Therapy, Combination; D005260:Female; D005283:Fentanyl; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D018490:Serotonin Agents; D020230:Serotonin Syndrome",
"nlm_unique_id": "100954394",
"other_id": null,
"pages": "E27-30",
"pmc": null,
"pmid": "25675067",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incidence of serotonin syndrome in patients treated with fentanyl on serotonergic agents.",
"title_normalized": "incidence of serotonin syndrome in patients treated with fentanyl on serotonergic agents"
} | [
{
"companynumb": "US-PFIZER INC-2015089333",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL CITRATE"
},
"drugadditional": null,
... |
{
"abstract": "Cutaneous carcinoma of the scrotum is rare with the most common type being squamous cell carcinoma. Here, we report 6 cases of poorly differentiated carcinoma with apocrine immunophenotype. Mean age at presentation was 68 years (range: 31-91 years). Clinical presentation included eczematous rash over mass, scrotal cyst, ulcerated mass, and mass. Tumor size ranged from 1.2 to 5.5 cm (average 2.5 cm). The tumors were solid with involvement of the dermis/hypodermis and composed of cords and nests of eosinophilic cells displaying nuclei with prominent nucleoli and surrounded by desmoplastic stroma. Focal squamous differentiation was evident in one case (17%). An intraductal component was seen in one case (17%). Pagetoid spread in the epidermis was seen in 3 cases. There was no morphologic evidence of apocrine differentiation. By immunohistochemistry, the tumor cells were positive for GCDFP-15 (n = 6/6), GATA3 (n = 6/6), CK7 (n = 5/5), AR (n = 4/4), and mammaglobin (n = 3/5). Five (83%) patients had metastases at diagnosis. Treatment included wide local excisions and inguinal lymph node dissection, followed by chemotherapy (gemcitabine, carboplatin; n = 3), trastuzumab/Lupron (n = 1), tamoxifen/Arimidex (n = 1), and radiotherapy (n = 1). Two patients (40%) were dead of disease, less than 2 years from diagnosis. Four patients developed metastases to lymph nodes, liver, bones, and lungs. Molecular analysis (n = 2) detected a HER-2 mutation in one and microsatellite instability in another. Although the presence of an intraepidermal pagetoid component could hint toward the diagnosis of invasive extramammary Paget disease, tumors without an intraepidermal component could be diagnostically challenging given the lack of morphologic evidence of apocrine differentiation.",
"affiliations": "Departments of Pathology, Urology, and Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD; Departments of Pathology, and Urology, Emory University School of Medicine, Atlanta, GA; Department of Pathology, Hospital Obrero, La Paz, Bolivia; and Department of Pathology, The Ohio State University, Columbus, OH.",
"authors": "Kamanda|Sonia|S|;Epstein|Jonathan I|JI|;Osunkoya|Adeboye O|AO|;Cimino-Mathews|Ashley|A|;Argani|Pedram|P|;Sangüeza|Martin|M|;Plaza|Jose Antonio|JA|;Matoso|Andres|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000002100",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": null,
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": null,
"nlm_unique_id": "7911005",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34726185",
"pubdate": "2021-11-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Poorly Differentiated Scrotal Carcinoma With Apocrine Immunophenotype.",
"title_normalized": "poorly differentiated scrotal carcinoma with apocrine immunophenotype"
} | [
{
"companynumb": "US-ROCHE-2994935",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Panton-Valentine leukocidin (PVL) represents an important virulence factor for many strains of Staphylococcus aureus. PVL is an esotoxin causing leucocyte destruction and tissue necrosis. We report on a case of osteomyelitis involving the hip joint with thromblophlebitis complicated by necrotizing pneumonia and life-threatening septic shock. The child required advance respiratory support for 14 days with circulatory support for 7 days in ICU (intensive care unit), surgical draninage via arthrotomy of hip joint and second-line antibiotic treatment for 1 month. Among a wide literature, in Europe over half of Panton-Valentine St. Aureus (PVL-SA) is MSSA. Investigations for PVL are not always available determining an under-recognition of the episodes. Data on prevalence of PVL-SA in Italy are scarce. With this clinical report, we emphasize the recognition of clinical features that must lead to suspect PVL-SA osteomyelitis in children, providing their adequate management.",
"affiliations": "Pediatric Institute Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome Italy.;UO Degenza e Servizi di Riabilitazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome Italy.;Pediatric Institute Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome Italy.;Pediatric Institute Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome Italy.;Istituti Clinici Scientifici Maugeri, IRCCS, Pavia, Italy.;Orthopedic and Traumatology Institute, Catholic University of the Sacred Heart, Rome, Italy.;UO Degenza e Servizi di Riabilitazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome Italy.",
"authors": "Cori|M S|MS|;Ronconi|G|G|;Masiello|E|E|;Valentini|P|P|;Ferriero|G|G|;Maccauro|G|G|;Ferrara|P E|PE|",
"chemical_list": "D001427:Bacterial Toxins; D005098:Exotoxins; D007956:Leukocidins; C078284:Panton-Valentine leukocidin",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0393-974X",
"issue": "34(3 Suppl. 2)",
"journal": "Journal of biological regulators and homeostatic agents",
"keywords": "Staphylococcus aureus infection; child; osteomyelitis",
"medline_ta": "J Biol Regul Homeost Agents",
"mesh_terms": "D001427:Bacterial Toxins; D002648:Child; D005060:Europe; D005098:Exotoxins; D006801:Humans; D007558:Italy; D007956:Leukocidins; D010019:Osteomyelitis; D000071067:Pneumonia, Necrotizing; D013211:Staphylococcus aureus; D013924:Thrombophlebitis",
"nlm_unique_id": "8809253",
"other_id": null,
"pages": "53-56. ADVANCES IN MUSCULOSKELETAL DISEASES AND INFECTIONS - SOTIMI 2019",
"pmc": null,
"pmid": "32856440",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Staphylococcus Aureus Panton-Valentine Leukocidin causing hip osteomyelitis, thrombophlebitis and necrotizing pneumonia in an immuocompetent child.",
"title_normalized": "staphylococcus aureus panton valentine leukocidin causing hip osteomyelitis thrombophlebitis and necrotizing pneumonia in an immuocompetent child"
} | [
{
"companynumb": "IT-PFIZER INC-2021487837",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Emphysematous gastritis is a rare medical condition characterized by the presence of intra-mural air in the stomach associated with portal venous air tracking to a variable degree. There are no established guidelines favoring surgery over medical management. We present a case of a 64-year-old Caucasian male with a history of stage four colon adenocarcinoma with peritoneal carcinomatosis, malignant ascites, and liver metastasis status post-three cycles of chemotherapy who presented to the emergency room with complaints of generalized abdominal pain, nausea, non-bilious vomiting, and melena stools. He was managed conservatively as a case of sepsis secondary to emphysematous gastritis and made a full recovery. To our knowledge, this is the first reported case of emphysematous gastritis in an adult with colon cancer. Although we cannot establish a causal link between his chemotherapy regimen and emphysematous gastritis, the combined effect of an immunosuppressive state caused by advanced malignancy and cytotoxic effects of chemotherapy are the probable risk factors in our patient. We described the possible mechanisms of mucosal disruption by fluorouracil and bevacizumab in our case. Despite historically having a poor prognosis, emphysematous gastritis can be managed conservatively on a case-by-case basis. Clinicians should be aware that chemotherapy can be a predisposing factor to developing this rare condition.",
"affiliations": "Internal Medicine, Cleveland Clinic Fairview Hospital, Cleveland, USA.;Hematology and Oncology, Cleveland Clinic Fairview Hospital, Cleveland, USA.;Hematology and Oncology, Cleveland Clinic Fairview Hospital, Cleveland, USA.",
"authors": "Ogbue|Olisaemeka D|OD|;Haddad|Abdo|A|;Daw|Hamed|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.18895",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.18895\nInternal Medicine\nGastroenterology\nOncology\nA Rare Case of Emphysematous Gastritis Secondary to Chemotherapy\nMuacevic Alexander\nAdler John R\nOgbue Olisaemeka D 1\nHaddad Abdo 2\nDaw Hamed 2\n1 Internal Medicine, Cleveland Clinic Fairview Hospital, Cleveland, USA\n2 Hematology and Oncology, Cleveland Clinic Fairview Hospital, Cleveland, USA\nOlisaemeka D. Ogbue olisboby@yahoo.com\n19 10 2021\n10 2021\n13 10 e1889519 10 2021\nCopyright © 2021, Ogbue et al.\n2021\nOgbue 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/74479-a-rare-case-of-emphysematous-gastritis-secondary-to-chemotherapy\nEmphysematous gastritis is a rare medical condition characterized by the presence of intra-mural air in the stomach associated with portal venous air tracking to a variable degree. There are no established guidelines favoring surgery over medical management. We present a case of a 64-year-old Caucasian male with a history of stage four colon adenocarcinoma with peritoneal carcinomatosis, malignant ascites, and liver metastasis status post-three cycles of chemotherapy who presented to the emergency room with complaints of generalized abdominal pain, nausea, non-bilious vomiting, and melena stools. He was managed conservatively as a case of sepsis secondary to emphysematous gastritis and made a full recovery. To our knowledge, this is the first reported case of emphysematous gastritis in an adult with colon cancer. Although we cannot establish a causal link between his chemotherapy regimen and emphysematous gastritis, the combined effect of an immunosuppressive state caused by advanced malignancy and cytotoxic effects of chemotherapy are the probable risk factors in our patient. We described the possible mechanisms of mucosal disruption by fluorouracil and bevacizumab in our case. Despite historically having a poor prognosis, emphysematous gastritis can be managed conservatively on a case-by-case basis. Clinicians should be aware that chemotherapy can be a predisposing factor to developing this rare condition.\n\nbevacizumab\nfluorouracil\ncolon adenocarcinoma\nchemotherapy\nemphysematous gastritis\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\nEmphysematous gastritis is a rare medical condition characterized by the presence of intra-mural air in the stomach associated with portal venous air tracking to a variable degree. A severe variant of pneumatosis intestinalis, emphysematous gastritis has been traditionally considered to have mortality rates as high as 60-80% [1]. There are no established guidelines favoring surgery over medical management.\n\nWe describe a unique case of emphysematous gastritis occurring during chemotherapy in a patient with advanced colon malignancy. The potential mechanisms of this extremely rare adverse effect of chemotherapy are discussed.\n\nCase presentation\n\nWe present a case of a 64-year-old Caucasian male with a history of stage four colon adenocarcinoma with peritoneal carcinomatosis, malignant ascites, and liver metastasis status post-three cycles of leucovorin, fluorouracil, irinotecan, and bevacizumab (FOLFIRI/Avastin) who presented to the emergency room with complaints of generalized abdominal pain, nausea, non-bilious vomiting, and melena stools.\n\nHe had complained of abdominal pain, nausea, and diarrhea two weeks prior at an outpatient oncology clinic while on chemotherapy for which he received diphenoxylate/atropine, antiemetics, and 2 mg dexamethasone. These medications provided only minimal relief. He had the dosing of 5-fluorouracil (5-FU) and irinotecan decreased at the completion of cycle three of the chemotherapy regimen due to these new-onset symptoms.\n\nHe then developed new-onset vomiting after two weeks with an increase in severity of abdominal pain and was advised to present to the emergency room by his oncologist out of concern for bowel obstruction.\n\nIn the emergency room, he was hypotensive (blood pressure 92/60), tachycardic (heart rate 104) and had diffuse abdominal tenderness with guarding. Laboratory investigations were notable for leukocytosis of 67.62 K/uL, which was neutrophil predominant (neutrophils 98% and absolute neutrophil count of 66.27 K/uL).\n\nThese symptoms were concerning for acute abdomen, thus, a CT scan of the abdomen and pelvis was done. Imaging showed emphysematous gastritis with extensive portal gas (Figures 1, 2).\n\nFigure 1 Coronal sectional view of the CT scan of the abdomen showing gas within the wall of the stomach. Arrow demonstrating intra-mural gastric air.\n\nFigure 2 Cross-sectional view of the same contrast-enhanced CT scan of the abdomen demonstrating portal venous air.\n\nHe was managed as a case of sepsis secondary to emphysematous gastritis. Samples for blood and urine cultures were taken. The patient was given intravenous fluids, broad-spectrum antibiotics and was transferred to the surgical intensive care unit in stable condition, where he was managed conservatively. Conservative management included bowel rest, nasogastric decompression, intravenous proton pump inhibitor in addition to empiric antibiotic coverage. Empiric antibiotics comprised of intravenous vancomycin, piperacillin-tazobactam, and fluconazole. This was de-escalated to intravenous ertapenem on receipt of negative blood and urine culture results. Gastroenterology service decided against endoscopy as the patient had improved clinically after one week on conservative treatment. His diet was advanced, and the patient was discharged on a two-week course of intravenous ertapenem. He had made a full recovery but unfortunately, due to cancer progression was transitioned to hospice and died four months later.\n\nDiscussion\n\nPneumatosis intestinalis is the occurrence of gas within the walls of the gastrointestinal tract. The rarest site of this occurrence is the stomach wall [2]. Emphysematous gastritis and gastric emphysema are distinct entities at opposite ends of the clinical spectrum. They both have radiologic evidence of intra-mural gastric air; the latter has a benign clinical course with no systemic signs. Differences between these two entities are summarized in Table 1.\n\nTable 1 Differences between gastric emphysema and emphysematous gastritis.\n\nEtiology\tNon-infective source of intra-mural gastric air\tInfective source. Gas-forming organisms\t\nPredisposing factors\tGastroenteritis, projectile vomiting, gastric outlet obstruction.\tDiabetes, immunosuppression and alcohol abuse.\t\nPresentation\tUsually asymptomatic and hemodynamically stable.\tAbdominal pain, hematemesis, melena, sepsis, and septic shock.\t\nImaging\tLinear pattern with no wall thickening or portal venous air.\tCT usually shows streaky and linear pattern of air in gastric wall. Associated air in portal venous system.\t\nClinical course\tBenign, usually self-limiting.\tRequires medical or surgical management, often fatal.\t\n\nThe gastric mucosal barrier is relatively resistant to infection due to its acidity and rich blood supply. In emphysematous gastritis, gas producing organisms invade the gastric mucosa resulting in a systemic inflammatory response. Organisms commonly implicated include Streptococcus species, Escherichia coli, Enterobacter species, Clostridium species, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Candida species. In 42.4% of cases, however, no organism is identified [3]. The exact mechanism of mucosal disruption and subsequent microbial invasion is often unknown; however, several predisposing factors have been described in the literature including diabetes, renal failure, leukemia, adenocarcinoma, immunosuppression, peptic ulcer disease, alcohol abuse, ingestion of foreign/corrosive materials, gastrostomy feeding, intra-abdominal surgery, and medications such as long-term steroids and non-steroidal anti-inflammatory drugs.\n\nThere have been less than 100 cases of emphysematous gastritis reported in existing literature in the English language. Pneumatosis intestinalis has been associated with chemotherapeutic agents such as fluorouracil, docetaxel, and cisplatin but emphysematous gastritis due to chemotherapy is extremely rare. There has been a case reported in a child with leukemia on chemotherapy and steroids [4]. To our knowledge, this is the first reported case of emphysematous gastritis in an adult with colon cancer. Although we cannot establish a causal link between his chemotherapy regimen (FOLFIRI/Avastin) and emphysematous gastritis, the combined effect of an immunosuppressive state caused by advanced malignancy and cytotoxic effects of chemotherapy are the probable risk factors in our patient. 5-FU, especially when administered with leucovorin is more commonly associated with large bowel toxicity. Small bowel and stomach toxicities are less commonly reported. A potential mechanism of mucosal disruption is stomach ulceration and alteration of mucosal blood flow caused by 5-FU. Fata et al. [5] described a group of six patients with adenocarcinoma of the colon, treated with 5-FU and leucovorin who developed extensive small bowel ulceration with no involvement of the colon. They propose that the local effects of 5-FU on the mucosal blood flow or thrombogenic and angiospastic effects on the vascular endothelium are responsible for small bowel ulceration in these patients.\n\nAvastin (bevacizumab) is a monoclonal antibody targeting vascular endothelial growth factor (VEGF). It is an anti-angiogenic drug that has been associated with gastric perforation [6]. Mechanisms of bowel perforation that have been suggested are attributed to the anti-VEGF effects compromising bowel wall integrity, impaired healing of bowel injury, and ischemia related to mesenteric thrombosis [7].\n\nThe mechanisms of action of chemotherapy agents that cause mucosal injury are described in Figure 3. The resultant mucosal disruption can serve as a nidus of infection for gas-forming organisms resulting in emphysematous gastritis.\n\nFigure 3 Mechanism of mucosal injury from effects of chemotherapy and malignancy.\n\n \n\n fdUMP: fluorordeoxyuridylate, 5-FU: 5-fluorouracil.\n\nOur patient presented with septic shock and radiologic features of portal venous gas but had no signs of peritonitis and thus was managed conservatively with bowel rest, nasogastric decompression, intravenous proton pump inhibitor, and broad-spectrum antibiotics. He had negative blood and urine cultures and this was the rationale for broad-spectrum coverage in our case. Early antibiotic administration has been associated with better mortality outcomes [8]. Conservative management is agreeable with current trends, which favor medical management of emphysematous gastritis. It has been observed that after the year 2000, fewer patients with emphysematous gastritis underwent surgical intervention compared to prior (62.5% before 2000 versus 22.2% after 2000, P = 0.002), and this was associated with a lower mortality rate (59.4% before 2000 versus 33.3% after 2000, P = 0.046) [3]. The role of endoscopy is not established as the diagnosis of emphysematous gastritis can be based on clinical and radiologic findings. Endoscopy, however, may be useful to identify the causative organism(s) from gastric tissue biopsy/culture to guide antibiotic therapy when blood cultures are negative.\n\nConclusions\n\nIn conclusion, we present a case of emphysematous gastritis occurring during chemotherapy. We described the possible mechanisms of mucosal disruption by 5-FU and bevacizumab in our case. Despite the historically poor prognosis, emphysematous gastritis can be managed conservatively on a case-by-case basis. Clinicians should be aware that chemotherapy can be a predisposing factor to developing this rare condition.\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 Is surgical intervention avoidable in cases of emphysematous gastritis? A case presentation and literature review Int J Surg Case Rep Szuchmacher M Bedford T Sukharamwala P Nukala M Parikh N Devito P 456 459 4 2013 23537915\n2 Vomiting-induced gastric emphysema: a rare self-limiting condition Am J Med Sci Majumder S Trikudanathan G Moezardalan K Cappa J 92 93 343 2012 22052415\n3 Emphysematous gastritis: a case series of three patients managed conservatively Int J Surg Case Rep Nasser H Ivanics T Leonard-Murali S Shakaroun D Woodward A 80 84 64 2019 31622931\n4 Emphysematous gastritis in a leukemic child Med Pediatr Oncol Rowen M Myers M Williamson RA 433 437 2 1976 1069899\n5 5-Fluorouracil-induced small bowel toxicity in patients with colorectal carcinoma Cancer Fata F Ron IG Kemeny N O'Reilly E Klimstra D Kelsen DP 1129 1134 86 1999 10506695\n6 Extreme complications related to bevacizumab use in the treatment of ovarian cancer: a case series from a III level referral centre and review of the literature Ann Transl Med Turco LC Ferrandina G Vargiu V 1687 8 2020 33490199\n7 Pneumatosis intestinalis and bowel perforation associated with molecular targeted therapy: an emerging problem and the role of radiologists in its management AJR Am J Roentgenol Shinagare AB Howard SA Krajewski KM Zukotynski KA Jagannathan JP Ramaiya NH 1259 1265 199 2012 23169717\n8 Emphysematous gastritis: effectiveness of early antibiotic therapy Gastroenterol Hepatol Elson MZ Monzón LL Orta JE Fierro PC Monteverde VV Arbeloa CS 393 395 39 2016 26190762\n\n",
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"issn_linking": "2168-8184",
"issue": "13(10)",
"journal": "Cureus",
"keywords": "bevacizumab; chemotherapy; colon adenocarcinoma; emphysematous gastritis; fluorouracil",
"medline_ta": "Cureus",
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"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": "33490199;31622931;1069899;10506695;26190762;22052415;23537915;23169717",
"title": "A Rare Case of Emphysematous Gastritis Secondary to Chemotherapy.",
"title_normalized": "a rare case of emphysematous gastritis secondary to chemotherapy"
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"abstract": "The objective of the study is to report the experience with acetaminophen in low doses as an alternative to the treatment of the ductus arteriosus of the preterm newborn.\nRetrospective study including preterm newborns with patent ductus arteriosus who received oral acetaminophen because treatment with indomethacin had failed or is contraindicated. A dosage consisted of a first dose of 25 mg/kg and maintenance doses of 30 mg/kg/day, for 3 to 7 days. A second cycle was administered in cases of reopening of the ductus arteriosus. The rates of ductal closure and surgery were calculated. Patients were categorized into responder and nonresponder groups for acetaminophen, and the average values of ductal diameter, weight, gestational age, and postnatal age were compared.\nEighty-seven preterm newborns, with a postnatal age from 3 to 27 days, with average values of ductus arteriosus equal to 2.5 ± 0.8 mm/kg, gestational age 27.2 ± 1.9 weeks, and birth weight 888.9 ± 241 g, received acetaminophen for 3 to 7 days. A second cycle was administered in 15 preterm newborns. The ductus closure rate, after one or two cycles, was 74.7%, and the recommendations for surgical closure were progressively reduced from 50% in the 1st year to 6.2% in the past year. Lower ductal closure rate occurred in the group of newborns with the lowest average weight (P = 0.018), the highest average ductal diameter (P = 0.002), and the lowest average gestational age (P = 0.09). Postnatal age at the start of acetaminophen use was shown to be irrelevant regarding the treatment (P = 0.591).\nAcetaminophen in low doses showed to be an effective alternative for the closure of the ductus arteriosus for preterm newborns in whom treatment with indomethacin or ibuprofen failed or was contraindicated.",
"affiliations": "Department of Pediatrics, Division of Neonatology, Hospital Foundation of Minas Gerais State, Minas Gerais, Brazil.;Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil.;Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil.;Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil.;Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil.;Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil.;Department of Pediatrics, Division of Neonatology, Hospital Foundation of Minas Gerais State, Minas Gerais, Brazil.;Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil.",
"authors": "Guimarães|Adriana Furletti Machado|AFM|;Araújo|Fátima Derlene Rocha|FDR|;Meira|Zilda Maria Alves|ZMA|;Tonelli|Henrique Assis Fonseca|HAF|;Duarte|Guilherme Gomes|GG|;Ribeiro|Lívia Castro|LC|;Rezende|Gabriele Queiroz Monteiro|GQM|;Castilho|Sandra Regina Tolentino|SRT|",
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"fulltext": "\n==== Front\nAnn Pediatr CardiolAnn Pediatr CardiolAPCAnnals of Pediatric Cardiology0974-20690974-5149Wolters Kluwer - Medknow India APC-12-9710.4103/apc.APC_42_18Original ArticleAcetaminophen in low doses for closure of the ductus arteriosus of the premature Guimarães Adriana Furletti Machado 12Araújo Fátima Derlene Rocha 2Meira Zilda Maria Alves 23Tonelli Henrique Assis Fonseca 2Duarte Guilherme Gomes 2Ribeiro Lívia Castro 2Rezende Gabriele Queiroz Monteiro 12Castilho Sandra Regina Tolentino 21 Department of Pediatrics, Division of Neonatology, Hospital Foundation of Minas Gerais State, Minas Gerais, Brazil2 Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil3 Department of Pediatrics, Division of Pediatric Cardiology, School of Medicine, Federal University of Minas Gerais, Minas Gerais, BrazilAddress for correspondence: Dr. Adriana Furletti Machado Guimarães, Avenida Professor Alfredo Balena, 110 - Santa Efigênia, Belo Horizonte, Minas Gerais, Brazil. E-mail: adriana.furletti@hotmail.comMay-Aug 2019 12 2 97 102 Copyright: © 2019 Annals of Pediatric Cardiology2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Objective:\nThe objective of the study is to report the experience with acetaminophen in low doses as an alternative to the treatment of the ductus arteriosus of the preterm newborn.\n\nMaterials and Methods:\nRetrospective study including preterm newborns with patent ductus arteriosus who received oral acetaminophen because treatment with indomethacin had failed or is contraindicated. A dosage consisted of a first dose of 25 mg/kg and maintenance doses of 30 mg/kg/day, for 3 to 7 days. A second cycle was administered in cases of reopening of the ductus arteriosus. The rates of ductal closure and surgery were calculated. Patients were categorized into responder and nonresponder groups for acetaminophen, and the average values of ductal diameter, weight, gestational age, and postnatal age were compared.\n\nResults:\nEighty-seven preterm newborns, with a postnatal age from 3 to 27 days, with average values of ductus arteriosus equal to 2.5 ± 0.8 mm/kg, gestational age 27.2 ± 1.9 weeks, and birth weight 888.9 ± 241 g, received acetaminophen for 3 to 7 days. A second cycle was administered in 15 preterm newborns. The ductus closure rate, after one or two cycles, was 74.7%, and the recommendations for surgical closure were progressively reduced from 50% in the 1st year to 6.2% in the past year. Lower ductal closure rate occurred in the group of newborns with the lowest average weight (P = 0.018), the highest average ductal diameter (P = 0.002), and the lowest average gestational age (P = 0.09). Postnatal age at the start of acetaminophen use was shown to be irrelevant regarding the treatment (P = 0.591).\n\nConclusions:\nAcetaminophen in low doses showed to be an effective alternative for the closure of the ductus arteriosus for preterm newborns in whom treatment with indomethacin or ibuprofen failed or was contraindicated.\n\nAcetaminophenductus arteriosusechocardiographyindomethacinpremature\n==== Body\nINTRODUCTION\nFailure in spontaneous closure of the ductus arteriosus occurs in 50%–60% of preterm newborns with a birth weight lower than 1000 g. Such incidence is inversely proportional to birth weight and gestational age.[1234567] Aorta to pulmonary artery shunting through the patent ductus arteriosus (PDA) renders the preterm newborns vulnerable to pulmonary overcirculation and diminished systemic blood flow. Moreover, it is associated with significant morbidity such as failure to thrive, pulmonary edema and hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, periventricular-intraventricular hemorrhage,[24567891011] and overall increased mortality.[2712]\n\nConventionally, PDA medical treatment is attempted with prostaglandin-synthesis inhibitors such as indomethacin and ibuprofen, with comparable efficacy between the two drugs (up to 70%–85%).[234567101113] Known side effects include peripheral vasoconstriction, gastrointestinal bleeding and perforation, decreased platelet aggregation, hyperbilirubinemia, and transient worsening of renal function.[24567891114]\n\nSurgical treatment is indicated for newborns with hemodynamically significant PDA when medical treatment fails and is associated with increased risk of bronchopulmonary dysplasia, severe retinopathy of prematurity, chylothorax, and neurosensorial lesion.[57101516]\n\nAcetaminophen is also an inhibitor of prostaglandin synthesis and has been considered a promising alternative for the medical treatment of preterm newborns with PDA as a means of reducing the need for surgery. In addition, treatment with acetaminophen has achieved a success rate of nearly 80%, without significant side effects.[234561117] Most studies have evaluated a treatment regimen which consists of a daily dose of acetaminophen of 60 mg/kg of body weight,[234561117] roughly twice the recommended dosage for pain relief (30 mg/kg/day).[1018192021] However, transient elevation of hepatic enzymes has been reported as a consequence of the increased dosage of acetaminophen.[72122]\n\nThis study aims to report the experience of a tertiary care center with the treatment of PDA using low doses of acetaminophen in preterm newborns in cases where treatment with indomethacin has failed or is contraindicated.\n\nMATERIALS AND METHODS\nThis observational, retrospective study was conducted between January 2012 and December 2016. In the hospital where the study was conducted, the drug of choice for pharmacological treatment (to closure) of the ductus arteriosus is oral indomethacin. Furthermore, ibuprofen is not available.\n\nAll preterm newborns who received acetaminophen for PDA closure during the study were included in the study, regardless of birth weight or gestational age. The criteria for acetaminophen usage were the presence of a large and hemodynamically significant ductus arteriosus, normal liver function (assessed by laboratory testing), and treatment failure with indomethacin or contraindications for its use. Treatment failure with indomethacin was defined as failure to achieve ductal closure after a complete cycle of indomethacin treatment. The following conditions were considered contraindications for indomethacin use: intraventricular hemorrhage, thrombocytopenia, necrotizing enterocolitis, coagulopathy or active bleeding, reduced urinary output, urea or creatinine elevation, and uncontrolled sepsis. Patients who died before treatment was complete or before final echocardiographic assessment were excluded from this study.\n\nThe first echocardiographic examination was performed between the 24th and 96th hrs of life on all preterm newborns with a birth weight <1100 g and on those with a birth weight >1100 g with a clinically suspicious PDA. Echocardiographic studies were conducted by pediatric cardiologists from the hospital where the study took place, using commercially available portable ultrasound devices. The size of the ductus arteriosus was quantified in millimeters (mm) and measured at its the narrowest point before entering the main pulmonary artery in the left parasternal short axis view. To correlate ductal width with body size, the ductus arteriosus diameter, measured in millimeters (mm), was indexed to body weight, measured in kg, yielding an index expressed in mm/kg. Patients who had a ductal diameter (mm) per body weight (kg) index > 1.5 mm/kg were considered to have a large and significant PDA.\n\nOn confirmation of normal liver function through laboratory testing, all preterm newborns who met the criteria above cited were given oral acetaminophen (acetaminophen oral solution 200 mg/mL) with the recommended dosage for analgesia.\n\nThe dosage consisted of a first dose of 25 mg/kg, followed by maintenance doses of 15 mg/kg twice daily for neonates <32 weeks’ gestational age or three times daily for those >32 weeks gestational age. The duration of treatment ranged from 3 to 7 days (determined by the achievement of ductal closure detected through echocardiographic assessment). A second cycle of acetaminophen treatment was used in patients who experienced reopening of the PDA or in those who had an initial response of ductal narrowing followed by ductus enlargement after drug cessation. Echocardiographic reassessment was carried out daily and after the completion of each cycle of acetaminophen.\n\nStatistical analysis\nPatient's data were collected from medical records, and a statistical analysis was performed with the Epiinfo 7.1.1.3 software (Atlanta, Georgia, US). The data were analyzed using central tendency measures and dispersion of continuous variables. In addition, medical and surgical treatment success rates were calculated, and patients were categorized into “acetaminophen-responder” and “nonresponder” groups. Groups’ characteristics, including average ductus diameter, gestational age, body weight, and postnatal age at the onset of treatment were compared using the ANOVA test, in accordance with Bartlett's test. Statistical significance level was set at P < 0.05.\n\nThis study was granted approval by the Hospital's Research Ethics Committee. Informed consent for this retrospective study was waived by the Hospital's Institutional Research Board.\n\nRESULTS\nBetween January 2012 and December 2016, 159 preterm newborns were identified with PDA, where pharmacologic treatment was recommended. A 108 of them were given three doses of indomethacin orally (0.2 mg/Kg, twice a day), between the 2nd and 7th day of life, achieving therapeutic success in 77 of them (71.3%). However, in seven patients (9%), the ductus arteriosus reopened. The gestational age and birth weight varied from 24:0 to 32:3 weeks (average value of 27.6 ± 1.9 weeks) and from 400 to 1520 g (average value of 855 ± 201.8 g), respectively.\n\nEighty-nine preterm newborns met the criteria for treatment with acetaminophen, 51 of them for having contraindications to treatment with indomethacin, and 38 for the treatment with indomethacin having failed (31 with no response and seven with reopening).\n\nTwo patients died before the final echocardiographic assessment and were excluded from the study.\n\nAmong the remaining 87 preterm newborns, the gestational age varied from 23.4 to 33.1 weeks (average value of 27.2 ± 1.9 weeks) and the birth weight varied from 470 to 1605 g (average value of 888.9 ± 241.0). The gestational age (P = 0.145) and birth weight (P = 0.286) were similar to the newborns’ who were responsive to indomethacin and paracetamol.\n\nDuctus arteriosus diameter and postnatal age at the onset of treatment with acetaminophen ranged between 1.5 and 4.8 mm/kg (average value of 2.5 ± 0.8 mm/kg) and between 3 and 27 days (average value of 10.4 ± 5.5 days), respectively. Preterm newborns with longer chronological age showed clinical and echocardiographic signs of hemodynamic repercussion as a consequence of PDA, and acetaminophen was used as an alternative to surgical treatment. The duration of the treatment with acetaminophen ranged between 3 and 7 days (average value of 4.6 ± 1.7). One patient received only the loading dose, due to a prescription mistake, and it resulted in PDA closure.\n\nAfter the first cycle of treatment, the efficacy of acetaminophen therapy in inducing ductal closure was 62% (54/87), with immediate closure after drug cessation (85.2%) or in the subsequent days (14.8%). A second cycle was performed in 15 patients with a success rate of 73.3% (11/15). The overall PDA closure rate after either one or two cycles was 74.7% (65/87).\n\nDifferent clinical and echocardiographic features between acetaminophen-responding and nonresponding groups such as average ductal diameter, body weight, gestational age, and chronological age at the onset of treatment are displayed on Table 1. The rate of indication for PDA surgical closure, after the acetaminophen therapy was introduced, was progressively reduced during the analyzed period, from 50% in the 1st year of the study to 6.2% in the past year [Figure 1].\n\nTable 1 Clinical and echocardiographic features of acetaminophen-responding and nonresponding groups\n\nVariables\tGroups\tP (ANOVA)\t\n\t\nResponding (n=61)\tNonresponding (n=26)\t\nGestational age (weeks)\t29.01 ± 2.36\t28.09 ± 2.05\t0.090\t\nWeight (g)\t926.06 ± 251\t793.73 ± 191.98\t0.018\t\nDuctal diameter (mm/kg)\t2.42 ± 0.81\t2.98 ± 0.71\t0.002\t\nPostnatal age (days of life)\t10.26 ± 5.93\t10.96 ± 4.47\t0.591\t\nFigure 1 Need for surgical treatment in premature newborns treated with acetaminophen, by year\n\nNo side effect was observed after the treatment with acetaminophen, and aminotransferase levels were maintained within reference limits. During treatment with indomethacin, about 10% of the newborns presented urinary volume reduction, which was normalized after the suspension of the medication.\n\nDISCUSSION\nTherapeutic approach of the PDA in the preterm newborns has been a recurrent clinical challenge for the pediatrician and pediatric cardiologist. Any discussion of treatment modalities should acknowledge the potential morbidity associated with the PDA itself and with medical and surgical treatments. First-line treatment drugs (indomethacin and ibuprofen) have well-established side effects which lead us to perennial questioning about when and how to treat a preterm newborn with a PDA.\n\nHammerman et al.[23] reported the first case series of preterm newborns with PDA successfully treated with acetaminophen. Subsequently, many studies on this new treatment alternative have been published, with success rates comparable to those observed with indomethacin and ibuprofen use but with no reported significant side effects.[234561117] Most authors of recently published studies comparing acetaminophen to ibuprofen in the treatment of PDA have used a treatment regimen of acetaminophen in a dosage of 60 mg/kg/day divided into four doses for 3 days, with efficacy ranging from 70% to 80%.[23617]\n\nIn this study, it has been observed that oral acetaminophen in lower doses, as recommended for pain relief – 25 mg/kg loading dose followed by a maintenance dosage of 30 mg/kg/day divided into two doses for preterm newborns <32 weeks’ gestational age or divided into three doses for >32 weeks,[19] for 3–7 days – was as efficient as acetaminophen in higher doses for the closure of the ductus arteriosus. Similarly, Aikio et al.[9] have demonstrated that intravenous acetaminophen administered prematurely (with 13.2 ± 13.7 h of life) with the goal of pain relief in 102 preterm newborns < 32 weeks’ gestational age (20 mg/kg loading dose followed by 30 mg/kg/day for 4.3 ± 3.1 days) reduced the incidence of PDA from 30.7% to 14.7% (P = 0.008). A clinical trial by Härkin et al.[14] comparing placebo to pain relief dosage intravenous acetaminophen (20 mg/kg loading dose and 30 mg/kg/day maintenance dose) has showed that the ductus arteriosus was closed earlier in the acetaminophen group (hazard ratio of 0.49; 95% confidence interval: 0.25–0.97, P = 0.016). Tekgunduz et al.[21] have reported an 83.3% (5/6) PDA closure rate with low dosage intravenous acetaminophen (30 mg/kg/day divided into three doses).\n\nDuring the present study, it was observed that some preterm newborns needed a longer treatment period to achieve ductal closure, which prompted a readjustment to the treatment protocol, and treatment duration was extended to 7 days. A clinical trial by Dash et al.,[4] comparing the use of oral acetaminophen to intravenous indomethacin, obtained a ductal closure rate of 100% (36/36) with a 7-day treatment with acetaminophen (60 mg/kg/day). El-Khuffash et al.[13] have compared long (7 days) to short (2 days) courses of oral acetaminophen (60 mg/kg/day) and obtained better results with the long course. Therefore, securing a higher plasma level or longer exposition to the drug might be necessary to achieve the desired therapeutic goals.\n\nThe efficacy of indomethacin for ductus arteriosus closure is lower in preterm newborns weighing <1000 g at birth,[24] with shorter gestational age, with greater ductal diameter, and with longer postnatal age.[25] In this study, a decreased rate of PDA closure has been observed in preterm newborns with lower birth weight (P = 0.018), greater ductal diameter (P = 0.002), and lower gestational age (yet without statistical significance, P = 0.09). Postnatal age at the onset of acetaminophen therapy did not affect treatment efficacy (P = 0.591). The drug was considered effective even when administered to neonates as late as at 27 days of postnatal age.\n\nThe possibility of adverse outcomes after surgical ligation of the ductus arteriosus in premature newborns has led to a trend, in recent years, to postpone or ultimately avoid surgical treatment in this group. Acetaminophen as an alternative drug has been presented as a promising treatment option to forestall PDA surgery particularly in preterm newborns for whom treatment with traditional nonsteroid anti-inflammatory drugs such as ibuprofen and indomethacin is contraindicated or has failed. This study has confirmed the efficacy of the treatment with acetaminophen in such clinical scenarios, which lead to decreased necessity for surgical treatment.\n\nWeisz et al.[15] evaluated 26 extremely premature neonates with moderate to important PDA and demonstrated that the use of oral acetaminophen (60 mg/kg/day, 3–7 days) significantly improved echocardiographic indexes of PDA hemodynamic repercussion in 12 (46%) of them, preventing surgery for these patients. Among patients who did not show echocardiographic improvement, 57% (8/14) underwent surgical treatment. Similarly, it was shown in this study significant reduction in surgical ligation of PDA after treatment with oral acetaminophen, even when using a lower dosage (30 mg/kg/day). A reduction of 90% in surgery recommendation was achieved over the past 2 years, after the duration of the treatment with acetaminophen was lengthened to 7 days.\n\nRegarding concerns about acetaminophen-related hepatotoxicity, it has been shown that even when used in dosage twice as high as the usually recommended for analgesia in preterm newborns, there were no significant adverse effects,[2461117] except for a few reports of transient elevation of liver enzymes. In the present study, there was no significant elevation in aminotransferase levels either. Most of the metabolism of acetaminophen in premature neonates is carried out by sulfation, a process that yields nontoxic metabolites, and might account for the drug's low hepatotoxicity in preterm newborns, even in those with relatively high plasma levels.[71011182627] However, neonates are also able to synthesize hepatotoxic metabolites, and available literature on acetaminophen safety does not include data from extremely premature neonates and does not consider side effects caused by its use for periods longer than 2–3 days.[101826] Unfortunately, a possible association between acetaminophen use and neurocognitive impairment which might lead to attention deficit disorder, hyperactivity, and autism spectrum disorders has been reported by some authors[7282930] and should be a reason for concern.\n\nThe retrospective data analysis, the modification of treatment protocol along the course of the studied period, and a lack of assessment regarding the long-term safety of acetaminophen use in preterm newborns were the major limitations of the present study. Nevertheless, the analysis included a significant population of extremely premature neonates, and the data were meticulously registered and retrieved because of the use of acetaminophen being considered off-label in such conditions, thus being guided by a rigorous treatment protocol.\n\nIt is possible to conclude that the treatment of PDA of the preterm newborn with oral acetaminophen in doses usually recommended for pain relief, for 3 to 7 days, has been shown to be an effective therapeutic alternative. The treatment duration should be determined by serial echocardiographic assessment to avoid prolonged and unnecessary exposition to the drug. Nonetheless, new studies on acetaminophen pharmacokinetics and pharmacodynamics are necessary to identify an optimal target concentration and therefore establish a dose that is both effective and safe in short and long terms, especially in the extremely preterm newborn.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Koch J Hensley G Roy L Brown S Ramaciotti C Rosenfeld CR Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less Pediatrics 2006 117 1113 21 16585305 \n2 Bagheri MM Niknafs P Sabsevari F Torabi MH Bahman Bijari B Noroozi E Comparison of oral acetaminophen versus ibuprofen in premature infants with patent ductus arteriosus Iran J Pediatr 2016 26 e3975 27713809 \n3 Dang D Wang D Zhang C Zhou W Zhou Q Wu H Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: A randomized controlled trial PLoS One 2013 8 e77888 24223740 \n4 Dash SK Kabra NS Avasthi BS Sharma SR Padhi P Ahmed J Enteral paracetamol or intravenous indomethacin for closure of patent ductus arteriosus in preterm neonates: A Randomized controlled trial Indian Pediatr 2015 52 573 8 26244949 \n5 Habibi M Nobakht M Pirbazari TJ Yazdi Z The effect of oral ibuprofen and oral acetaminophen in the patent ductus arteriosus (PDA) in preterm infants born in Kouvsar hospital of Qazvin (a comparative study) WJPMR 2016 2 203 7 \n6 Oncel MY Yurttutan S Erdeve O Uras N Altug N Oguz SS Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: A randomized controlled trial J Pediatr 2014 164 510 40 24359938 \n7 Singh Y Gooding N Paracetamol for the treatment of patent ductus arteriosus in very low birth weight infants J Neonatal Biol 2016 5 3 \n8 Pharande P Watson H Tan K Sehgal A Oral paracetamol for patent ductus arteriosus rescue closure Pediatr Cardiol 2018 39 183 90 29043398 \n9 Aikio O Härkin P Saarela T Hallman M Early paracetamol treatment associated with lowered risk of persistent ductus arteriosus in very preterm infants J Matern Fetal Neonatal Med 2014 27 1252 6 24111688 \n10 Allegaert K Anderson B Simons S van Overmeire B Paracetamol to induce ductus arteriosus closure: Is it valid? Arch Dis Child 2013 98 462 6 23606713 \n11 El-Mashad AE El-Mahdy H El Amrousy D Elgendy M Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates Eur J Pediatr 2017 176 233 40 28004188 \n12 Sellmer A Bjerre JV Schmidt MR McNamara PJ Hjortdal VE Høst B Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3 Arch Dis Child Fetal Neonatal Ed 2013 98 F505 10 23893268 \n13 El-Khuffash A Jain A Corcoran D Shah PS Hooper CW Brown N Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: Evidence from human and murine studies Pediatr Res 2014 76 238 44 24941212 \n14 Härkin P Härmä A Aikio O Valkama M Leskinen M Saarela T Paracetamol accelerates closure of the ductus arteriosus after premature birth: A randomized trial J Pediatr 2016 177 72 7.e2 27215779 \n15 Weisz DE Martins FF Nield LE El-Khuffash A Jain A McNamara PJ Acetaminophen to avoid surgical ligation in extremely low gestational age neonates with persistent hemodynamically significant patent ductus arteriosus J Perinatol 2016 36 649 53 27054842 \n16 Kabra NS Schmidt B Roberts RS Doyle LW Papile L Fanaroff A Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: Results from the trial of indomethacin prophylaxis in preterms J Pediatr 2007 150 229 34, 234e1 17307535 \n17 Yang B Gao X Ren Y Wang Y Zhang Q Oral paracetamol vs. Oral ibuprofen in the treatment of symptomatic patent ductus arteriosus in premature infants: A randomized controlled trial Exp Ther Med 2016 12 2531 6 27698754 \n18 Pacifici GM Allegaert K Clinical pharmacology of paracetamol in neonates: A review Curr Ther Res Clin Exp 2015 77 24 30 25709719 \n19 Young TE Neofax 2011 24th ed Montvale, NJ, USA Thomson Reuters \n20 Palmer GM Atkins M Anderson BJ Smith KR Culnane TJ McNally CM I.V. Acetaminophen pharmacokinetics in neonates after multiple doses Br J Anaesth 2008 101 523 30 18628265 \n21 Tekgunduz KS Ceviz N Demirelli Y Olgun H Caner I Sahin IO Intravenous paracetamol for patent ductus arteriosus in premature infants – A lower dose is also effective. Concerning the article by M.Y. Oncel et al. : Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weightinfants [Neonatology 2013;103:166-169] Neonatology 2013 104 6 7 23548678 \n22 Alan S Kahvecioglu D Erdeve O Atasay B Arsan S Is paracetamol a useful treatment for ibuprofen-resistant patent ductus arteriosus? Concerning the article by M.Y. Oncel et al. : Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants [Neonatology 2013;103:166-169] Neonatology 2013 104 168 9 23921529 \n23 Hammerman C Bin-Nun A Markovitch E Schimmel MS Kaplan M Fink D Ductal closure with paracetamol: A surprising new approach to patent ductus arteriosus treatment Pediatrics 2011 128 e1618 21 22065264 \n24 Van Overmeire B Chemtob S The pharmacologic closure of the patent ductus arteriosus Semin Fetal Neonatal Med 2005 10 177 84 15701582 \n25 Van Overmeire B Van de Broek H Van Laer P Weyler J Vanhaesebrouck P Early versus late indomethacin treatment for patent ductus arteriosus in premature infants with respiratory distress syndrome J Pediatr 2001 138 205 11 11174617 \n26 Anderson BJ van Lingen RA Hansen TG Lin YC Holford NH Acetaminophen developmental pharmacokinetics in premature neonates and infants: A pooled population analysis Anesthesiology 2002 96 1336 45 12170045 \n27 Sebben VC Lugoch RW Schlinker CS Arbo MD Vianna RL Validation of analytical methodology and stability study for serum quantification of paracetamol J Bras Patol Med Lab 2010 46 143 8 \n28 Liew Z Ritz B Rebordosa C Lee PC Olsen J Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders JAMA Pediatr 2014 168 313 20 24566677 \n29 Schultz ST Klonoff-Cohen HS Wingard DL Akshoomoff NA Macera CA Ji M Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: The results of a parent survey Autism 2008 12 293 307 18445737 \n30 van den Anker JN Allegaert K Acetaminophen to prevent symptomatic patent ductus arteriosus: Another drug bites the dust? J Pediatr 2016 177 7 9 27448839\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0974-5149",
"issue": "12(2)",
"journal": "Annals of pediatric cardiology",
"keywords": "Acetaminophen; ductus arteriosus; echocardiography; indomethacin; premature",
"medline_ta": "Ann Pediatr Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101495459",
"other_id": null,
"pages": "97-102",
"pmc": null,
"pmid": "31143033",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "11174617;12170045;15701582;16585305;17307535;18445737;18628265;22065264;23548678;23606713;23893268;23921529;24111688;24223740;24359938;24566677;24941212;25709719;26244949;27054842;27215779;27448839;27698754;27713809;28004188;29043398",
"title": "Acetaminophen in low doses for closure of the ductus arteriosus of the premature.",
"title_normalized": "acetaminophen in low doses for closure of the ductus arteriosus of the premature"
} | [
{
"companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-280495",
"fulfillexpeditecriteria": "1",
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{
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"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
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{
"abstract": "We report the case of a patient with a BRCA2 germline mutation who developed a localized pleomorphic soft tissue sarcoma of the leg with poor prognostic features. BRCA2 germline mutations were not previously reported to be associated with pleomorphic sarcoma. BRCA2 loss-of-heterozygosity was found in the tumor, resulting in a complete BRCA2 loss-of-function. BRCA2 deficiency is associated with sensitivity to cisplatin-based chemotherapy in breast and ovarian cancer patients. We used a cisplatin-based chemotherapy. A rapid major partial response was obtained, which allowed a curative and conservative surgical resection of the sarcoma followed by adjuvant irradiation. This case illustrates that sarcoma patients may present unexpected but targetable genetic abnormalities and that BRCA2 loss-of-function may be targetable in sarcoma as it is associated with enhanced sensitivity to cisplatin. Our observation emphasizes the input of genomic medicine in clinical practice, its importance for treatment decisions, and the overlap between constitutional and somatic genetics.",
"affiliations": "Molecular Genetic and Biology Department, Netsarc National Network, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Paris, France; EA7331 Department, Université Paris Descartes, Paris, France; Medical Oncology Department, Netsarc National Network, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Paris,France. Electronic address: camille.tlemsani@aphp.fr.;Molecular Genetic and Biology Department, Netsarc National Network, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Paris, France; EA7331 Department, Université Paris Descartes, Paris, France.;Medical Oncology Department, Netsarc National Network, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Paris,France.;Medical Oncology Department, Netsarc National Network, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Paris,France.;Orthopedic Surgery Department, Netsarc National Network, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Paris, France.;Pathology Department, Sarcoma Center, Netsarc National Network, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Paris, France.;Translational Research Department, Institut Curie, PSL Research University, Genomics Platform, Paris, France.;Translational Research Department, Institut Curie, PSL Research University, Genomics Platform, Paris, France.;Medical Oncology Department, Netsarc National Network, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Paris,France.;Molecular Genetic and Biology Department, Netsarc National Network, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Paris, France; EA7331 Department, Université Paris Descartes, Paris, France.;Orthopedic Surgery Department, Netsarc National Network, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Paris, France.;Molecular Genetic and Biology Department, Netsarc National Network, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Paris, France.;Medical Oncology Department, Netsarc National Network, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Paris,France.",
"authors": "Tlemsani|Camille|C|;Pasmant|Eric|E|;Boudou-Rouquette|Pascaline|P|;Bellesoeur|Audrey|A|;Even|Julien|J|;Larousserie|Frédérique|F|;Reyes|Cécile|C|;Gentien|David|D|;Alexandre|Jérôme|J|;Vidaud|Michel|M|;Anract|Philippe|P|;Leroy|Karen|K|;Goldwasser|François|F|",
"chemical_list": "D000970:Antineoplastic Agents; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjms.2018.04.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9629",
"issue": "356(4)",
"journal": "The American journal of the medical sciences",
"keywords": "BRCA2; Cancer predisposition; Cisplatin; Genomic medicine; Pleomorphic sarcoma",
"medline_ta": "Am J Med Sci",
"mesh_terms": "D000970:Antineoplastic Agents; D024682:BRCA2 Protein; D001943:Breast Neoplasms; D002945:Cisplatin; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D000073658:Loss of Function Mutation; D008875:Middle Aged; D010051:Ovarian Neoplasms; D012509:Sarcoma",
"nlm_unique_id": "0370506",
"other_id": null,
"pages": "404-407",
"pmc": null,
"pmid": "30041945",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "BRCA2 Loss-of-Function and High Sensitivity to Cisplatin-Based Chemotherapy in a Patient With a Pleomorphic Soft Tissue Sarcoma: Effect of Genomic Medicine.",
"title_normalized": "brca2 loss of function and high sensitivity to cisplatin based chemotherapy in a patient with a pleomorphic soft tissue sarcoma effect of genomic medicine"
} | [
{
"companynumb": "FR-TEVA-2018-FR-991705",
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"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
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... |
{
"abstract": "A 73-year-old woman was admitted to hospital because of progressive dyspnea on exertion. Computed tomography revealed a large hepatic tumor, which was proved to be a hepatic epithelioid hemangioendothelioma (EHE). Echocardiography demonstrated high cardiac output, for which the tumor was considered to be the leading cause. A transcatheter arterial chemoembolization (TACE) was performed sequentially at 1-month intervals to reduce the size of the hepatic tumor, and this temporarily improved the patient's cardiac condition and quality of life. In this case, we successfully used TACE in the treatment of hepatic EHE with high-output heart failure. TACE is a reasonable choice of treatment both for managing malignant hepatic tumors and resolving low systemic vascular resistance by embolization of the abnormal neoangiogenic vessels. Nevertheless, clinicians should be aware of the potential adverse effect of hepatic decompensation induced by TACE, especially when the tumor involvement is widespread and poorly preserved hepatic function is encountered.",
"affiliations": "Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan; Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan.",
"authors": "Hsu|Chien-Yi|CY|;Liu|Yao-Chung|YC|;Li|Chung-Pin|CP|;Huang|Po-Hsun|PH|;Lin|Chin-Hsuan|CH|;Chao|Yee|Y|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/ajco.12056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-7555",
"issue": "10(2)",
"journal": "Asia-Pacific journal of clinical oncology",
"keywords": null,
"medline_ta": "Asia Pac J Clin Oncol",
"mesh_terms": "D000368:Aged; D016461:Chemoembolization, Therapeutic; D019468:Disease Management; D005260:Female; D006333:Heart Failure; D018323:Hemangioendothelioma, Epithelioid; D006801:Humans; D008113:Liver Neoplasms; D011788:Quality of Life",
"nlm_unique_id": "101241430",
"other_id": null,
"pages": "e118-21",
"pmc": null,
"pmid": "23384412",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Malignant hepatic epithelioid hemangioendothelioma with high-output heart failure: successful management of heart failure with transcatheter arterial chemoembolization.",
"title_normalized": "malignant hepatic epithelioid hemangioendothelioma with high output heart failure successful management of heart failure with transcatheter arterial chemoembolization"
} | [
{
"companynumb": "TW-CELGENEUS-153-20785-14063175",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "THALIDOMIDE"
},
"drugadditional": null... |
{
"abstract": "OBJECTIVE\nA case of symptomatic hyponatremia induced by hyperinsulinemia-euglycemia (HIE) therapy is reported.\n\n\nCONCLUSIONS\nA 59-year-old, 81.65-kg woman with hypertension, major depressive disorder, and anxiety arrived at a tertiary medical center 1.5 hours after an intentional overdose of oral amlodipine 200 mg, metoprolol tartrate 2,000 mg, and isosorbide mononitrate 1,200 mg. Upon arrival, her pulse was 63 beats/min and blood pressure was 106/56 mm Hg. The patient's blood pressure was refractory to fluids, calcium gluconate, and norepinephrine, resulting in initiation of HIE therapy. She had recurrent episodes of hypoglycemia, which required increases of the dextrose infusion and resulted in the patient receiving a total of 6.9 L of dextrose with free water. Seventeen hours into the hospitalization, the patient became obtunded due to hyponatremia (serum sodium concentration, 121 mmol/L). HIE therapy was discontinued, an infusion of 5% dextrose injection with sodium bicarbonate added was started, and a bolus of 3% sodium chloride was administered. Nine hours after the presentation of hyponatremia, the patient's serum sodium concentration normalized (137 mmol/L), and her symptoms resolved. The patient's blood pressure, pulse, and mental status continued to improve, and the patient was transferred out of the medical intensive care unit 41 hours after her arrival at the hospital.\n\n\nCONCLUSIONS\nA woman who overdosed on amlodipine, metoprolol tartrate, and isosorbide mononitrate was treated with HIE therapy and developed symptomatic hyponatremia. Hyponatremia resolved after administration of dextrose with sodium bicarbonate infusion and 3% sodium chloride infusion and cessation of HIE therapy.",
"affiliations": "Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, TN.;Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, TN joanna.stollings@vanderbilt.edu.;Division of Allergy/Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN.",
"authors": "Beavers|Jennifer R|JR|;Stollings|Joanna L|JL|;Rice|Todd W|TW|",
"chemical_list": "D007328:Insulin; D005947:Glucose",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp160262",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "74(14)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": "beta blocker; calcium channel blocker; hyperinsulinemia-euglycemia therapy; hyponatremia; toxicity",
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D062787:Drug Overdose; D005260:Female; D005947:Glucose; D015309:Glucose Clamp Technique; D006801:Humans; D006946:Hyperinsulinism; D007010:Hyponatremia; D007262:Infusions, Intravenous; D007328:Insulin; D008875:Middle Aged",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1062-1066",
"pmc": null,
"pmid": "28687552",
"pubdate": "2017-07-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hyponatremia induced by hyperinsulinemia-euglycemia therapy.",
"title_normalized": "hyponatremia induced by hyperinsulinemia euglycemia therapy"
} | [
{
"companynumb": "US-PFIZER INC-2017306687",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISOSORBIDE MONONITRATE"
},
"drugadditional": "... |
{
"abstract": "Buprenorphine/samidorphan (BUP/SAM; ALKS 5461) is an investigational opioid system modulator for the adjunctive treatment of patients with major depressive disorder (MDD), who did not respond adequately to prior antidepressant therapy (ADT). FORWARD-2, an open-label extension study, assessed long-term safety and tolerability of adjunctive BUP/SAM treatment in these patients. Patients from four short-term trials and de novo patients were enrolled; all had confirmed MDD and a current major depressive episode lasting 2-24 months. Patients were treated with an established ADT for ≥8 weeks before receiving sublingual, adjunctive BUP/SAM 2 mg/2 mg for up to 52 weeks. Safety (primary objective) was assessed via adverse events (AEs), the Columbia-Suicide Severity Rating Scale, and the Clinical Opiate Withdrawal Scale (COWS). Exploratory evaluation of efficacy was done using the Montgomery-Åsberg Depression Rating Scale (MADRS). Of 1485 patients, 50% completed the study and 11% discontinued due to AEs. AEs of nausea, headache, constipation, dizziness, and somnolence, each occurred in ≥10% of patients. There was no evidence of increased suicidal ideation or behavior. Euphoria-related AEs were uncommon (1.2%). Following abrupt BUP/SAM discontinuation, \"drug withdrawal\" AEs were infrequent (0.4%), and the incidence of COWS categorical worsening after abrupt drug discontinuation was low (6.5%). Improvements in mean MADRS scores were maintained until study end, suggesting durability of antidepressant effect in patients continuing treatment. BUP/SAM was generally well tolerated, with a low risk of abuse and an AE profile consistent with those seen in placebo-controlled studies. Withdrawal reports were uncommon and of limited clinical impact.",
"affiliations": "Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania School of Medicine, 3535 Market Street, Suite 670, Philadelphia, PA, 19104-3309, USA. thase@mail.med.upenn.edu.;Alkermes, Inc., Waltham, MA, USA.;Alkermes, Inc., Waltham, MA, USA.;Alkermes, Inc., Waltham, MA, USA.;Alkermes, Inc., Waltham, MA, USA.;McLean Hospital, Belmont, MA, USA.;University of Texas Southwestern Medical Center, Dallas, TX, USA.;Harvard Medical School, Boston, MA, USA.;Alkermes, Inc., Waltham, MA, USA.;Alkermes, Inc., Waltham, MA, USA.",
"authors": "Thase|Michael E|ME|;Stanford|Arielle D|AD|;Memisoglu|Asli|A|;Martin|William|W|http://orcid.org/0000-0002-8740-9014;Claxton|Amy|A|;Bodkin|J Alexander|JA|;Trivedi|Madhukar H|MH|http://orcid.org/0000-0002-2983-1110;Fava|Maurizio|M|;Yu|Miao|M|;Pathak|Sanjeev|S|",
"chemical_list": "D000928:Antidepressive Agents; D002047:Buprenorphine; D009271:Naltrexone; C000606131:3-carboxamido-4-hydroxynaltrexone",
"country": "England",
"delete": false,
"doi": "10.1038/s41386-019-0451-3",
"fulltext": "\n==== Front\nNeuropsychopharmacologyNeuropsychopharmacologyNeuropsychopharmacology0893-133X1740-634XSpringer International Publishing Cham 45110.1038/s41386-019-0451-3ArticleResults from a long-term open-label extension study of adjunctive buprenorphine/samidorphan combination in patients with major depressive disorder Thase Michael E. +215-746-6680thase@mail.med.upenn.edu 1Stanford Arielle D. 2Memisoglu Asli 2http://orcid.org/0000-0002-8740-9014Martin William 2Claxton Amy 2Bodkin J. Alexander 34http://orcid.org/0000-0002-2983-1110Trivedi Madhukar H. 5Fava Maurizio 46Yu Miao 2Pathak Sanjeev 21 0000 0004 1936 8972grid.25879.31Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania School of Medicine, 3535 Market Street, Suite 670, Philadelphia, PA 19104-3309 USA 2 grid.422303.4Alkermes, Inc., Waltham, MA USA 3 0000 0000 8795 072Xgrid.240206.2McLean Hospital, Belmont, MA USA 4 000000041936754Xgrid.38142.3cHarvard Medical School, Boston, MA USA 5 0000 0000 9482 7121grid.267313.2University of Texas Southwestern Medical Center, Dallas, TX USA 6 0000 0004 0386 9924grid.32224.35Massachusetts General Hospital, Boston, MA USA 29 6 2019 29 6 2019 12 2019 44 13 2268 2276 30 1 2019 22 5 2019 11 6 2019 © The Author(s) 2019Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Buprenorphine/samidorphan (BUP/SAM; ALKS 5461) is an investigational opioid system modulator for the adjunctive treatment of patients with major depressive disorder (MDD), who did not respond adequately to prior antidepressant therapy (ADT). FORWARD-2, an open-label extension study, assessed long-term safety and tolerability of adjunctive BUP/SAM treatment in these patients. Patients from four short-term trials and de novo patients were enrolled; all had confirmed MDD and a current major depressive episode lasting 2–24 months. Patients were treated with an established ADT for ≥8 weeks before receiving sublingual, adjunctive BUP/SAM 2 mg/2 mg for up to 52 weeks. Safety (primary objective) was assessed via adverse events (AEs), the Columbia-Suicide Severity Rating Scale, and the Clinical Opiate Withdrawal Scale (COWS). Exploratory evaluation of efficacy was done using the Montgomery–Åsberg Depression Rating Scale (MADRS). Of 1485 patients, 50% completed the study and 11% discontinued due to AEs. AEs of nausea, headache, constipation, dizziness, and somnolence, each occurred in ≥10% of patients. There was no evidence of increased suicidal ideation or behavior. Euphoria-related AEs were uncommon (1.2%). Following abrupt BUP/SAM discontinuation, “drug withdrawal” AEs were infrequent (0.4%), and the incidence of COWS categorical worsening after abrupt drug discontinuation was low (6.5%). Improvements in mean MADRS scores were maintained until study end, suggesting durability of antidepressant effect in patients continuing treatment. BUP/SAM was generally well tolerated, with a low risk of abuse and an AE profile consistent with those seen in placebo-controlled studies. Withdrawal reports were uncommon and of limited clinical impact.\n\nSubject terms\nDrug developmentOutcomes researchAlkermes, Inc.issue-copyright-statement© American College of Neuropsychopharmacology 2019\n==== Body\nIntroduction\nMajor depressive disorder (MDD) is a leading cause of global disability [1] and morbidity [2] and is among the most common mental health disorders [3]. Nearly two-thirds of patients receiving first-line drugs for depression fail to achieve remission, more than half fail to respond [4], and there is substantial risk of relapse among patients who do achieve full remission [5]. Switching is recommended if the initial treatment is unsuccessful but is often only modestly effective [4]. Adjunctive therapy is usually the next step if switching is unsuccessful [6, 7].\n\nMany pharmacotherapies that are currently approved for treatment of MDD, including selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and bupropion, target monoaminergic pathways [8, 9]. The only approved adjunctive therapies for MDD are atypical drugs for psychosis. These drugs also work through monoamine modulation and are associated with significant and sometimes permanent side effects, including metabolic abnormalities, weight gain, and movement disorders (such as akathisia and tardive dyskinesia) [10, 11].\n\nThere is an urgent need for novel drugs for depression and adjunctive agents with nonmonoaminergic mechanisms of action. The development of new medications should include approaches to minimizing adverse effects as well as discontinuation syndromes [12].\n\nThe endogenous opioid system plays a critical role in fundamental psychological processes affected by depression (e.g., motivation, social functioning/attachment) [13–15], and evidence supports opioid modulation as a potential treatment target for MDD [15–17]. Buprenorphine (BUP), a μ-opioid receptor partial agonist and κ-opioid receptor antagonist, has shown potential antidepressant activity in open-label [18–21] and double-blind, placebo-controlled studies in patients with MDD [22–25]. However, the use of opioids in MDD treatment has been limited by their risk of abuse and dependence [22]. Samidorphan (SAM), a µ-opioid receptor antagonist with a low intrinsic activity at κ- and δ-opioid receptors, was combined with BUP to mitigate its abuse and dependence potential while preserving its antidepressant effects [26, 27].\n\nFour randomized, double-blind, placebo-controlled trials were conducted to evaluate efficacy, safety, and tolerability of buprenorphine/samidorphan (BUP/SAM; ALKS 5461) in patients who experienced an inadequate response to one or two drugs for depression during their current major depressive episode (MDE) [24, 27, 28]. To assess the long-term effects of BUP/SAM, eligible patients from these acute treatment studies (including those who completed and those who were ineligible for the double-blind treatment period), as well as de novo patients, were enrolled in FORWARD-2 (FORWARD: Focused on Results with a Rethinking of Depression), a 52-week open-label study.\n\nPatients and methods\nStudy design and patients\nFORWARD-2 (ClinicalTrials.gov ID: NCT02141399) was an open-label, 52-week study to evaluate the long-term safety and tolerability of BUP/SAM 2 mg/2 mg as adjunctive therapy to drugs for depression for the treatment of MDD. FORWARD-2 enrolled patients from 14 May, 2014 to 31 October, 2017, and was conducted in the United States (138 sites), Bulgaria (9), Germany (9), Canada (5), Hungary (4), Australia (4), and Poland (4).\n\nPatients who completed the FORWARD-1 (NCT02085135; 8-week trial), FORWARD-3 (NCT02158546; 10-week trial), FORWARD-4 (NCT02158533; 12-week trial), or FORWARD-5 (NCT02218008; 11-week trial) studies within 10 days of FORWARD-2 entry were eligible. Three of the aforementioned studies included a prospective lead-in period to identify patients for the blinded randomized phase. Patients who responded during this prospective lead-in but did not meet the criterion of remission (Montgomery–Åsberg Depression Rating Scale [MADRS] ≤10) were eligible for FORWARD-2. Patients who did not respond during the prospective lead-in and were not in remission were eligible to enter the blinded randomized phase of FORWARD-3, FORWARD-4, or FORWARD-5. Patients who completed participation in these studies could enroll in FORWARD-2. De novo patients who had not participated in a prior study of BUP/SAM within the last 2 years were also enrolled. Patients who participated in FORWARD-1, FORWARD-3, FORWARD-4, or FORWARD-5 who did not complete their respective study (i.e., withdrew for any reason) were not eligible for FORWARD-2.\n\nAll eligible patients met Diagnostic and Statistical Manual for Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria for MDD, were experiencing an MDE lasting 2–24 months and were aged 18–70 years. Patients who had completed a prior BUP/SAM study and de novo patients were required to have demonstrated one or two inadequate responses to a drug for depression (verified by historical records or by prospectively collected response data). Inadequate response was defined as <50% reduction in depressive symptom severity to an adequate dose of a drug for depression for ≥8 weeks (inclusive of up to 3 weeks for titration into the adequate dose range) during the current MDE. For de novo patients, response to a drug for depression was assessed by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire. For patients who participated in a prior BUP/SAM study, response was not reassessed.\n\nAll patients continued their current drug for depression throughout the study; the dosage could be adjusted based on tolerability, but no change in therapy was allowed. Patients received a once-daily sublingual tablet of BUP/SAM 2 mg/2 mg as adjunctive treatment for up to 52 weeks. Patients newly initiating BUP/SAM 2 mg/2 mg (those who received placebo or no study drug prior to FORWARD-2 entry) and patients who had received a lower dose or paused BUP/SAM treatment during the follow-up period in the previous study underwent a 1-week titration period during week 1. Titration was blinded for patients continuing from the randomized controlled trials (FORWARD-3 and FORWARD-5) to maintain the blindness of randomized treatment in the prior study and unblinded for patients from FORWARD-4, as they were off study drug prior to entry. At study completion, patients stopped BUP/SAM treatment without a taper.\n\nThe study protocol was reviewed by an independent ethics committee or institutional review board at each site and was conducted following Good Clinical Practice principles derived from the Declaration of Helsinki, and in accordance with local regulations and International Council for Harmonisation guidelines. All enrolled participants provided written informed consent.\n\nEvaluation of safety\nThe primary objective was to assess the long-term safety and tolerability of BUP/SAM. Study visits during the treatment phase occurred at weeks 1, 2, 4, 6, 8, 14, 20, 26, 32, 38, 44, and 52 as well as follow-up visits at weeks 53, 54, and 56.\n\nSafety and tolerability assessments included treatment-emergent adverse events (AEs; screening and continuously at and between every study visit); vital signs (oral body temperature, respiratory rate, blood pressure, and pulse; screening and every study visit); weight (screening and every study visit); 12-lead electrocardiogram (ECG; screening and weeks 1, 26, 52, and 56); clinical laboratory parameters (chemistry, hematology, and urinalysis, including evaluation of hepatic effect in alanine aminotransferase [ALT] and aspartate aminotransferase [AST]; screening and weeks 1, 14, 26, 38, 52, and 56); Columbia-Suicide Severity Rating Scale (C-SSRS; screening and every study visit); and Clinical Opiate Withdrawal Scale (COWS; weeks 52 [baseline], 53, 54, and 56). Seven separate safety assessments were used to collect data by phone during the follow-up period, and if any AEs relating to opioid withdrawal were reported, the patient was asked to come into the clinic to receive a COWS assessment.\n\nThe C-SSRS is an evidence-supported suicidal ideation and behavior questionnaire with binary (yes/no) response categories. The percent of patients with “yes” answers to C-SSRS items and item shift from first the C-SSRS assessment were evaluated. The COWS is a 11-item questionnaire designed to measure the level of opiate withdrawal; a higher score indicates more severe signs and symptoms of withdrawal (0–4 = no withdrawal; 5–12 = mild; 13–24 = moderate; 25–36 = moderately severe; >36 = severe). COWS scores by mean days post last dose and a summary of COWS category shift from the first COWS assessment to the highest value were evaluated.\n\nSerious AEs (SAEs) were defined as those resulting in death or immediate risk of death, inpatient hospitalization/prolonging of existing hospitalization, or disability/incapability. SAEs also included any congenital anomaly or important medical events that may not result in death, be immediately life threatening, or require hospitalization but may jeopardize the patient and/or require intervention to prevent one of the other outcomes listed above.\n\nAEs of special interest were selected based on class effects that have been reported with BUP or SAM alone or with approved drugs for depression, including abuse potential, dependence, and opioid withdrawal, during the post-discontinuation period, hypomania/mania, sexual dysfunction, and suicidal ideation and behavior. To evaluate for abuse potential, preferred terms were selected according to FDA regulatory guidance and classified as related to abuse behavior, euphoria-related, or nonspecific in nature. The full list of preferred terms for each category of special interest is provided in the Supplementary Materials.\n\nEvaluation of efficacy\nExploratory outcomes included efficacy of up to 52 weeks of adjunctive BUP/SAM 2 mg/2 mg treatment. MADRS and the Clinical Global Impression of Severity (CGI-S) scores were measured at screening and every study visit through week 52. The 10-item MADRS questionnaire (with each item yielding a score between 0 and 6) and CGI-S scale (scored between 1 and 7) are each clinician administered, and higher scores indicate a more severe condition. The mean change from efficacy baseline (defined as initiation of BUP/SAM treatment) in MADRS and CGI-S scores at each study visit was reported. The proportion of patients who achieved remission (defined as MADRS ≤ 10) at each study visit and the time to remission were determined.\n\nStatistical methodology\nDemographic and safety data were summarized using descriptive statistics. Demographics and baseline characteristics at study entry were collected at screening for de novo patients. Data from patients enrolled in one of the four prior studies were carried over from baseline of the prior study. To assess potential differences between patients with and without prior exposure to BUP/SAM, two subgroups were created: no prior exposure to BUP/SAM and prior exposure to BUP/SAM. Patients in the no prior exposure to BUP/SAM group included de novo patients and those who received placebo or no study drug in a prior BUP/SAM study. Patients in the prior exposure to the BUP/SAM group were those who completed one of the prior studies in one of the BUP/SAM treatment groups (BUP/SAM 0.5/0.5 mg, 1/1 mg, or 2/2 mg).\n\nSafety was evaluated in all patients who received at least one dose of BUP/SAM in the long-term study (safety population). AEs, vital signs, laboratory analytes, and ECGs were tabulated and recorded throughout the long-term study. Patients meeting Temple’s corollary criteria (those with ALT or AST levels ≥3 times upper limit of normal range compared with placebo or nonhepatotoxic control drug) were tabulated [29]. Median duration was assessed for common AEs (those occurring in ≥5% of patients with or without prior BUP/SAM exposure). Safety baseline was defined as before or on the day of BUP/SAM initiation in the FORWARD-2 study. For C-SSRS shift analysis, patients were required to have a baseline and at least one post-baseline assessment. For analyses of dependence and withdrawal, patients were required to have ≥4 weeks’ exposure, a COWS baseline (the first COWS assessment after discontinuation of study drug) within 2 days of the last dose of the study drug, and at least one post-baseline COWS assessment.\n\nEfficacy was explored in all patients who received at least one dose of BUP/SAM and had at least one post-baseline complete MADRS assessment in FORWARD-2; baseline was defined as the time of BUP/SAM initiation (in FORWARD-2 or in one of the prior short-term studies). Descriptive statistics with observed cases were used to assess mean MADRS, MADRS remission, and CGI-S scores by study visit.\n\nThe time to study discontinuation was estimated using Kaplan–Meier methods.\n\nResults\nPatients\nOf the 1486 patients enrolled, 1485 entered the treatment phase of the study: 929 with no prior exposure to BUP/SAM, and 556 with prior exposure to BUP/SAM (Fig. S1). Patients were predominantly women (64.9%) and white (72.7%), with a mean age of 46.5 years; the majority were concurrently prescribed either SSRIs (62.3%) or SNRIs (26.6%) as their primary drug for depression (Table 1). Approximately 50% of enrolled patients completed the study (Fig. S2); withdrawal by patient (16.0%), AE (10.6%), and loss to follow-up (10.2%) were the most common reasons for discontinuation. Patients without prior BUP/SAM exposure discontinued due to AEs (13.1%) at twice the rate as those with prior BUP/SAM exposure (6.5%). The incidence of discontinuation for lack of efficacy was 4.2%. Of patients who entered the treatment phase, 978 (65.9%) had ≥6 months of BUP/SAM exposure and 769 (51.8%) had ≥12 months of exposure (including exposure during the prior studies) by the end of the long-term treatment period.Table 1 Baselinea demographic and clinical characteristics\n\nCharacteristic\tNo prior exposure to BUP/SAM (n = 929)\tPrior exposure to BUP/SAM (n = 556)\tAll patients (N = 1485)\t\nAge, years, mean (SD)\t46.1 (12.4)\t47.3 (12.1)\t46.5 (12.3)\t\nSex, female, n (%)\t616 (66.3)\t348 (62.6)\t964 (64.9)\t\nPrimary race, n (%)\t\n White\t681 (73.3)\t399 (71.8)\t1080 (72.7)\t\n Black or African American\t224 (24.1)\t138 (24.8)\t362 (24.4)\t\n American Indian or Alaska Native\t3 (0.3)\t4 (0.7)\t7 (0.5)\t\n Asian\t15 (1.6)\t13 (2.3)\t28 (1.9)\t\n Native Hawaiian or other Pacific Islander\t6 (0.6)\t2 (0.4)\t8 (0.5)\t\nRegion, n (%)\t\n United States\t735 (79.1)\t469 (84.4)\t1204 (81.1)\t\n Non-United States\t194 (20.9)\t87 (15.6)\t281 (18.9)\t\nBMI (kg/m2), mean (SD)\t29.6 (5.6)\t29.4 (5.7)\t29.5 (5.6)\t\nMADRS total score, mean (SD)b\t19.6 (9.8)\t28.5 (6.4)\t22.9 (9.7)\t\nDuration of current MDE (months), mean (SD)\t11.6 (8.6)\t13.2 (5.5)\t12.2 (7.6)\t\nClass of drug for depression for current MDE, n (%)\t\n SSRI\t566 (60.9)\t359 (64.6)\t925 (62.3)\t\n SNRI\t256 (27.6)\t139 (25.0)\t395 (26.6)\t\n Bupropion\t107 (11.5)\t58 (10.4)\t165 (11.1)\t\nNo. of inadequate responses for current MDEc, mean (SD)\t\n 0\t334 (36.0)\t1 (0.2)d\t335 (22.6)d\t\n 1\t522 (56.2)\t450 (80.9)d\t972 (65.5)d\t\n 2+\t73 (7.9)\t67 (12.1)d\t140 (9.4)d\t\nBMI body mass index, BUP buprenorphine, MADRS Montgomery–Åsberg Depression Rating Scale, MDE major depressive episode, SAM samidorphan, SD standard deviation, SNRI serotonin–norepinephrine reuptake inhibitor, SSRI selective serotonin reuptake inhibitor\n\naBaseline was defined as time of BUP/SAM initiation (in FOWARD-2 or lead-in acute study); data shown are for patients who enrolled and had at least one dose of BUP/SAM in the FORWARD-2 study\n\nbBaseline MADRS displayed for patients who also had at least one post-baseline assessment (N = 1453) and were included in efficacy analysis\n\ncFor de novo, this value is the number at visit 2 of FORWARD-2; for patients participating in the prospective lead-in period in the antecedent study (PLI failures), this value represents the number at the end of antecedent study; for patients who roll over from FORWARD-1, this value was not collected at randomization of antecedent study; for others, this value is the number at randomization of antecedent study\n\ndThe 38 patients in the prior exposure group who participated in FORWARD-1 have missing values for this variable, since it was not collected in the prior study\n\n\n\nSafety\nAEs were reported by 1124 (75.7%) of the 1485 study participants (78.6% of no prior exposure to BUP/SAM group and 70.9% of prior exposure to the BUP/SAM group; Table 2). The majority (91.7%) of AEs reported were mild or moderate in severity. Severe events were reported by 123 patients (8.3%), and no specific severe event, as defined by a preferred term, was reported in ≥2% of patients. The most common AEs (occurring in ≥10% of patients) were nausea, headache, constipation, and dizziness (Table 2). Most common AEs were transient (median duration 1–2 weeks), except for constipation and dry mouth (median duration >5 weeks each) (Table S1). A total of 154 patients (10.4%) discontinued due to an AE (Table 2). AEs that led to discontinuation in ≥1% of patients were nausea, vomiting, and dizziness; although no tardive dyskinesia was reported, four (0.3%) patients discontinued due to tremor (Table S2).Table 2 Summary of adverse events\n\nPatients with event, n (%)\tNo prior exposure to BUP/SAM (n = 929)\tPrior exposure to BUP/SAM (n = 556)\tAll patients (N = 1485)\t\nAny AE\t730 (78.6)\t394 (70.9)\t1124 (75.7)\t\nAny SAE\t33 (3.6)\t14 (2.5)\t47 (3.2)\t\nCommon SAEs (≥2 patients in any treatment group)\t\n Depression\t2 (0.2)\t1 (0.2)\t3 (0.2)\t\n Suicidal ideation\t3 (0.3)\t0\t3 (0.2)\t\n Colitis\t2 (0.2)\t0\t2 (0.1)\t\n Sepsis\t2 (0.2)\t0\t2 (0.1)\t\n Pneumonia\t2 (0.2)\t0\t2 (0.1)\t\n Uterine leiomyoma\t2 (0.2)\t0\t2 (0.1)\t\n Myocardial infarction\t1 (0.1)\t1 (0.2)\t2 (0.1)\t\nAE leading to study discontinuation\t122 (13.1)\t32 (5.8)\t154 (10.4)\t\nCommon AEs (≥5% in any treatment group)\t\n Nausea\t234 (25.2)\t88 (15.8)\t322 (21.7)\t\n Headache\t103 (11.1)\t53 (9.5)\t156 (10.5)\t\n Constipation\t112 (12.1)\t39 (7.0)\t151 (10.2)\t\n Dizziness\t116 (12.5)\t34 (6.1)\t150 (10.1)\t\n Somnolence\t100 (10.8)\t24 (4.3)\t124 (8.4)\t\n Vomiting\t83 (8.9)\t33 (5.9)\t116 (7.8)\t\n Dry mouth\t66 (7.1)\t21 (3.8)\t87 (5.9)\t\n Fatigue\t62 (6.7)\t23 (4.1)\t85 (5.7)\t\n Upper respiratory tract infection\t50 (5.4)\t33 (5.9)\t83 (5.6)\t\n Insomnia\t55 (5.9)\t26 (4.7)\t81 (5.5)\t\n Nasopharyngitis\t46 (5.0)\t34 (6.1)\t80 (5.4)\t\n Sedation\t51 (5.5)\t15 (2.7)\t66 (4.4)\t\n Hyperhidrosis\t48 (5.2)\t9 (1.6)\t57 (3.8)\t\nAEs were coded by preferred terms and system organ class using the Medical Dictionary for Regulatory Activities, version 19.0\n\nAE adverse event, BUP buprenorphine, SAE serious adverse event, SAM samidorphan\n\n\n\nSAEs were reported in 47 patients (3.2%) (Table 2 [common SAEs]; Table S3 [complete listing]). There was no identifiable pattern of events, and no particular SAE by preferred term occurred in >3 (0.2%) patients. Two deaths were reported during the study, both in the no prior exposure to the BUP/SAM group—respiratory arrest in a reportedly nonadherent patient with undisclosed chronic obstructive pulmonary disease and cerebral hemorrhage in a patient with medical and familial risk factors. Both deaths were deemed unrelated to study drug by the investigators and were reported to the relevant IRB. Full details of the patient deaths can be found in the Supplementary Results.\n\nThere were no completed suicides during the study. Seven patients (0.5%) reported suicidal ideation events, and no other AE potentially associated with suicidal ideation or behavior was reported. At baseline, C-SSRS suicidal ideation was reported for 4.8% of patients, and no C-SSRS suicidal behavior was reported in any patient. At any post-baseline visit, C-SSRS suicidal ideation and behavior, respectively, were reported in 153 (10.3%) and one (0.1%) patient; at the last visit, 53 (3.6%) and one (0.1%). One hundred patients (6.8%) reported an increase in C-SSRS suicidal ideation from baseline; only one patient without suicidal ideation at baseline reported C-SSRS serious suicidal ideation during treatment (Table S4). Of the 71 patients who reported any C-SSRS suicidal ideation at baseline, 58 (81.7%) improved during treatment. Of those with post-baseline C-SSRS suicidal ideation, only four patients (0.2%) reported active ideation (two with some intent to act without a plan and two with a specific plan and intent).\n\nThe incidence of any AE potentially associated with sexual dysfunction was low (1.8%). Three patients (0.2%) discontinued due to sexual dysfunction-related AEs (decreased libido: two [concomitant SSRI and concomitant SNRI, respectively]; ejaculation failure: one [concomitant SNRI]). There was no evidence of increased risk of hypomania/mania based on evaluation of clustering of AEs potentially associated with hypomania/mania (i.e., ≥3 AEs of this class in a single patient).\n\nAEs potentially associated with abuse potential were experienced by 321 patients (21.6%) (Table 3). The majority of these events (98.1%; 315/321) were nonspecific in nature (e.g., dizziness, somnolence, and other AEs potentially associated with abuse potential, but which also occur in drugs with no abuse potential). Euphoria-related events were infrequent and were reported in 18 patients (1.2%). All were single events, and none reoccurred. There were no AEs potentially associated with abuse behavior (e.g., intentional overdose, product tampering) or dependence (e.g., drug dependence antepartum/postpartum).Table 3 Adverse events to evaluate for abuse potential\n\nPatients with event, n (%)\tNo prior exposure to BUP/SAM (n = 929)\tPrior exposure to BUP/SAM (n = 556)\tAll patients (N = 1485)\t\nAny AESI to evaluate abuse potential\t248 (26.7)\t73 (13.1)\t321 (21.6)\t\nEuphoria related\t16 (1.7)\t2 (0.4)\t18 (1.2)\t\n Feeling abnormal\t7 (0.8)\t2 (0.4)\t9 (0.6)\t\n Euphoric mood\t6 (0.6)\t0\t6 (0.4)\t\n Feeling drunk\t2 (0.2)\t0\t2 (0.1)\t\n Hallucination, auditory\t1 (0.1)\t0\t1 (0.1)\t\nAbuse behavior\t0\t0\t0\t\nAbuse potential nonspecific\t242 (26.0)\t73 (13.1)\t315 (21.2)\t\n Dizziness\t116 (12.5)\t34 (6.1)\t150 (10.1)\t\n Somnolence\t100 (10.8)\t24 (4.3)\t124 (8.4)\t\n Sedation\t51 (5.5)\t15 (2.7)\t66 (4.4)\t\n Disturbance in attention\t9 (1.0)\t4 (0.7)\t13 (0.9)\t\n Confusional state\t2 (0.2)\t0\t2 (0.1)\t\n Cognitive disorder\t0\t1 (0.2)\t1 (0.1)\t\n Disorientation\t1 (0.1)\t0\t1 (0.1)\t\n Dissociation\t1 (0.1)\t0\t1 (0.1)\t\n Mood swings\t1 (0.1)\t0\t1 (0.1)\t\n Paranoia\t1 (0.1)\t0\t1 (0.1)\t\nAdverse events were coded by preferred terms and system organ class using the Medical Dictionary for Regulatory Activities, version 19.0. A full list of preferred terms evaluated are in the Supplementary Materials\n\nAESI adverse event of special interest, BUP buprenorphine, SAM samidorphan\n\n\n\nFollowing BUP/SAM discontinuation, fewer than 10% of patients reported AEs potentially associated with opioid withdrawal (Table 4). The most common of these AEs (≥1% of patients) were insomnia (2.0%), headache (1.6%), diarrhea (1.2%), and anxiety (1.1%). Of the nine patients who had ≥3 events possibly related to withdrawal, only one received prescription treatment for symptoms. There were four (0.4%) reported cases of drug-withdrawal syndrome. The highest post-discontinuation COWS scores among these four patients were categorized as no withdrawal (n = 2) and mild withdrawal (n = 1); one patient had no COWS score recorded. No opioids were reported as prior or concomitant medication for any of these four patients. The drug-withdrawal syndrome event resolved without treatment in all but one of these four patients (who was treated with clonidine 0.1 mg twice daily, until the event resolved in 11 days). Full details for these four patients can be found in the Supplementary Results.Table 4 Post-discontinuation adverse events to evaluate opioid withdrawal potential\n\nPatients with event, n (%)\tAll patients (N = 1109)\t\nAny PDAE associated with opioid withdrawal\t109 (9.8)\t\nPDAEs associated with opioid withdrawal occurring in ≥3 patients\t\n Insomnia\t22 (2.0)\t\n Headache\t18 (1.6)\t\n Diarrhea\t13 (1.2)\t\n Anxiety\t12 (1.1)\t\n Irritability\t10 (0.9)\t\n Nausea\t9 (0.8)\t\n Rhinorrhea\t9 (0.8)\t\n Hyperhidrosis\t8 (0.7)\t\n Pain\t8 (0.7)\t\n Restlessness\t8 (0.7)\t\n Arthralgia\t6 (0.5)\t\n Drug withdrawal syndrome\t4 (0.4)\t\n Yawning\t4 (0.4)\t\n Chills\t3 (0.3)\t\nAdverse events were coded by preferred terms and system organ class using the Medical Dictionary for Regulatory Activities, version 19.0. A full list of preferred terms evaluated are in the Supplementary Materials\n\nPDAE post-discontinuation adverse event\n\n\n\nIn the overall population, mean COWS scores were <1.0 at every assessment throughout the 4-week follow-up period, and the mean change from the post-discontinuation baseline at each follow-up visit was <1.0 (Table S5). COWS scores ≤ 4 are categorized as no withdrawal. The incidence of COWS score categorical worsening from no withdrawal at baseline was low (n = 58; 6.5%). Of these 58 cases, 49 were categorized as mild withdrawal (5.5%) and the remaining nine were moderate (1.0%). None of the patients who worsened from no withdrawal to moderate withdrawal required prescription treatment, and of those who worsened to mild withdrawal, only three required treatment (benzodiazepine for sleep and/or anxiety). No patient experienced a worsening from no withdrawal at baseline to moderately severe or severe withdrawal.\n\nBUP/SAM was not associated with meaningful changes in weight during the study (Table S6). A total of 23 unique patients (1.6%) met Temple’s corollary criteria. There were no other clinically meaningful mean changes from baseline in lipids or other chemistry analytes, hematology laboratory analyses, or urinalyses (Table S7). Mean changes from baseline in heart rate, blood pressure, respiratory rate, and temperature were within the normal range. There were no potentially clinically significant changes in vital signs or body weight at the last visit (Table S8). No changes in ECG records were deemed clinically significant.\n\nExploratory evaluation of efficacy\nMADRS scores showed sustained improvement in those patients continuing BUP/SAM treatment, persisting until the end of the 52-week study (Fig. 1a). More than half of all patients (60.2%) were in remission at the last study visit (55.0 and 63.7% of those with and without prior exposure to BUP/SAM, respectively) (Fig. 1b). The median time to remission was 99.0 days from study drug initiation. CGI-S scores improved during long-term BUP/SAM treatment, with a mean change from baseline at the last study assessment of –1.0 (SD ± 1.3).Fig. 1 a Mean MADRS scores over time and b proportion of patients achieving remission during BUP/SAM treatment. Data were based on observed cases. Week 0 refers to baseline of this study and was the baseline for patients without prior BUP/SAM exposure. PBL refers to the prior baseline for those patients with prior BUP/SAM exposure, i.e., their baseline from study FORWARD-1, FORWARD-3, FORWARD-4, or FORWARD-5. Each subsequent week refers to week of study visit during FORWARD-2 and corresponds to week since BUP/SAM initiation for patients with no prior BUP/SAM exposure. Remission was defined as Montgomery–Åsberg Depression Rating Scale score ≤ 10. BUP/SAM buprenorphine/samidorphan, MADRS Montgomery–Åsberg Depression Rating Scale, PBL prior baseline\n\n\n\nDiscussion\nIn the 52-week FORWARD-2 study, adjunctive treatment with BUP/SAM 2 mg/2 mg was generally well tolerated, with no new or unexpected safety signals arising from long-term treatment. BUP/SAM demonstrated low risk of abuse. There was little evidence of withdrawal upon abrupt discontinuation, as assessed by AEs and COWS, and there was low incidence of other AEs commonly associated with drugs for depression and adjunctive agents used in the treatment of MDD.\n\nMDD is a chronic condition for which long-term treatment is recommended [30–32]. Currently approved drugs for psychosis used as adjunctive treatment of MDD belong to a single class. Given that BUP/SAM has a novel mechanism of action, its favorable tolerability and safety profile over 52 weeks is noteworthy. The AE profile in FORWARD-2 was consistent with that reported in prior short-term, placebo-controlled studies of BUP/SAM. There were no suicide attempts during the treatment period, nor was there any evidence of increased risk for suicidal ideation or behavior with BUP/SAM [24, 27, 28]. AEs were predominantly gastrointestinal and sedation-related events, occurring with frequency similar to those observed in long-term studies of approved monotherapies and adjunctive agents [33–36]. In addition, the AE rates were higher in patients starting treatment in this study than in those who participated in prior BUP/SAM studies, indicating that events are associated with initiation. The rate of discontinuation due to AEs was 10.6%, which is also consistent with rates reported with approved drugs for depression. In long-term MDD studies of adjunctive aripiprazole and brexpiprazole, the rates of discontinuation due to AEs were 23.0% and 14.1%, respectively [10, 37, 38]. The discontinuation rates reported with up to 14 weeks of treatment with adjunctive lithium and triiodothyronine (T3) were 23.0 and 9.6%, respectively [39]. The discontinuation rates observed for open-label extension studies with monotherapies, such as duloxetine, escitalopram, and vortioxetine range from 6 to 12% [33, 35, 36, 40].\n\nAdjunctive atypical drugs for psychosis are commonly associated with weight gain and adverse metabolic changes [10, 11]. Adjunctive aripiprazole has been associated with akathisia (number needed to harm [NNH]: 4) and significant weight gain (≥7% from baseline; NNH: 29). Weight gain has also been associated with adjunctive olanzapine/fluoxetine (≥10% from baseline; NNH: 9) and adjunctive quetiapine (≥7% from baseline; NNH: 37). Weight remained stable with long-term adjunctive BUP/SAM treatment and BUP/SAM was not associated with clinically meaningful changes in metabolic parameters, vital signs, laboratory tests, or ECG parameters. No akathisia was reported, and although there was low incidence (n = 4) of discontinuation due to tremor, no tardive dyskinesia was reported.\n\nBUP and other μ-opioid receptor agonists have shown antidepressant potential in the treatment of MDD [19, 20, 25, 41], but the established abuse liability of μ-opioid receptor agonists limits their utility [19, 41, 42]. SAM was included in the BUP/SAM combination to mitigate the risk of abuse and dependence associated with BUP [22]. The results of FORWARD-2 are consistent with those of the short-term studies of BUP/SAM treatment of patients with MDD, providing empirical evidence of the safety and tolerability for longer-term BUP/SAM therapy. The incidence of euphoria-related events was low and there was no indication of abuse behavior or dependence as assessed by AEs and investigator report; most of the AEs reported to evaluate for abuse potential were nonspecific (i.e., dizziness and somnolence). These results support and extend the finding of reduced abuse potential of BUP/SAM compared with BUP demonstrated in a human abuse potential study [26] by providing evidence that SAM mitigated the abuse potential associated with BUP over a 1-year period in patients with MDD.\n\nThere was little evidence of withdrawal after abrupt discontinuation of BUP/SAM, as evidenced by AE and COWS assessments. Withdrawal is associated with abrupt discontinuation of many commonly used antidepressants [43–45]. Abrupt discontinuation of BUP alone is associated with mild-to-moderate opioid withdrawal in almost all patients and usually requires symptomatic management of opioid withdrawal [46–49]. As abrupt discontinuation of BUP/SAM after up to 52 weeks of treatment was well tolerated, this differentiates BUP/SAM from unmitigated µ-opioid receptor agonists and further indicates that SAM attenuated the μ-agonist activity of BUP, precluding the development of physical dependence associated with BUP alone.\n\nAn exploratory assessment of efficacy found an antidepressant effect with demonstrated durability for up to 52 weeks. These data support the efficacy findings from short-term, placebo-controlled studies [24, 27, 28] covering treatment in more than 700 patients over a full year. The improvement in mean MADRS scores was sustained among patients who continued BUP/SAM treatment for up to 52 weeks. In addition, ∼60% of patients continuing treatment achieved remission by study end. The rate of remission is comparable to that seen with other adjunctive treatments for patients with MDD who are inadequate responders to first-line antidepressant therapy [50, 51]. This is promising, given the favorable long-term safety and tolerability results. The baseline MADRS scores for patients with prior BUP/SAM exposure, which represent the baseline scores from the prior study, were higher than baseline MADRS scores of patients in this study without prior BUP/SAM exposure, because the inclusion criteria for FORWARD-1, FORWARD-3, FORWARD-4, and FORWARD-5 required a more severe depression rating at enrollment than FORWARD-2. This also may have contributed to the slight difference in remission rate between the two groups, because patients without prior BUP/SAM exposure who entered the study with lower MADRS scores could more easily attain a MADRS score ≤ 10.\n\nFindings should be interpreted with consideration of the study’s limitations. The open-label design and lack of control group limit the ability to attribute AEs solely to adjunctive BUP/SAM treatment, because some AEs may have resulted from the long-term use of background drugs for depression and/or the natural course of the illness. In addition, the clinically meaningful reduction in MADRS scores and achievement of remission by ~60% of study completers must be seen in the context of both a lack of a control arm and the dropout rate. With nearly half of study participants dropping out, it is possible that nonremitters dropped out at a greater rate than remitters. However, the overall dropout rate due to lack of efficacy was low (4.2%), and the study findings are strengthened by the large number and diverse background of patients with MDD who received BUP/SAM over 1 year.\n\nThe opioid system modulating BUP/SAM combination represents a promising potential adjunctive treatment that works primarily via a nonaminergic mechanism for patients with MDD who do not respond adequately to drugs for depression. Consistent with its intended effect, SAM mitigated the abuse potential of BUP, with the combination exhibiting little evidence of abuse potential or withdrawal symptoms after a year of treatment. Moreover, treatment with BUP/SAM was generally well tolerated; the safety profile was consistent with that observed in placebo-controlled studies, including a favorable profile for suicidal ideation and behavior. Further, durability of therapeutic effect was observed with long-term treatment. These data suggest that BUP/SAM may help to address the critical need for new treatments capable of providing long-term benefit for patients with MDD.\n\nFunding and disclosure\nThe study, including study design, collection, analysis, and interpretation of data, was sponsored by Alkermes, Inc. The Perelman School of Medicine of the University of Pennsylvania received a grant from Assurex so that Dr. Thase could conduct the research protocol described in this report at his site. Dr. Thase has served as an advisor or consultant to Acadia, Akilii, Alkermes, Inc, Allergan (includes Forest Laboratories and Naurex), AstraZeneca, Cerecor, Eli Lilly, Fabre-Kramer, Gerson Lehrman Group, Guidepoint Global, Johnson & Johnson Pharmaceutical Research & Development LLC (Janssen, Ortho-McNeil), Lundbeck, MedAvante, Merck, Moksha8, Nestlé (PamLab), Novartis, Otsuka, Pfizer, Shire, Sunovion, and Takeda; he has received grant support from Acadia, Agency for Healthcare Research and Quality, Alkermes, Inc, Avanir, Forest, Intracellular, Janssen, National Institute of Mental Health, Otsuka, Patient Centered Outcomes Research Institute, and Takeda; he has received royalties from American Psychiatric Press, Guilford Publications, Herald House, and WW Norton & Company Inc; and Dr Thase’s spouse is employed by Peloton Advantage, which does business with a number of pharmaceutical companies. Dr. Bodkin has served as an advisor to Alkermes, Inc; he has received research support from McLean Hospital via Alkermes, Inc. Dr. Trivedi has served as an advisor or consultant to AcademyHealth, Alkermes, Inc, Akili Interactive, Allergan Pharmaceuticals, ACADIA Pharmaceuticals Inc, American Society of Clinical Psychopharmacology, Brain Institute Canada (CAN-BIND), Brintellix Global, Global Medical Education, Healthcare Global Village, Health Research Associates, Jazz Pharmaceuticals, Lundbeck Research USA, Medscape LLC, MSI Methylation Sciences Inc, Nestlé Health Science—Pamlab Inc, Naurex Inc, Navitor, One Carbon Therapeutics, Otsuka America Pharmaceutical Inc, Saatchi, and Takeda Global Research; he has received grant support from National Institute of Mental Health, National Institute on Drug Abuse, Johnson & Johnson Pharmaceutical Research & Development LLC, and Janssen Research & Development LLC; he has received royalties from Janssen Research & Development LLC; he has publications for Janssen Asia Pacific and Oxford University Press. Dr. Fava has received research support from Abbott Laboratories, Acadia Pharmaceuticals, Alkermes, Inc, American Cyanamid, Aspect Medical Systems, AstraZeneca, Avanir Pharmaceuticals, AXSOME Therapeutics, BioResearch, BrainCells Inc; Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Cerecor, Clintara, LLC, Covance, Covidien, Eli Lilly & Co, EnVivo Pharmaceuticals Inc, Euthymics Bioscience Inc, Forest Pharmaceuticals Inc, FORUM Pharmaceuticals, Ganeden Biotech Inc, GlaxoSmithKline, Harvard Clinical Research Institute, Hoffman-LaRoche, i3 Innovus/Ingenix, Icon Clinical Research, Janssen R&D LLC, Jed Foundation, Johnson & Johnson Pharmaceutical Research & Development LLC, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Lundbeck Inc, Marinus Pharmaceuticals, MedAvante, Methylation Sciences Inc, National Alliance for Research on Schizophrenia & Depression, National Center for Complementary and Alternative Medicine, National Coordinating Center for Integrated Medicine, National Institute of Drug Abuse, National Institute of Mental Health, Neuralstem Inc, NeuroRx, Novartis AG, Organon Pharmaceuticals, Otsuka Pharmaceutical Development Inc, PamLab LLC, Pfizer Inc, Pharmacia-Upjohn, Pharmaceutical Research Associates Inc, Pharmavite LLC, PharmoRx Therapeutics, Photothera, RCT Logic LLC (formerly Clinical Trials Solutions LLC), Reckitt Benckiser, Roche Pharmaceuticals, Sanofi-Aventis US LLC, Shire, Solvay Pharmaceuticals Inc, Stanley Medical Research Institute, Synthelabo, Taisho Pharmaceuticals, Takeda Pharmaceuticals, Tal Medical, VistaGen, and Wyeth-Ayerst Laboratories; he has served as an advisor or consultant to Abbott Laboratories, Acadia, Affectis Pharmaceuticals AG, Alkermes, Inc, Amarin Pharma Inc, Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Avanir Pharmaceuticals, AXSOME Therapeutics, Bayer AG, Best Practice Project Management Inc, Biogen, BioMarin Pharmaceuticals Inc, Biovail Corporation, BrainCells Inc, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon Inc, Cerecor, CNS Response Inc, Compellis Pharmaceuticals, Cypress Pharmaceutical Inc, DiagnoSearch Life Sciences (P) Ltd, Dinippon Sumitomo Pharma Co Inc, Dov Pharmaceuticals Inc, Edgemont Pharmaceuticals Inc, Eisai Inc, Eli Lilly & Co, EnVivo Pharmaceuticals Inc, ePharmaSolutions, EPIX Pharmaceuticals Inc, Euthymics Bioscience Inc, Fabre-Kramer Pharmaceuticals Inc, Forest Pharmaceuticals Inc, Forum Pharmaceuticals, GenOmind LLC, GlaxoSmithKline, Grunenthal GmbH, i3 Innovus/Ingenis, Indivior, Intracellular, Janssen Pharmaceuticals, Jazz Pharmaceuticals Inc, Johnson & Johnson Pharmaceutical Research & Development LLC, Knoll Pharmaceuticals Corp, Labopharm Inc, Lorex Pharmaceuticals, Lundbeck Inc, Marinus Pharmaceuticals, MedAvante Inc, Merck & Co Inc, MSI Methylation Sciences Inc, Naurex Inc, Navitor Pharmaceuticals Inc, Nestlé Health Sciences, Neuralstem Inc, Neuronetics Inc, NextWave Pharmaceuticals, Novartis AG, Nutrition 21, Orexigen Therapeutics Inc, Organon Pharmaceuticals, Osmotica, Otsuka Pharmaceuticals, Pamlab LLC, Pfizer Inc, PharmaStar, Pharmavite LLC, PharmoRx Therapeutics, Precision Human Biolaboratory, Prexa Pharmaceuticals Inc PPD, PsychoGenics, Psylin Neurosciences Inc, Purdue Pharma, Puretech Ventures, RCT Logic LLC (formerly Clinical Trials Solutions LLC), Relmada Therapeutics Inc, Rexahn Pharmaceuticals Inc, Ridge Diagnostics Inc, Roche Pharmaceuticals, Sanofi-Aventis US LLC, Sepracor Inc, Servier Laboratories, Schering-Plough Corporation, Shenox Pharmaceuticals, Solvay Pharmaceuticals Inc, Somaxon Pharmaceuticals Inc, Somerset Pharmaceuticals Inc, Sunovion Pharmaceuticals, Supernus Pharmaceuticals Inc, Synthelabo, Taisho Pharmaceuticals, Takeda Pharmaceutical Co Ltd, Tal Medical Inc, Tetragenex, Teva Pharmaceuticals, TransForm Pharmaceuticals Inc, Transcept Pharmaceuticals Inc, Usona Institute Inc, Vanda Pharmaceuticals Inc, Versant Venture Management LLC, and VistaGen; he has had speaking or publishing roles for Adamed Co, Advanced Meeting Partners, American Psychiatric Association, American Society of Clinical Psychopharmacology, AstraZeneca, Belvoir Media Group, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Cephalon Inc, CME Institute/Physicians Postgraduate Press, Inc, Eli Lilly & Co, Forest Pharmaceuticals Inc, GlaxoSmithKline, Imedex LLC, MGH Psychiatry Academy/Primedia, Massachusetts General Hospital (MGH) Psychiatry Academy/Reed Elsevier, Novartis AG, Organon Pharmaceuticals, Pfizer Inc, PharmaStar, United BioSource Corp, and Wyeth-Ayerst Laboratories; he is named on patents for sequential parallel comparison design, licensed by MGH to Pharmaceutical Product Development, and pharmacogenomics of depression treatment with folate; he has a patent application for a combination of ketamine plus scopolamine in major depressive disorder, licensed by MGH to Biohaven; he is a copyright holder for the MGH Cognitive & Physical Functioning Questionnaire, Sexual Functioning Inventory, Antidepressant Treatment Response Questionnaire, Discontinuation-Emergent Signs & Symptoms, Symptoms of Depression Questionnaire, and SAFER; he has publications for Lippincott, Williams & Wilkins, Wolkers Kluwer, and World Scientific Publishing. Drs. Stanford, Memisoglu, Martin, Claxton, Yu, and Pathak are employees and stockholders of Alkermes, Inc.\n\nSupplementary information\n\nSupplemental Material\n\n \nSupplemental Figure 1\n\n \nSupplemental Figure 2\n\n \n\n\nPublisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary Information accompanies this paper at (10.1038/s41386-019-0451-3).\n\nAcknowledgements\nMedical writing and editorial support was provided by Andrew Hill (scientific writer at PAREXEL) and funded by Alkermes, Inc.\n\nAuthor contributions\nAll authors conceived and/or designed the work that led to the submission, acquired data, and/or played an important role in interpreting the results, drafted or revised the paper, and approved the final version of this report.\n\nData availability\nAll data on which conclusions of the paper rely are available within the main text and/or Supplementary Materials.\n==== Refs\nReferences\n1. 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"fulltext_license": "CC BY",
"issn_linking": "0893-133X",
"issue": "44(13)",
"journal": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology",
"keywords": null,
"medline_ta": "Neuropsychopharmacology",
"mesh_terms": "D000328:Adult; D000928:Antidepressive Agents; D002047:Buprenorphine; D003865:Depressive Disorder, Major; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009271:Naltrexone; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome",
"nlm_unique_id": "8904907",
"other_id": null,
"pages": "2268-2276",
"pmc": null,
"pmid": "31254971",
"pubdate": "2019-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Results from a long-term open-label extension study of adjunctive buprenorphine/samidorphan combination in patients with major depressive disorder.",
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"abstract": "Obesity hypoventilation syndrome (OHS) is a disorder in which patients with a body mass index ≥30 kg/m2 develop awake hypercapnia with a partial pressure of carbon dioxide ≥45 mm Hg, in the absence of other diseases that may produce alveolar hypoventilation. Additional clinical features include sleep disordered breathing, restrictive lung disease, polycythemia, hypoxemia, and an increased serum bicarbonate concentration (≥27 mEq/L). Anesthesia providers should be familiar with OHS because it is often undiagnosed, it is associated with a higher mortality rate than obstructive sleep apnea, and it is projected to increase in prevalence along with the obesity epidemic. In this case, a 33-year-old obese woman with presumed OHS developed respiratory acidosis during induction of labor. Continuous positive airway pressure treatment was initiated, but the patient continued to have hypercapnia. A cesarean delivery was recommended. The patient had baseline orthopnea due to her body habitus; thus, despite adequate labor analgesia, a cesarean delivery was completed with general endotracheal anesthesia. We believe this patient had OHS despite a serum bicarbonate <27 mEq/L, a partial pressure of oxygen >70 mm Hg, and a hemoglobin <16 g/dL, which would typically rule out OHS. Pregnant women experience a decrease in serum bicarbonate concentration due to progesterone-mediated hyperventilation, an increase in arterial oxygenation from increased minute ventilation and higher cardiac output, and a decrease in hemoglobin due to the physiologic anemia of pregnancy. Thus, OHS may be defined differently in pregnant than in non-pregnant patients.",
"affiliations": "Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA.;Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA.;Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA.;Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA.",
"authors": "Togioka|Brandon M|BM|https://orcid.org/0000-0002-8285-7811;McConville|Sarah S|SS|;Penchoen-Lind|Rachael M|RM|;Schenning|Katie J|KJ|https://orcid.org/0000-0002-1784-0749",
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"doi": "10.1155/2021/8096212",
"fulltext": "\n==== Front\nCase Rep Anesthesiol\nCase Rep Anesthesiol\nCRIA\nCase Reports in Anesthesiology\n2090-6382\n2090-6390\nHindawi\n\n10.1155/2021/8096212\nCase Report\nDiagnosis and Management of Obesity Hypoventilation Syndrome during Labor\nhttps://orcid.org/0000-0002-8285-7811\nTogioka Brandon M. togioka@ohsu.edu\n1 2\nMcConville Sarah S. 1 3\nPenchoen-Lind Rachael M 1\nhttps://orcid.org/0000-0002-1784-0749\nSchenning Katie J. 1\n1Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA\n2Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, USA\n3Department of Neurology, Oregon Health & Science University, Portland, OR, USA\nAcademic Editor: Anjan Trikha\n\n2021\n25 8 2021\n2021 80962129 6 2021\n29 7 2021\n14 8 2021\nCopyright © 2021 Brandon M. Togioka et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nObesity hypoventilation syndrome (OHS) is a disorder in which patients with a body mass index ≥30 kg/m2 develop awake hypercapnia with a partial pressure of carbon dioxide ≥45 mm Hg, in the absence of other diseases that may produce alveolar hypoventilation. Additional clinical features include sleep disordered breathing, restrictive lung disease, polycythemia, hypoxemia, and an increased serum bicarbonate concentration (≥27 mEq/L). Anesthesia providers should be familiar with OHS because it is often undiagnosed, it is associated with a higher mortality rate than obstructive sleep apnea, and it is projected to increase in prevalence along with the obesity epidemic. In this case, a 33-year-old obese woman with presumed OHS developed respiratory acidosis during induction of labor. Continuous positive airway pressure treatment was initiated, but the patient continued to have hypercapnia. A cesarean delivery was recommended. The patient had baseline orthopnea due to her body habitus; thus, despite adequate labor analgesia, a cesarean delivery was completed with general endotracheal anesthesia. We believe this patient had OHS despite a serum bicarbonate <27 mEq/L, a partial pressure of oxygen >70 mm Hg, and a hemoglobin <16 g/dL, which would typically rule out OHS. Pregnant women experience a decrease in serum bicarbonate concentration due to progesterone-mediated hyperventilation, an increase in arterial oxygenation from increased minute ventilation and higher cardiac output, and a decrease in hemoglobin due to the physiologic anemia of pregnancy. Thus, OHS may be defined differently in pregnant than in non-pregnant patients.\n==== Body\npmc1. Introduction\n\nObesity hypoventilation syndrome (OHS) is a disorder in which patients with body mass index (BMI) >30 kg/m2 develop awake hypercapnia with partial pressure of carbon dioxide (PaCO2) >45 mm Hg, in the absence of other diseases that may produce alveolar hypoventilation [1]. Additional clinical features include restrictive lung disease and polycythemia (hemoglobin >16 g/dL) [1]. Obstructive sleep apnea (OSA) is present in 90% of individuals with OHS [2]. Serum bicarbonate has been used to screen for OHS, with a level <27 mEq/L decreasing the probability of the disease [3, 4]. The prevalence of OHS has been estimated to be between 0.15 and 0.4% of the world's adult population [5, 6]. The prevalence of OHS is expected to increase along with the obesity epidemic [7, 8]. Patients with OHS are high healthcare utilizers and they generate higher physician fees [9]. OHS is associated with a higher mortality rate than OSA [10] and obesity without hypoventilation [11]; thus, it is critical that anesthesia providers learn how to diagnose OHS [12]. However, OHS may be defined differently in pregnant than in non-pregnant patients.\n\nOur first objective is to highlight OHS as a risk factor for respiratory acidosis during labor. Our second objective is to illustrate that the established tests for OHS lack utility in the obstetric population. Health Insurance Portability and Accountability Act written authorization for publication of this case report was obtained from the patient. This paper adheres to the CARE guidelines [13].\n\n2. Case Presentation\n\nA 33-year-old woman with a BMI of 58.6 kg/m2, type 2 diabetes (hemoglobin A1C 6.6%) with nephropathy (baseline creatinine 1.5–1.7 mg/dL), and a prior myocardial infarction was admitted to the hospital for sustained blood pressures >200/100 mm Hg and a posterior cranial headache. Her hypertensive emergency was attributed to 10 days without anti-hypertension medications; she was prescribed 10 mg once daily oral amlodipine and 50 mg once daily oral hydrochlorothiazide. During that admission, the patient's serum bicarbonate ranged between 27 and 33 mmol/L, consistent with OHS.\n\nTwo years later, with a 35-week gestational pregnancy, the patient was again admitted to the hospital for hypertension and a headache. A diagnosis of preeclampsia superimposed upon chronic hypertension (baseline systolic blood pressure of 130–145 mm Hg) was made after blood pressures of 157/74 mm Hg (automated oscillometric technique) and 164/92 mm Hg (manual auscultatory technique) were recorded four hours apart. The patient's chronic hypertension was treated with 200 mg twice daily oral labetalol and 10 mg once daily oral amlodipine. She reported no missed medication doses.\n\nThe patient's obstetric history included one prior full-term vaginal delivery. Her admission non-stress test was categorized as reactive with a baseline heart rate of 125 beats per minute, moderate variability, and qualifying accelerations present. Her medical history additionally included mild intermittent asthma (no wheezing or coughing during pregnancy), anemia (hemoglobin 11.1 g/dL), and moderate likely extrapulmonary restrictive lung disease (2nd trimester spirometry FEV1 68%, FVC 65%, total lung capacity 78%) [14]. She was confirmed to be euthyroid with 2nd trimester testing (thyroid-stimulating hormone 1.78 uIU/ml).\n\nPhysical examination revealed a neck circumference >40 cm, Mallampati class IV airway, and clear lungs. The patient was in a labor bed that had been modified to a sitting position due to prepregnancy chest discomfort and subjective shortness of breath (oxygen saturation 98% on room air) that occurred when the patient was supine. A home sleep study was completed 4 days prior to admission, due to a history of snoring and chronic fatigue, but the results were not finalized at the time of admission.\n\nDespite increasing oral labetalol to 600 mg twice daily, the patient's blood pressure climbed to 167/90 mm Hg and her creatinine increased to 1.5 mg/dL. Cervical ripening, lactated ringer's infusion, and magnesium (4 gram load followed by 1 gram/hour) were initiated. The patient described worsening shortness of breath and was given a non-rebreather mask (NRB) delivering oxygen at 10 liters per minute. Her oxygen saturation remained low at 92%. Albuterol (2.5 mg of nebulizer solution) was empirically administered despite a lack of wheezing on auscultation. Albuterol did not improve her oxygen saturation or shortness of breath. Pulmonology was consulted and continuous positive airway pressure (CPAP) was prescribed for “likely OSA,” but the patient declined it.\n\nThe next day, the patient was taken to the operating room (given high fetal station) for epidural placement, artificial rupture of membranes, and placement of an internal fetal monitor followed by misoprostol administration and initiation of oxytocin infusion. An epidural was placed at the L3/4 vertebral interspace, and 7.5 mL of 0.055% bupivacaine with 1 mcg/mL sufentanil solution was administered, causing an upper level of loss of pinprick sensation to the T10 dermatome. Epidural analgesia was maintained using the CADD-Solis Infusion System version 3.0 (Smiths Medical, Minneapolis, MN) with a 7 mL programmed bolus every 45 minutes and a 5 mL patient-controlled bolus every 10 minutes. The patient reported no pain and maintained modified Bromage grade 0 (free movement of legs and feet) motor function throughout her induction [15].\n\nSixteen hours after epidural placement, the patient was not in active labor and she complained of difficulty in breathing. A chest radiograph revealed an elevated diaphragm without consolidation or pulmonary edema. A formal transthoracic echocardiogram revealed severe concentric left ventricular hypertrophy with an ejection fraction of 65%, a severely dilated left atrium, and a right ventricle with normal size and function. There was no tricuspid regurgitation, and thus pulmonary artery pressure could not be assessed. An arterial blood gas (ABG) and metabolic panel revealed normochloremic acidosis (pH 7.27, bicarbonate 21 mmol/L, and chloride 106 mmol/L), hypercarbia (PaCO2 47 mmHg), hypoxia (PaO2 96 mmHg on NRB delivering oxygen at 10 LPM), and hypermagnesemia (4.9 mg/dL) (Table 1 and Figure 1). For comparison, a normal term pregnancy ABG is pH 7.43, PaCO2 30.4 mmHg, PaO2 101.8 mmHg on 21% oxygen, and bicarbonate 21.7 mmol/L [8]. The patient's hypoxia and hypercarbia were attributed to increased carbon dioxide production associated with induction of labor, myasthenia caused by hypermagnesemia, and respiratory muscle fatigue. The patient agreed to use CPAP (10 cm H2O, 100% oxygen), but an ABG one hour later did not show an improvement in respiratory acidosis: pH 7.26, PaCO2 49 mmHg, PaO2 124 mmHg, and bicarbonate 21 mmol/L (Table 1). A cesarean delivery was recommended for maternal respiratory compromise, but the patient declined.\n\nSeven hours after initiating CPAP treatment, cervical dilation was unchanged and the patient agreed to cesarean delivery. Despite adequate epidural analgesia, the patient required general anesthesia with endotracheal intubation for baseline orthopnea due to her body habitus. She was administered 30 ml oral sodium citrate, induced with propofol, paralyzed with rocuronium, and intubated with a video laryngoscope in the reverse-Trendelenburg position. Skin incision to delivery took 20 minutes. Significant adipose tissue made surgical dissection to the lower uterine segment and fetal head extraction difficult. Although the hysterotomy had to be extended resulting in a 2000 mL blood loss, hemodynamic stability was maintained with administration of 3000 mL lactated ringer's solution, and blood transfusion was not administered. Apgar scores were 1 (1 minute) and 4 (5 minutes), and the neonate was intubated. The neonate was extubated the next day and discharged home in good health. After surgery, the patient was transported intubated to the intensive care unit (ICU).\n\nThe patient was afebrile, but remained mechanically ventilated due to preeclampsia-related acute on chronic kidney injury (creatinine 2.82 mg/dL and potassium 6.7 mmol/L). Hyperkalemia was successfully treated with a 20 mg/hour intravenous furosemide infusion, renal function improved without hemodialysis, and the patient was extubated on postdelivery day 2. One day after extubation, the patient's serum bicarbonate was 29 mmol/L (Figure 1).\n\nThe remainder of the patient's hospitalization was unremarkable. On the day of discharge, the patient's home sleep study was finalized revealing an apnea hypopnea index of 46.8 events/hour, an obstructive apnea index of 18.2 events/hour, a 90% mean oxygen saturation, and a 68% oxygen saturation nadir. The patient was discharged home with an auto-CPAP machine set to a range of 5–15 cm H2O.\n\nDue to COVID-19 precautionary measures, the patient had a telephone appointment with the sleep disorders clinic 5 months after discharge. The patient reported rare CPAP use, due to not liking the face mask fit. A plan was made to complete a positive airway pressure titration study to determine if bilevel positive airway pressure may reduce the number of obstructive or hypoxic events the patient experienced at night. No date has been set for this appointment. A phone call one year after delivery confirmed that the patient and infant are doing well and CPAP use has remained inconsistent.\n\n3. Discussion\n\nAlthough the prevalence of OHS is increasing in the obstetric population and OHS is known to increase risk for perioperative morbidity and mortality [16], there are limited reports of obstetric patients with OHS. We found only one case report describing OHS during pregnancy, in which a parturient with obesity-related hypoventilation and hypercarbia had cardiac arrest after developing severe hypokalemia due to hyperemesis gravidarum [17]. By contrast, increased attention is being paid to the diagnosis and treatment of OSA during pregnancy. OSA is common in pregnant women, the incidence increases with higher gestational age [18] and BMI [19], and it is associated with preeclampsia and gestational diabetes [18, 19]. While the two diseases share clinical manifestations and pathogenesis, it is important to distinguish between them by assessing for awake hypercapnia (PaCO2 >45 mm Hg) because patients with OHS have poorer prognoses and higher mortality rates than patients with OSA [9, 20].\n\nIn this case, a patient with presumed OHS developed acute respiratory acidosis as a result of multiple physiologic challenges during induction of labor, including increased carbon dioxide production, a blunted respiratory response to hypercarbia, and respiratory muscle fatigue. CPAP therapy was initiated, but the patient continued to have hypercapnia. It was determined that cesarean delivery may help the patient regain acid-base homeostasis. The patient had baseline orthopnea due to her body habitus; thus, despite adequate labor analgesia, a cesarean delivery was completed with general endotracheal anesthesia.\n\nAppropriate screening and identification of OHS in this patient may have facilitated vaginal delivery with neuraxial labor analgesia. In the short term, positive pressure ventilation (PPV) can reduce chest discomfort and upper airway obstruction for patients in the supine position [21]. Long-term PPV has been shown to normalize PaCO2, improve oxygenation, reduce daytime sleepiness, improve functional status, improve pulmonary mechanics, stimulate central respiratory response to hypercarbia, and reduce mortality [22–25]. Therefore, a formal diagnosis of OHS earlier in pregnancy, conditioning to PPV, and use of PPV during induction of labor may have prevented the need for mechanical ventilation.\n\nThe established differential diagnosis for acute respiratory acidosis during labor includes asthma exacerbation, pneumonia, cardiogenic and non-cardiogenic pulmonary edema, hypermagnesemia, and pulmonary embolism. In the present case, these diagnoses were deemed less likely than respiratory acidosis related to OHS: asthma (no wheezing and no response to albuterol), pneumonia (no fever and clear chest radiograph), pulmonary edema (clear chest radiograph), hypermagnesemia (lack of hyporeflexia and a peak magnesium concentration of 4.9 mg/dL, whereas levels >15 mg/dL are typically associated with respiratory arrest), and pulmonary embolism (no chest pain, hemoptysis, or cough).\n\nThe preponderance of evidence supports a diagnosis of OHS, and that it led to the patient's acute respiratory acidosis. The patient possessed many of the criteria used to diagnose OHS: high BMI (58.6 kg/m2), restrictive lung disease, diaphragm elevation on chest radiograph, severe OSA (apnea hypopnea index 46.8 events/hour), and daytime awake hypercapnia (PaCO2 >45 mm Hg) [1]. Although PaCO2 >45 mm Hg is not impressive outside of pregnancy, during pregnancy it is consistent with significant respiratory acidosis, as normal term pregnancy PaCO2 is 30 mm Hg [8].\n\nThe diagnostic criteria for OHS that the patient did not possess (serum bicarbonate ≥27 mEq/L, PaO2 <70 mm Hg, and hemoglobin >16 g/dL) can be explained by physiologic changes associated with pregnancy and labor (Table 2).\n\nSerum bicarbonate concentration ≥27 mEq/L was found to predict hypercapnia on arterial blood gas measurement with 92% sensitivity [26]. This prompted the recommendation that clinicians use this easily obtainable lab value as an initial screening test for OHS [26]. In this case, the patient's serum bicarbonate was ≥27 mEq/L before becoming pregnant and after delivery; however, her serum bicarbonate was 20–23 mEq/L during her induction of labor (Figure 1). Serum bicarbonate decreases during pregnancy due to metabolic compensation for progesterone-mediated respiratory alkalosis [8]. Serum bicarbonate may further decrease during labor when pain causes hyperventilation. Therefore, the 27 mEq/L threshold for serum bicarbonate may have lower sensitivity in pregnant women. Consequently, we suggest a measurement of PaCO2 from an ABG in pregnant women, in whom suspicion for OHS is high.\n\nThe patient was not hypoxemic during the majority of her peripartum course (Table 1). PaO2 increases 10 mmHg during pregnancy due to increased minute ventilation, lower PaCO2 (which increases PaO2 as calculated by the alveolar gas equation), and a smaller drop in venous oxygen concentration due to increased cardiac output [8]. Hence, physiologic changes associated with pregnancy decrease the likelihood that parturients will be hypoxic, which would increase the number of false negatives and decrease the sensitivity of PaO2 <70 mm Hg for diagnosing OHS.\n\nThough the patient's hemoglobin was never >16 g/dL, the patient's hemoglobin dropped from 14.6 g/dL at 8 weeks gestational age to 10.9–11.3 g/dL in the third trimester. The patient's hemoglobin was not measured prior to pregnancy. The body prepares for blood loss during delivery by increasing plasma volume more than red cell mass, known as physiologic anemia of pregnancy [8]. Thus, polycythemia is rare during pregnancy and may not be useful as a diagnostic test for OHS during pregnancy.\n\nIn conclusion, the diagnosis of OHS in pregnancy is not straightforward. The diagnostic criteria for OHS in non-pregnant patients have low sensitivity in patients with physiologic changes associated with pregnancy and labor. We have outlined the diagnostic findings associated with OHS in non-pregnant patients, the associated physiologic changes of pregnancy, and the impact of pregnancy on the sensitivity of those diagnostic criteria (Table 2). We described a case of hypercapnic respiratory failure in a pregnant woman with presumed OHS, who required general endotracheal anesthesia for cesarean delivery—highlighting the need for early diagnosis and treatment with PPV in these patients.\n\nAcknowledgments\n\nSupport was provided solely by institutional and departmental sources within Oregon Health & Science University, as part of the employment of the authors. The authors would like to thank Marie Kane for her assistance with manuscript preparation, editing, and formatting.\n\nData Availability\n\nThe data used to support the findings of this study are available from the corresponding author upon request.\n\nConflicts of Interest\n\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n\nAuthors' Contributions\n\nBrandon M. Togioka, MD, cared for the patient and conceived, drafted, edited, and revised the manuscript. Sarah S. McConville, MD, cared for the patient and helped edit and revise the manuscript. Rachael M. Penchoen-Lind helped edit and revise the manuscript. Katie J. Schenning, MD, helped draft, edit, and revise the manuscript.\n\nFigure 1 Serum bicarbonate changes from preconception to postpartum. ICU, intensive care unit; L, liter; mmol, millimole.\n\nTable 1 Arterial blood gas values from preconception to postpartum.\n\nTime point, relative to day of admission\tPartial pressure of carbon dioxide (mm Hg)\tPartial pressure of oxygen (mm Hg)\tSerum bicarbonate concentration (mmol/L)\tOxygen delivery type\tFraction of inspired oxygen (%) or delivery of oxygen (L/min)\t\n2 years prior to admission\tn/a\tn/a\t27–33\tNatural airway\t21%\t\nHospital day 1, time 23 : 11\tn/a\tn/a\t21\tNatural airway\t21%\t\nHospital day 2, time 7 : 01\tn/a\tn/a\t22\tNatural airway\t21%\t\nHospital day 2, time 16 : 27\tn/a\tn/a\t21\tNatural airway\t21%\t\nHospital day 2, time 21 : 23\tn/a\tn/a\t22\tNatural airway\t21%\t\nHospital day 3, time 6 : 15\tn/a\tn/a\t21\tNatural airway\t21%\t\nHospital day 3, time 10 : 39\tn/a\tn/a\t21\tNatural airway\t21%\t\nHospital day 3, time 15 : 38\tn/a\tn/a\t22\tNatural airway\t21%\t\nHospital day 3, time 17 : 26\tn/a\tn/a\t20\tNatural airway\t21%\t\nHospital day 3, time 21 : 14\tn/a\tn/a\t21\tNatural airway\t21%\t\nHospital day 4, time 2 : 30\tn/a\tn/a\t22\tNatural airway\t21%\t\nHospital day 4, time 8 : 39\tn/a\tn/a\t20\tNatural airway\t21%\t\nHospital day 4, time 14 : 44\tn/a\tn/a\t23\tNRM\t10 l/min\t\nHospital day 4, time 15 : 40\t47\t96\t21\tNRM\t10 l/min\t\nHospital day 4, time 17 : 13\t49\t124\t21\tCPAP\t100%\t\nHospital day 4, time 21 : 20\t48\t125\t20\tETT\t100%\t\nHospital day 4, time 23 : 27\tn/a\tn/a\t22\tETT\t40%\t\nHospital day 4, time 23 : 39\t68\t90\t22\tETT\t40%\t\nHospital day 5, time 1 : 05\t61\t63\t23\tETT\t40%\t\nHospital day 5, time 2 : 32\tn/a\tn/a\t22\tETT\t80%\t\nHospital day 5, time 2 : 33\t54\t94\t22\tETT\t80%\t\nHospital day 5, time 3 : 33\t47\t78\t21\tETT\t50%\t\nHospital day 5, time 4 : 22\tn/a\tn/a\t20\tETT\t50%\t\nHospital day 5, time 7 : 58\tn/a\tn/a\t21\tETT\t50%\t\nHospital day 5, time 8 : 28\t43\t83\t22\tETT\t50%\t\nHospital day 5, time 11 : 40\tn/a\tn/a\t22\tETT\t50%\t\nHospital day 5, time 16 : 39\tn/a\tn/a\t24\tETT\t50%\t\nHospital day 5, time 21 : 37\t41\t90\t21\tETT\t50%\t\nHospital day 6, time 4 : 05\tn/a\tn/a\t23\tETT\t40%\t\nHospital day 6, time 6 : 24\t42\t93\t26\tETT\t40%\t\nHospital day 6, time 10 : 20\tn/a\tn/a\t26\tETT\t40%\t\nHospital day 6, time 12 : 05\t42\t101\t27\tETT\t40%\t\nHospital day 6, time 15 : 05\tn/a\tn/a\t26\tCPAP\t25%\t\nHospital day 6, time 16 : 21\t37\t69\t27\tCPAP\t25%\t\nHospital day 6, time 22 : 29\tn/a\tn/a\t25\tNatural airway\t21%\t\nHospital day 7, time 4 : 10\tn/a\tn/a\t24\tCPAP\t25%\t\nHospital day 7, time 10 : 11\tn/a\tn/a\t29\tNatural airway\t21%\t\nHospital day 7, time 22 : 36\tn/a\tn/a\t26\tCPAP\t25%\t\nHospital day 8, time 7 : 32\tn/a\tn/a\t27\tCPAP\t25%\t\nCPAP, continuous positive airway pressure; ETT, endotracheal tube; L, liter; min, minute; mm Hg, millimeter of mercury; mmol, millimole; n/a, not available; NRM, non-rebreather mask.\n\nTable 2 Impact of physiologic changes of pregnancy on diagnostic findings associated with obesity hypoventilation syndrome.\n\nDiagnostic finding\tPertinent physiologic changes of pregnancy\tImpact of pregnancy on likelihood of meeting diagnostic criteria\t\nBMI >30 kg/m2\tHealthy weight gain in pregnancy, which can be up to 40 pounds\tIncreased likelihood\t\n\t\nAwake hypercapnia, PaCO2 >45 mm Hg\tProgesterone-mediated 40–50% increase in minute ventilation causing respiratory alkalosis\tDecreased likelihood\t\n\t\nAwake hypoxemia, PaO2 <70 mm Hg\tPaO2 increases 10 mm Hg during normal pregnancy due to hyperventilation, a lower PaCO2, and a smaller drop in venous oxygen concentration due to increased cardiac output\tDecreased likelihood\t\n\t\nElevated serum bicarbonate ≥27 mEq/L\tRespiratory alkalosis with renal compensation, which decreases plasma bicarbonate\tDecreased likelihood\t\n\t\nPolycythemia, hemoglobin >16 g/dL\tPhysiologic anemia of pregnancy, 30% increase in plasma volume with lower increase in red cell mass\tDecreased likelihood\t\n\t\nRestrictive lung pattern on PFT, FVC <80% predicted\tLung restriction due to enlarged uterus\tIncreased likelihood\t\n\t\nElevation diaphragm on chest X-ray\tElevation of diaphragm due to enlarged uterus\tIncreased likelihood\t\nBMI, body mass index; FVC, forced vital capacity; kg, kilogram; L, liter; m, meter; mEq, milliequivalent; mm Hg, millimeter of mercury; PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen; PFT, pulmonary function test.\n==== Refs\n1 Mokhlesi B. Kryger M. H. Grunstein R. R. Assessment and management of patients with obesity hypoventilation syndrome Proceedings of the American Thoracic Society 2008 5 2 218 225 10.1513/pats.200708-122mg 2-s2.0-39049158182 18250215\n2 Kessler R. Chaouat A. Schinkewitch P. The obesity-hypoventilation syndrome revisited Chest 2001 120 2 369 376 10.1378/chest.120.2.369 2-s2.0-0034821544 11502631\n3 Macavei V. M. Spurling K. J. Loft J. Makker H. K. Diagnostic predictors of obesity-hypoventilation syndrome in patients suspected of having sleep disordered breathing Journal of Clinical Sleep Medicine 2013 9 9 879 884 10.5664/jcsm.2986 2-s2.0-84888148627 23997700\n4 Mokhlesi B. Masa J. F. Brozek J. L. Evaluation and management of obesity hypoventilation syndrome. An official American thoracic society clinical practice guideline American Journal of Respiratory and Critical Care Medicine 2019 200 3 e6 e24 10.1164/rccm.201905-1071st 2-s2.0-85070877856 31368798\n5 Masa J. F. Pépin J.-L. Borel J.-C. Mokhlesi B. Murphy P. B. Sánchez-Quiroga M. Á. Obesity hypoventilation syndrome European Respiratory Review 2019 28 151 180097 10.1183/16000617.0097-2018 2-s2.0-85062962527\n6 Chau E. H. L. Lam D. Wong J. Mokhlesi B. Chung F. Warner D. S. Obesity hypoventilation syndrome Anesthesiology 2012 117 1 188 205 10.1097/aln.0b013e31825add60 2-s2.0-84862774867 22614131\n7 Mokhlesi B. Obesity hypoventilation syndrome: a state-of-the-art review Respiratory Care 2010 55 10 1347 1355 20875161\n8 Epstein J. N. Chaudhuri K. Santos A. C. Obstetric Anesthesia 2015 New York, NY, USA McGraw Hill Education\n9 Berg G. Delaive K. Manfreda J. Walld R. Kryger M. H. The use of health-care resources in obesity-hypoventilation syndrome Chest 2001 120 2 377 383 10.1378/chest.120.2.377 2-s2.0-0034821156 11502632\n10 Castro-Añón O. Pérez de Llano L. A. De la Fuente Sánchez S. Obesity-hypoventilation syndrome: increased risk of death over sleep apnea syndrome PLoS One 2015 10 2 e0117808 10.1371/journal.pone.0117808 2-s2.0-84923247486\n11 Nowbar S. Burkart K. M. Gonzales R. Obesity-associated hypoventilation in hospitalized patients: prevalence, effects, and outcome The American Journal of Medicine 2004 116 1 1 7 10.1016/j.amjmed.2003.08.022 2-s2.0-0346969989 14706658\n12 Priou P. Hamel J.-F. Person C. Long-term outcome of noninvasive positive pressure ventilation for obesity hypoventilation syndrome Chest 2010 138 1 84 90 10.1378/chest.09-2472 2-s2.0-77954713677 20348200\n13 Riley D. S. Barber M. S. Kienle G. S. CARE guidelines for case reports: explanation and elaboration document Journal of Clinical Epidemiology 2017 89 218 235 10.1016/j.jclinepi.2017.04.026 2-s2.0-85020746212 28529185\n14 Pellegrino R. Viegi G. Brusasco V. Interpretative strategies for lung function tests European Respiratory Journal 2005 26 5 948 968 10.1183/09031936.05.00035205 2-s2.0-24644496531\n15 Bromage P. R. A comparison of the hydrochloride and carbon dioxide salts of lidocaine and prilocaine in epidural analgesia Acta Anaesthesiologica Scandinavica 1965 16 55 69 10.1111/j.1399-6576.1965.tb00523.x 2-s2.0-84946684597 5322004\n16 Chau E. H. L. Mokhlesi B. Chung F. Obesity hypoventilation syndrome and anesthesia Sleep Medicine Clinics 2013 8 1 135 147 10.1016/j.jsmc.2012.11.006 2-s2.0-84875243255 23503584\n17 Iwashita A. Baba Y. Usui R. Ohkuchi A. Muto S. Matsubara S. Respiratory arrest in an obese pregnant woman with hyperemesis gravidarum Case reports in obstetrics and gynecology 2015 2015 278391 10.1155/2015/278391\n18 Facco F. L. Parker C. B. Reddy U. M. Association between sleep-disordered breathing and hypertensive disorders of pregnancy and gestational diabetes mellitus Obstetrics & Gynecology 2017 129 1 31 41 10.1097/aog.0000000000001805 2-s2.0-85001967130 27926645\n19 Dominguez J. E. Grotegut C. A. Cooter M. Krystal A. D. Habib A. S. Screening extremely obese pregnant women for obstructive sleep apnea American Journal of Obstetrics and Gynecology 2018 219 6 613.e1 613.e10 10.1016/j.ajog.2018.09.001 2-s2.0-85055553976 30217579\n20 BaHammam A. Acute ventilatory failure complicating obesity hypoventilation: update on a “critical care syndrome” Current Opinion in Pulmonary Medicine 2010 16 6 543 551 10.1097/mcp.0b013e32833ef52e 2-s2.0-77958151919 20829697\n21 Lin C.-C. Wu K.-M. Chou C.-S. Liaw S.-F. Oral airway resistance during wakefulness in eucapnic and hypercapnic sleep apnea syndrome Respiratory Physiology & Neurobiology 2004 139 2 215 224 10.1016/j.resp.2003.10.004 2-s2.0-1442360062 15123004\n22 De Lucas-Ramos P. De Miguel-Díez J. Santacruz-Siminiani A. González-Moro J. M. R. Buendía-García M. J. Izquierdo-Alonso J. L. Benefits at 1 year of nocturnal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome Respiratory Medicine 2004 98 10 961 967 10.1016/j.rmed.2004.03.014 2-s2.0-11144307426 15481272\n23 Heinemann F. Budweiser S. Dobroschke J. Pfeifer M. Non-invasive positive pressure ventilation improves lung volumes in the obesity hypoventilation syndrome Respiratory Medicine 2007 101 6 1229 1235 10.1016/j.rmed.2006.10.027 2-s2.0-34247590232 17166707\n24 Budweiser S. Riedl S. G. Jörres R. A. Heinemann F. Pfeifer M. Mortality and prognostic factors in patients with obesity-hypoventilation syndrome undergoing noninvasive ventilation Journal of Internal Medicine 2007 261 4 375 383 10.1111/j.1365-2796.2007.01765.x 2-s2.0-33947540321 17391112\n25 De Llano L. A. P. Golpe R. Piquer M. O. Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome Chest 2005 128 2 587 594 10.1378/chest.128.2.587 2-s2.0-23744486187 16100142\n26 Mokhlesi B. Tulaimat A. Faibussowitsch I. Wang Y. Evans A. T. Obesity hypoventilation syndrome: prevalence and predictors in patients with obstructive sleep apnea Sleep and Breathing 2007 11 2 117 124 10.1007/s11325-006-0092-8 2-s2.0-34248583558 17187265\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6390",
"issue": "2021()",
"journal": "Case reports in anesthesiology",
"keywords": null,
"medline_ta": "Case Rep Anesthesiol",
"mesh_terms": null,
"nlm_unique_id": "101581025",
"other_id": null,
"pages": "8096212",
"pmc": null,
"pmid": "34484837",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "30872398;11502631;20875161;16100142;23503584;16264058;28529185;17391112;31368798;30217579;17166707;20829697;14706658;26693367;15481272;20348200;25671545;15123004;22614131;27926645;17187265;5322004;23997700;11502632;18250215",
"title": "Diagnosis and Management of Obesity Hypoventilation Syndrome during Labor.",
"title_normalized": "diagnosis and management of obesity hypoventilation syndrome during labor"
} | [
{
"companynumb": "US-Appco Pharma LLC-2121669",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LABETALOL\\LABETALOL HYDROCHLORIDE"
},
"dru... |
{
"abstract": "Acute acalculous cholecystitis (AAC) is an inflammation of the gallbladder without the presence of gallstones. In children with malignancies or chemotherapy-induced neutropenia, AAC is very rare. Clinical diagnosis of AAC remains difficult in this patient population but an early recognition followed by an appropriate intervention may confer a benefit. Only three pediatric patients with underlying hematological malignancies whose clinical treatment course was complicated by the development of AAC have been described. We describe a neutropenic pediatric patient who developed AAC following chemotherapy for acute T-cell acute lymphoblastic leukemia (T-ALL), which was successfully managed with conservative treatment.\n\n\nBACKGROUND\nAAC: Acute acalculous cholecystitis; T-ALL: T-cell acute lymphoblastic leukemia; TPN: Total parenteral nutrition.",
"affiliations": "a Division of Paediatric Infections Disease , Royal Aberdeen Children's Hospital , Aberdeen , UK.;b Division of Paediatric Haemato-Oncology , Royal Aberdeen Children's Hospital , Aberdeen , UK.;c Department of Radiology , Aberdeen Royal Infirmary , Aberdeen , UK.;d Division of Paediatric Infectious Disease , Royal Aberdeen Children's Hospital , Aberdeen , UK.",
"authors": "Naselli|Aldo|A|;Bishop|Hugh|H|;Walker|Shonagh|S|;Warris|Adilia|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/08880018.2016.1265034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0888-0018",
"issue": "34(1)",
"journal": "Pediatric hematology and oncology",
"keywords": "AAC; T-LLA; conservative management; neutropenic fever",
"medline_ta": "Pediatr Hematol Oncol",
"mesh_terms": "D042101:Acalculous Cholecystitis; D002648:Child; D006801:Humans; D008297:Male; D009503:Neutropenia; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "8700164",
"other_id": null,
"pages": "24-28",
"pmc": null,
"pmid": "28085529",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neutropenic acute acalculous cholecystitis (AAC) in a 12-year-old boy with T-acute lymphoblastic leukemia successfully managed with conservative treatment.",
"title_normalized": "neutropenic acute acalculous cholecystitis aac in a 12 year old boy with t acute lymphoblastic leukemia successfully managed with conservative treatment"
} | [
{
"companynumb": "GB-PFIZER INC-2017191315",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE SODIUM PHOSPHATE"
},
"drugadditi... |
{
"abstract": "Pleuropericardial effusion is an extremely rare complication of gemcitabine chemotherapy. The patient was a 56-year-old woman administered systemic chemotherapy with gemcitabine for local recurrence of pancreatic cancer and lymph node metastasis developing 4 years after pancreaticoduodenectomy. Four months after the start of the chemotherapy, she presented with exertional dyspnea and edema in both her legs and face. Echocardiography and computed tomography revealed pericardial and bilateral pleural effusion. A pericardiocentesis was immediately performed to prevent the development of cardiac tamponade as well as to examine the cause of the pericardial effusion. As a result, the patient's exertional dyspnea and edema resolved. No metastases to the thorax or mediastinum were noted. A cytological study of the pericardial and pleural effusions revealed no malignant cells. Cultures for bacteria, mycobacteria and fungi were negative. Tests for autoantibodies indicating autoimmune disease were also negative, and hormonal assays for the detection of endocrine disease were normal. She was followed up after discontinuation of the gemcitabine treatment, and no further episodes of pericardial or pleural effusion occurred. Thus, it is speculated that the pericardial effusion and bilateral pleural effusion may have been caused by gemcitabine.",
"affiliations": "Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Tokyo 104-0045, Japan.",
"authors": "Kido|Hidenori|H|;Morizane|Chigusa|C|;Tamura|Tetsutaro|T|;Hagihara|Atsushi|A|;Kondo|Shunsuke|S|;Ueno|Hideki|H|;Okusaka|Takuji|T|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hys099",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "42(9)",
"journal": "Japanese journal of clinical oncology",
"keywords": null,
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010190:Pancreatic Neoplasms; D016577:Pancreaticoduodenectomy; D010490:Pericardial Effusion; D010996:Pleural Effusion",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "845-50",
"pmc": null,
"pmid": "22782959",
"pubdate": "2012-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gemcitabine-induced pleuropericardial effusion in a patient with pancreatic cancer.",
"title_normalized": "gemcitabine induced pleuropericardial effusion in a patient with pancreatic cancer"
} | [
{
"companynumb": "JP-PFIZER INC-2020437030",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Seizures and epilepsy are a common problem in childhood. Nonepileptic paroxysmal events are conditions that can mimic seizure and frequent in early childhood. Nonepileptic paroxysmal events can be due to physiological or exaggerated physiological responses, parasomnias, movement disorders, behavioral or psychiatric disturbances, or to hemodynamic, respiratory, or gastrointestinal dysfunction. Vitamin B12 deficiency is a treatable cause of failure to thrive and developmental regression, involuntary movements, and anemia. Involuntary movements rarely may appear a few days after the initiation of vitamin B12 treatments and might be misdiagnosed as seizure. Here, we report 2 patients who presented with involuntary movements with his video image.",
"affiliations": "From the Divisions of *Pediatric Neurology and †Pediatric Hematology, Gaziantep Children's Hospital, Gaziantep, Turkey.",
"authors": "Carman|Kursat Bora|KB|;Belgemen|Tugba|T|;Yis|Uluc|U|",
"chemical_list": "D002998:Clonazepam; D014805:Vitamin B 12",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0b013e3182aa475e",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "29(11)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D001284:Atrophy; D001921:Brain; D001942:Breast Feeding; D002998:Clonazepam; D003951:Diagnostic Errors; D004409:Dyskinesia, Drug-Induced; D004569:Electroencephalography; D004630:Emergencies; D004828:Epilepsies, Partial; D005260:Female; D006130:Growth Disorders; D006801:Humans; D007223:Infant; D007273:Injections, Intramuscular; D008279:Magnetic Resonance Imaging; D008297:Male; D008895:Milk, Human; D011595:Psychomotor Agitation; D013226:Status Epilepticus; D014805:Vitamin B 12; D014806:Vitamin B 12 Deficiency",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "1223-4",
"pmc": null,
"pmid": "24196096",
"pubdate": "2013-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": null,
"title": "Involuntary movements misdiagnosed as seizure during vitamin B12 treatment.",
"title_normalized": "involuntary movements misdiagnosed as seizure during vitamin b12 treatment"
} | [
{
"companynumb": "TR-WATSON-2014-16202",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYANOCOBALAMIN"
},
"drugadditional": null,
... |
{
"abstract": "Abciximab reduces major adverse cardiac events in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention (pPCI). Standard protocol is intravenous abciximab bolus during PCI plus abciximab infusion for 12-18 h post pPCI. Intracoronary (IC) abciximab bolus administration results in high local drug concentrations and hence it should have higher antiplatelet effect. In this study, we assess the short-term efficacy and safety of IC compared to IV bolus of abciximab in ACS patients during pPCI.\nWe compared the clinical outcomes between the IC (n = 56) and standard protocol (n = 170) group of patients. Primary endpoints included bleeding/vascular/ischemic complications and MACE.\nThe two groups were similar with respect to baseline characteristics. IC abciximab bolus only reduced bleeding complications, with no moderate bleed versus 7.2% in standard protocol group (p value 0.04). Ischemic/vascular complications had statistically insignificant difference between the two groups.\nWe found no significant difference between IC abciximab bolus only and standard abciximab therapy in terms of ischemic/vascular complications and MACE. But there was higher risk of moderate bleed in standard therapy group. The IC bolus route of abciximab may be superior to the intravenous route. Prospective randomized trials are warranted to validate these findings.",
"affiliations": "Mount Auburn Hospital, Cambridge, MA.;Mount Auburn Hospital, Cambridge, MA.;Aga Khan University, Karachi, Pakistan.",
"authors": "Shakoor|Muhammad Tariq|MT|;Ayub|Samia|S|;Dhakam|Sajid|S|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.ijchv.2014.03.007",
"fulltext": "\n==== Front\nInt J Cardiol Heart VesselInt J Cardiol Heart VesselInternational Journal of Cardiology. Heart & Vessels2214-7632Elsevier S2214-7632(14)00017-010.1016/j.ijchv.2014.03.007Original ArticleComplications of intracoronary abciximab bolus-only versus standard protocol during percutaneous coronary intervention in acute coronary syndrome Shakoor Muhammad Tariq mts2703@hotmail.com*Ayub Samia Mount Auburn Hospital, Cambridge, MADhakam Sajid Aga Khan University, Karachi, Pakistan* Corresponding author at: Baystate Medical Center, MA, United States. Tel.: + 1 413 231 2431 (Cell)Corresponding author at: Baystate Medical CenterTel.: + 1 413 231 2431 (Cell)MAUnited States mts2703@hotmail.com19 3 2014 6 2014 19 3 2014 3 64 67 26 2 2014 10 3 2014 © 2014 The Authors2014This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Background\nAbciximab reduces major adverse cardiac events in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention (pPCI). Standard protocol is intravenous abciximab bolus during PCI plus abciximab infusion for 12–18 h post pPCI. Intracoronary (IC) abciximab bolus administration results in high local drug concentrations and hence it should have higher antiplatelet effect. In this study, we assess the short-term efficacy and safety of IC compared to IV bolus of abciximab in ACS patients during pPCI.\n\nMethods\nWe compared the clinical outcomes between the IC (n = 56) and standard protocol (n = 170) group of patients. Primary endpoints included bleeding/vascular/ischemic complications and MACE.\n\nResults\nThe two groups were similar with respect to baseline characteristics. IC abciximab bolus only reduced bleeding complications, with no moderate bleed versus 7.2% in standard protocol group (p value 0.04). Ischemic/vascular complications had statistically insignificant difference between the two groups.\n\nConclusion\nWe found no significant difference between IC abciximab bolus only and standard abciximab therapy in terms of ischemic/vascular complications and MACE. But there was higher risk of moderate bleed in standard therapy group. The IC bolus route of abciximab may be superior to the intravenous route. Prospective randomized trials are warranted to validate these findings.\n\nKeywords\nPrimary percutaneous coronary interventionAcute coronary syndromeAbciximab\n==== Body\n1 Introduction\nPrimary percutaneous coronary intervention (pPCI) is the ideal and standard regimen in restoring epicardial perfusion in a ST-elevation myocardial infarction (STEMI) [1]. Adjunctive therapy with glycoprotein IIb/IIIa receptor inhibitor (GPI) aims at coronary microcirculation and improves the myocardial tissue perfusion which has considerable prognostic impact 2, 3. There is robust data available in literature that supports the beneficial anti-ischemic effects of GPI use during PCI decreasing major adverse cardiac events (MACE) 4, 5, 6.\n\nIntravenous abciximab is the standard route of administration, and has been studied in various clinical trials. Standard protocol is intravenous abciximab bolus during PCI plus abciximab infusion for 12–18 h post pPCI. If given as an intracoronary (IC) bolus, it is expected to produce high local concentrations at the PCI site with higher anti platelet action, although at present clinical experience in the efficacy of intracoronary abciximab administration is limited 3, 7, 8, 9, 10. Hence we are conducting this study in order to compare the short-term efficacy and safety of IC compared to IV bolus of abciximab in ACS patients during pPCI.\n\n2 Methods\n2.1 Patient population\nThe study was approved by our ethical and research committee. Patient consent for analysis of their data was standard. There were a total of 170 patients in the standard therapy group versus 56 patients in IC abciximab bolus only.\n\nInclusion criteria: We included all ACS patients who underwent PCI from November 2007–December 2009 and received IC or IV bolus of abciximab with the procedure.\n\nExclusion criteria: Patients who presented with cardiogenic shock, those who could not get the drug due to any compelling contraindications or got GPI other than abciximab were excluded from the study population.\n\n2.2 Periprocedure pharmacology\nAll the patients got standard therapy for acute coronary syndrome like aspirin (300 mg), clopidogrel (300–600 mg) and intravenous heparin (60 units/kg) before they are wheeled to the cath lab, as per standard guidelines. Abciximab was given as 0.25 mg/kg bolus plus 0.125 μg/kg/min infusion for 12 h or 0.15–0.25 mg/kg IC bolus only during the coronary intervention, and hence the two groups were IC abciximab bolus only or IV abciximab bolus plus infusion.\n\n2.3 Study endpoints\nOur primary endpoints were vascular, bleeding, ischemic complications and MACE as summarized in Table 1. Vascular complications included pseudoaneurysm, arteriovenous fistula, dissection and loss of distal pulse. Bleeding complications were classified as major, moderate and mild as per GUSTO classification [11]. It included percutaneous entry site bleeding and bleeding other than the entry site (e.g. retroperitoneal, gastrointestinal, genitourinary), diagnosed on clinical grounds but confirmed by further imaging.Table 1 Study endpoints.\n\nVascular complications\tPseudoaneurysm, AV fistula, dissection, loss of distal pulse\t\nBleeding complications\tMild, moderate and major\t\nIschemic complications\tPeri-procedural CK-MB elevation (≥ 3 times upper normal limit), acute or subacute stent thrombosis, unplanned CABG, repeat target vessel revascularization\t\nMACE (major adverse cardiac events)\tComposite of death, urgent target vessel revascularization and periprocedural CK-MB elevation ≥ 3 times upper normal limit\t\n\n\nIschemic complications comprised of peri-procedural CK-MB elevation (≥ 3 times upper normal limit), acute or subacute stent thrombosis, unplanned CABG and repeat target vessel revascularization.\n\nMACE was the composite of death, urgent target vessel revascularization and periprocedural CK-MB elevation ≥ 3 times upper normal limit. Data was retrieved from the files of the respective patients by the research staff that was not related to the cardiac intervention.\n\n2.4 Statistical analysis\nStatistical analysis was performed using SPSS 17. Percentages were used to express categorical data and Chi-square test was used for comparison. Continuous variables were expressed as mean ± standard deviation and compared with Student t test. A p-value of ≤ 0.05 was considered significant.\n\n3 Results\n3.1 Baseline clinical characteristics\nThey were similar in both the groups as reported in Table 2, however there was a higher prevalence of dyslipidemia in bolus plus infusion group (p < 0.01). Also more people had a history of prior PCI in the bolus only group with statistical significant p value. All the patients received aspirin, clopidogrel and heparin in their initial emergency management. When we take a look at acute coronary syndrome distribution between two groups, bolus only group has higher number of STEMI patients and standard therapy group mainly consists of unstable angina and NSTEMI but p value was not significant. All the variations in the baseline characteristics were adjusted by using logistic regression.Table 2 Baseline clinical characteristics.\n\n\tStandard therapy (n = 170)\tIC bolus only (n = 56)\tp\t\nFamily history of premature CAD (< 50 years) (%)\t38 (22.4)\t13 (23.2)\t0.89\t\nDyslipidemia (%)\t122 (71.8)\t22 (39.3)\t< 0.01\t\nDiabetes (%)\t60 (35.3)\t16 (28.6)\t0.36\t\nHypertension (%)\t87 (51.2)\t30 (53.6)\t0.76\t\nSmoking (%)\t62 (36.5)\t22 (39.3)\t0.71\t\nPrior history of CHF (%)\t6 (3.5)\t2 (3.6)\t0.98\t\nPrior MI (%)\t36 (21.2)\t12 (21.4)\t0.97\t\nCerebrovascular disease (%)\t6 (3.5)\t0\t0.15\t\nPeripheral vascular disease (%)\t0\t1 (1.8)\t0.08\t\nPrevious CABG (%)\t5 (2.9)\t3 (5.4)\t0.39\t\nPrevious PCI (%)\t8 (4.7)\t13 (23.2)\t< 0.01\t\n\n\n\t\nMedications\t\nAspirin (%)\t170 (100)\t54 (96.4)\t0.06\t\nClopidogril (%)\t156 (91.8)\t54 (96.4)\t0.38\t\nHeparin (%)\t139 (81.8)\t45 (80.4)\t0.81\t\nAngina/NSTEMI/STEMI (%)\t35 (22)/32 (20.1)/92 (57.9)\t5 (8.9)/10 (17.9)/41 (73.2)\t0.06\t\n\n\n3.2 Angiographic characteristics\nAngiographic characteristics were almost the same in both the groups as shown in Table 3. Except more patients in standard therapy group achieved post PCI TIMI III flow as compared to bolus only group and probably it can be described by more high risk lesions in bolus only group.Table 3 Angiographic characteristics.\n\n\tStandard therapy %\tIC bolus only %\tp-Value\t\nVessel disease\t\t\t\t\nSingle vessel\t48.9\t43.8\t0.76\t\nDouble vessel\t37.8\t46.9\t\t\nTriple vessel\t10.4\t6.3\t\t\nTIMI flow\t\t\t\t\nPre I/II/III\t13/8.4/46.6\t12.5/3.1/34.4\t0.24\t\nPost I/II/III\t1.5/9.9/88.5\t3.1/9.4/81.3\t0.03\t\nDirect stenting\t17.6\t37.5\t0.04\t\nAspiration device\t30.2\t31.3\t\t\nPCI to graft\t0.8\t0\t0.65\t\nPCI to > single vessel\t0.1\t0.01\t0.54\t\nLesion risk\t\t\t\t\nLow/medium/high\t9.9/41.2/46.6\t9.4/6.3/78.1\t0.002\t\nNo reflow\t6.9\t3.1\t0.11\t\n\n\n3.3 Vascular/bleeding complications\nWe found no difference in terms of vascular complications. But when bleeding complications were stratified into major, moderate and mild, we found that moderate bleed was higher in standard therapy group as compared to bolus only group (p value = 0.04) as per Table 4.Table 4 Vascular and bleeding complications.\n\n\tStandard therapy (n = 170)\tIC bolus only (n = 56)\tp\t\nPercutaneous entry site complications (%)\t24 (21.6)\t7 (12.5)\t.15\t\nBleeding (req. surgery/transfusion) (%)\t16 (14.4)\t6 (10.7)\t.50\t\nOcclusion (%)\t0\t0\t\t\nLoss of distal pulse (%)\t5 (4.5)\t0\t.10\t\nDissection (%)\t0\t0\t\t\nPseudo-aneurysm (%)\t1 (0.9)\t1 (1.8)\t.62\t\nAV-fistula (%)\t0\t0\t\t\nPeripheral embolization (%)\t0\t0\t\t\nInfection (%)\t3 (2.7)\t0\t.21\t\nThrombocytopenia (%)\t4 (3.6)\t3 (5.4)\t.60\t\nBleeding not related to percutaneous entry site (%)\t13 (11.7)\t2 (3.6)\t.08\t\nRetroperitoneal bleeding (%)\t1 (0.9)\t0\t.48\t\nGastrointestinal bleeding (%)\t6 (5.4)\t1 (1.8)\t.27\t\nGenital-Urinary bleeding (%)\t4 (3.6)\t1 (1.8)\t.51\t\nBleeding-other/unknown cause (%)\t3 (2.7)\t0\t.21\t\nMajor bleed (%)\t0\t0\t\t\nModerate bleed (%)\t8 (7.2)\t0\t.04\t\nMild bleed (%)\t25 (22.5)\t7 (12.5)\t.12\t\n\n\n3.4 Ischemic complication and MACE\nIschemic complications had statistically insignificant difference between the two groups. MACE for in hospital stay was the same in both groups. Study endpoints summarized in Table 5.Table 5 Study endpoints.\n\n\tStandard therapy % (n = 170)\tIC bolus only % (n = 56)\tp-Value\t\nVascular complications\t18.9 (21)\t12.5 (7)\t0.29\t\nBleeding complications\t11.7 (13)\t3.6 (2)\t0.08\t\nPeriprocedural CK-MB elevation > 3 × upper normal limit\t67.9 (19)\t74.5 (38)\t0.52\t\nStent thrombosis\t1.8 (2)\t0\t0.31\t\nUrgent target vessel revascularization\t1.8 (2)\t0\t0.31\t\nDeath\t3.6 (4)\t3.6 (2)\t0.98\t\nMACE (in hospital stay)\t71.9 (23)\t75 (39)\t0.75\t\n\n\n4 Discussion\nGlycoprotein IIb/IIIa receptors are present on the platelet surface and mediate the final common pathway of platelet aggregation, which plays an important role in the formation of a platelet plug [12]. GPI are potent platelet antagonists that inhibit aggregation of platelets at the site of a disrupted plaque during PCI. There are three well known GPI; abciximab, eptifibatide and tirofiban. Some studies show that eptifibatide and tirofiban are non-inferior to abciximab and some show abciximab is superior 13, 14, 15. Most of the hospitals don't use abciximab because of the cost issues [16].\n\nIn vitro studies have demonstrated that there is nearly complete saturation of glycoprotein IIb/IIIa receptors with abciximab concentration of 0.034 μmol/L, which corresponds to an IV bolus of 0.15 mg/kg. This abciximab concentration inhibits 75% of the mechanical effects of platelets on fibrin [17]. This stands as a strong base to hypothesize that small dose of local abciximab bolus is enough to achieve maximum efficacy.\n\nThe standard practice of GPI administration is, as an intravenous bolus during the PCI procedure followed by a prolonged 12 to 18 h of infusion 18, 19. The need for an infusion was established by the evaluation of c7E3 (chimeric monoclonal-antibody Fab fragment directed against the platelet glycoprotein IIb/IIIa receptor) for the prevention of ischemic complications in EPIC trial which supported that the primary composite endpoint death, myocardial infarction and urgent revascularization reduced a greater degree in the arm with abciximab bolus followed by a 12-hour infusion, compared with IV abciximab bolus-only at 30 days and at late follow-up [18]. However bleeding complications were higher in the former group. We should consider the fact that the EPIC trial was conducted during the percutaneous transluminal coronary balloon angioplasty (PTCA) era, when threat of acute thrombotic complications outweighed over the concerns of bleeding. With the advent of stents and thienopyridine use, there has been a considerable decrease in the incidence of acute stent thrombosis.\n\nIn our study no difference was seen in stent thrombosis or other ischemic complications between the two groups. Also in hospital stay MACE was statistically similar in both bolus and bolus plus infusion arms, this is in accordance with Kini et al. [20], but literature does show reduction of long term outcomes of death and MI in patients who got intracoronary bolus of abciximab rather than the regular intravenous route [9].\n\nIn literature, decrease in vascular/bleeding complication was found with bolus dosing versus infusion, [21] however in our study statistically significant difference was not found between the two groups, although when, the variable, bleeding was stratified into major, moderate and minor, reduction in moderate bleed was observed in the bolus only group (p = 0.04).\n\nData advocates that IC bolus administration targets at the PCI site precisely and therefore decrease the infarct size and improves microvascular perfusion 3, 21. According to CICERO trial (N = 530) IC administration of abciximab is associated with improved myocardial reperfusion as assessed by myocardial blush grade and a smaller enzymatic infarct size [22]. This may be the reason that despite high-risk lesions (p < 0.01) in the bolus only group we were able to achieve post PCI TIMI III flow also seen by Romagnoli et al. [23].\n\nFour meta-analysis studies comparing IC versus IV abciximab administration in the setting of pPCI have been published recently and all spreading a consistent message, showing superiority of IC over IV administration of abciximab regarding clinical outcome further reinforcing our results 24, 25, 26, 27, 28, 29, 30, 31. Holger Thiele and colleagues reported no mortality difference between interventions in the AIDA STEMI trial [24] but this randomized control trial has been criticized a lot with respect to study methodology [32].\n\nAlso in some recent trials researchers concluded that abciximab bolus only was associated with similar outcomes compared with bolus followed by infusion 33, 34 and it is of notice that in the new treatment regimen there is not only a decrease in the dose of the bolus, but also infusion is discontinued relative to the standard treatment strategy. Moreover, the route of administration is IC, which will provide high local concentrations of abciximab at the PCI site. As mentioned above this therapeutic range of bolus is adequate to inhibit maximum platelet aggregation in order to produce the desired anti-platelet action. Therefore by administering an appropriate dosage of bolus (according to the weight of a patient) that lies within this therapeutic range, and not giving the infusion of abciximab we bring down the cost substantially down which is one of the biggest hurdle towards using abciximab in most of the hospital. Another big randomized trial (COCTAIL II) is on its way, comparing IC bolus versus standard protocol, with the endpoint of number of cross-sections with thrombus area more than 10% immediately after stent implantation [35]. Hopefully this study will help us in revising the protocol.\n\n5 Study limitations\nIt is a descriptive type of study. Another major limitation of this study is the sample size of the bolus only group, because intracoronary abciximab bolus dose is an emerging strategy.\n\n6 Conclusion\nWe found no significant difference between IC abciximab bolus only and standard abciximab therapy in terms of ischemic, vascular complications and MACE. But there was higher risk of moderate bleed in standard therapy group. Hence, adopting a bolus only GPI strategy via IC route would not only provide the desired early protective anti-ischemic action but also reduce the bleeding complications. The IC bolus route of abciximab may be superior to the intravenous route. Prospective randomized trials are warranted to validate these findings.\n\nAvailable online 19 March 2014\n==== Refs\nReferences\n1 Antman E.M. Anbe D.T. Armstrong P.W. Bates E.R. Green L.A. Hand M. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: executive summary Circulation 110 2004 588 636 15289388 \n2 Lerman A. Holmes D.R. Herrmann J. Gersh B.J. Microcirculatory dysfunction in ST-elevation myocardial infarction: cause, consequence, or both? Eur Heart J 28 2007 788 797 17347176 \n3 Thiele H. Schindler K. Friedenberger J. Eitel I. Fürnau G. Grebe E. Intracoronary compared with intravenous bolus abciximab application in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. The randomized Leipzig immediate percutaneous coronary intervention abciximab IV versus IC in ST-elevation myocardial infarction trial Circulation 118 2008 49 57 18559698 \n4 Topol E.J. Lincoff A.M. Kereiakes D.J. Kleiman N.S. Cohen E.A. Ferguson J.J. Multi-year follow-up of abciximab therapy in three randomized, placebo-controlled trials of percutaneous coronary revascularization Am J Med 113 2002 1 6 12106616 \n5 EPISTENT Investigators Randomised placebo-controlled and balloon- angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade Lancet 352 1998 87 92 9672272 \n6 Investigators I.M.P.A.C.T.-I.I. Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II Lancet 349 1997 1422 1428 9164315 \n7 Bellandi F. Maioli M. Gallopin M. Toso A. Dabizzi R.P. Increase of myocardial salvage and left ventricular function recovery with intracoronary abciximab downstream of the coronary occlusion in patients with acute myocardial infarction treated with primary coronary intervention Catheter Cardiovasc Interv 62 2004 186 192 15170708 \n8 Galache Osuna J.G. Sánchez-Rubio J. Calvo I. Diarte J.A. Lukic A. Placer L.J. Does intracoronary abciximab improve the outcome of percutaneous coronary interventions? A randomized controlled trial [in Spanish] Rev Esp Cardiol 59 2006 567 574 16790200 \n9 Kakkar A.K. Moustapha A. Hanley H.G. Weiss M. Caldito G. Misra P. Comparison of intracoronary vs. intravenous administration of abciximab in coronary stenting Catheter Cardiovasc Interv 61 2004 31 34 14696156 \n10 Wöhrle J. Grebe O.C. Nusser T. Al-Khayer E. Schaible S. Kochs M. Reduction of major adverse cardiac events with intracoronary compared with intravenous bolus application of abciximab in patients with acute myocardial infarction or unstable angina undergoing coronary angioplasty Circulation 107 1840–1843 2003 \n11 Rao S.V. O'Grady K. Pieper K.S. Granger C.B. Newby L.K. Mahaffey K.W. A comparison of the clinical impact of bleeding measured by two different classifications among patients with acute coronary syndromes J Am Coll Cardiol 47 4 Feb 21 2006 809 816 [Epub 2006 Jan 26] 16487850 \n12 Harker L.A. Role of platelets and thrombosis in mechanisms of acute occlusion and restenosis after angioplasty Am J Cardiol 60 Suppl. 1987 20B 28B 3604939 \n13 Valgimigli M. Campo G. Percoco G. Bolognese L. Vassanelli C. Colangelo S. The MULTISTRATEGY randomized trial JAMA 299 15 2008 1788 1799 18375998 \n14 Zeymer U. Margenet A. Haude M. Bode C. Lablanche J.M. Heuer H. EVA-AMI trial JACC 56 6 Aug 3 2010 463 469 20670755 \n15 Deliargyris E.N. Upadhya B. Applegate R.J. Kutcher M.A. Gandhi S.K. Sane D.C. Superior in-hospital and 30-day outcomes with abciximab versus eptifibatide: a contemporary analysis of 495 consecutive percutaneous coronary interventions J Invasive Cardiol 16 11 2004 \n16 Investigators P.R.I.C.E. Comparative 30-day economic and clinical outcomes of platelet glycoprotein IIb/IIIa inhibitor use during elective percutaneous coronary intervention: Prairie ReoPro versus Integrilin Cost Evaluation (PRICE) trial Am Heart J 141 3 Mar 2001 402 409 11231437 \n17 Collet J.P. Montalescot G. Lesty C. Soria J. Mishal Z. Thomas D. Disaggregation of in-vitro preformed platelet-rich clots by abciximab increases fibrin exposure and fibrinolysis Arterioscler Thromb Vasc Biol 21 2001 142 148 11145946 \n18 The E.P.I.C. Investigators Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty N Engl J Med 330 1994 956 961 8121459 \n19 The E.S.P.R.I.T. investigators Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial Lancet 356 2000 2037 2044 11145489 \n20 Kini A.S. Chen V.H. Krishnan P. Lee P. Kim M.C. Mares A. Bolus-only versus bolus + infusion of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention Am Heart J 156 3 2008 Sep 513 519 18760134 \n21 Gu Y.L. Kampinga M.A. Wieringa W.G. Fokkema M.L. Nijsten M.W. Hillege H.L. Intracoronary versus intravenous administration of abciximab in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention with thrombus aspiration: the comparison of intracoronary versus intravenous abciximab administration during emergency reperfusion of ST-segment elevation myocardial infarction (CICERO) trial Circulation 122 25 2010 Dec 21 2709 2717 21098442 \n22 Romagnoli E. Burzotta F. Trani C. Mazzari M.A. Biondi-Zoccai G.G. De Vita M. Angiographic evaluation of the effect of intracoronary abciximab administration in patients undergoing urgent PCI Int J Cardiol 105 2005 250 255 16274764 \n23 Thiele H. Wöhrle J. Neuhaus P. Brosteanu O. Sick P. Prondzinsky R. Intracoronary compared with intravenous bolus abciximab application during primary percutaneous coronary intervention: design and rationale of the Abciximab Intracoronary versus intravenously Drug Application in ST-Elevation Myocardial Infarction (AIDA STEMI) trial Am Heart J 159 4 Apr 2010 547 554 20362711 \n24 Shimada Y.J. Nakra N.C. Fox J.T. Kanei Y. Meta-analysis of prospective randomized controlled trials comparing intracoronary versus intravenous abciximab in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention Am J Cardiol 109 2012 624 628 22152971 \n25 Piccolo R. Gu Y.L. Iversen A.Z. Dominguez-Rodriguez A. de Smet B.J. Mahmoud K.D. Clinical impact of intracoronary abciximab in patients undergoing primary percutaneous coronary intervention: an individual patient data pooled analysis of randomized studies Heart 2012 \n26 Wang Y. Wu B. Shu X. Meta-analysis of randomized controlled trials comparing intracoronary and intravenous administration of glycoprotein IIb/IIIa inhibitors in patients with ST-elevation myocardial infarction Am J Cardiol 109 2012 1124 1130 22245413 \n27 Navarese E.P. Kozinski M. Obonska K. Margheri M. Gurbel P.A. Kubica J. Clinical efficacy and safety of intracoronary vs. intravenous abciximab administration in STEMI patients undergoing primary percutaneous coronary intervention: a meta-analysis of randomized trials Platelets 23 4 June 2012 274 281 21988317 \n28 Thiele H. Wöhrle J. Hambrecht R. Rittger H. Birkemeyer R. Lauer B. Intracoronary versus intravenous bolus abciximab during primary percutaneous coronary intervention in patients with acute ST-elevation myocardial infarction: a randomised trial Lancet 379 2012 923 931 22357109 \n29 Prati F. Capodanno D. Pawlowski T. Ramazzotti V. Albertucci M. La Manna A. Local delivery versus intracoronary infusion of abciximab in patients with acute coronary syndromes JACC Cardiovasc Interv 3 9 Sep 2010 928 934 20850091 \n30 Iversen A. Abildgaard U. Galloe A. Hansen P.R. Galatius S. Madsen J.K. Intracoronary compared to intravenous bolus abciximab during primary percutaneous coronary intervention in ST-segment elevation myocardial infarction (STEMI) patients reduces 30-day mortality and target vessel revascularization: a randomized trial J Interv Cardiol 24 2 2011 \n31 Eitel I. Friedenberger J. Fuernau G. Dumjahn A. Desch S. Schuler G. Intracoronary versus intravenous bolus abciximab application in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: 6-month effects on infarct size and left ventricular function Clin Res Cardiol 100 5 May 2011 425 432 [Epub 2010 Dec 2] 21125288 \n32 Iddriss A. Mortality in intracoronary versus intravenous abciximab Lancet 380 9836 July 7 2012 25 \n33 Bagur R. Bertrand OF Rodés-Cabau J. Larose E. Rinfret S. Nguyen C.M. Long term efficacy of abciximab bolus-only compared to abciximab bolus and infusion after transradial coronary stenting Catheter Cardiovasc Interv 74 7 Dec 1 2009 1010 1016 19753635 \n34 Bertrand O.F. Rodés-Cabau J. Larose E. Nguyen C.M. Roy L. Déry J.P. One-year clinical outcome after abciximab bolus-only compared with abciximab bolus and 12-hour infusion in the randomized early discharge after transradial stenting of coronary arteries (EASY) study Am Heart J 156 1 2008 Jul 135 140 18585508 \n35 Prati F. Di Vito L. Ramazzotti V. Imola F. Pawlowski T. Materia L. Randomized trial of standard versus ClearWay-infused abciximab and thrombectomy in myocardial infarction: rationale and design of the COCTAIL II study J Cardiovasc Med (Hagerstown) 14 5 2013 May 364 371 22929568\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-7632",
"issue": "3()",
"journal": "International journal of cardiology. Heart & vessels",
"keywords": "Abciximab; Acute coronary syndrome; Primary percutaneous coronary intervention",
"medline_ta": "Int J Cardiol Heart Vessel",
"mesh_terms": null,
"nlm_unique_id": "101640846",
"other_id": null,
"pages": "64-67",
"pmc": null,
"pmid": "29450173",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
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"title": "Complications of intracoronary abciximab bolus-only versus standard protocol during percutaneous coronary intervention in acute coronary syndrome.",
"title_normalized": "complications of intracoronary abciximab bolus only versus standard protocol during percutaneous coronary intervention in acute coronary syndrome"
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"abstract": "Serotonin-active drugs are detected relatively frequently in Victorian deaths. During 2002-2008, there were 1123 fatalities where one or more of the serotonin-active drugs tramadol, venlafaxine, fluoxetine, sertraline, citalopram, paroxetine and MDMA, were detected. These deaths were reviewed using pathology, toxicology and police reports, to determine the contribution of these drugs to the cause of death, particularly if serotonin toxicity was the mechanism of death. There were 28 cases of most interest to this research because of the presence of the target drugs and the circumstances suggesting the likelihood of serotonin toxicity involvement in death. There were 5 cases of reported serotonin toxicity and 23 other deaths suspected to have involved this form of toxicity. Tramadol featured most commonly out of the seven target drugs and was frequently detected in combination with serotonergic antidepressants. MDMA was also detected relatively commonly and was associated with moclobemide in 4 cases of confirmed serotonin toxicity. There were an additional 1095 cases where natural disease, external injury or the misuse of other drugs caused death, of which 2 reported the incidental contribution of serotonin toxicity.",
"affiliations": "Victorian Institute of Forensic Medicine, Department of Forensic Medicine, Monash University, Victoria, Australia.",
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"delete": false,
"doi": "10.1016/j.forsciint.2010.01.014",
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"issue": "198(1-3)",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D002423:Cause of Death; D015283:Citalopram; D003511:Cyclohexanols; D005260:Female; D005473:Fluoxetine; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D017374:Paroxetine; D018490:Serotonin Agents; D020280:Sertraline; D014147:Tramadol; D000069470:Venlafaxine Hydrochloride",
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"publication_types": "D016428:Journal Article",
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"title": "Deaths involving serotonergic drugs.",
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"abstract": "This is an observational-retrospective study comparing the real-world outcomes associated with posaconazole vs itraconazole as prophylaxis treatments. Two hundred and ninety-three patient admissions attributable to 174 patients were included in the study. Patients were treated with itraconazole (n = 114 admissions; 39%) or posaconazole (n = 179; 61%). Antifungal prophylaxis failure (APF) due to treatment-related adverse events (in 34 out of 293 patient admissions; 11.6%) was more frequent in the posaconazole group (6.1% vs 15.1%; P = .024). There were 9 patient admissions for episodes of APF due to probable/proven breakthrough fungal infection (primary endpoint): 6 and 3 in the itraconazole and posaconazole group respectively (5.3% vs 1.7%; P = .095). All of them were associated with invasive pulmonary aspergillosis (IPA). APF was more frequent with itraconazole (65% vs 30%; P < .001), along with failure due to possible/probable/proven IPA (25% vs 10%; P = .002) and overall failure by any of the 3 different causes of prophylaxis failure (70% vs 38%; P < .001). In agreement with clinical trial data, this real-world evidence supports the use of posaconazole over itraconazole in AML or MDS patients undergoing intensive chemotherapy.",
"affiliations": "Hematology Service, Hospital Clínico Universitario-INCLIVA, Valencia, Spain.;Hematology Service, Hospital Clínico Universitario-INCLIVA, Valencia, Spain.;Hematology Service, Hospital Clínico Universitario-INCLIVA, Valencia, Spain.;Hematology Service, Hospital Clínico Universitario-INCLIVA, Valencia, Spain.;Hematology Service, Hospital Clínico Universitario-INCLIVA, Valencia, Spain.;Microbiology Service, Hospital Clínico Universitario-INCLIVA, Valencia, Spain.;Hematology Service, Hospital Clínico Universitario-INCLIVA, Valencia, Spain.",
"authors": "Tormo|Mar|M|http://orcid.org/0000-0001-9622-1649;Pérez-Martínez|Ariadna|A|;Calabuig|Marisa|M|http://orcid.org/0000-0002-3250-820X;Hernández-Boluda|Juan Carlos|JC|http://orcid.org/0000-0002-4289-3113;Amat|Paula|P|http://orcid.org/0000-0001-6321-4952;Navarro|David|D|http://orcid.org/0000-0003-3010-4110;Solano|Carlos|C|http://orcid.org/0000-0003-3702-0817",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; D017964:Itraconazole; C101425:posaconazole",
"country": "Germany",
"delete": false,
"doi": "10.1111/myc.12728",
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"issn_linking": "0933-7407",
"issue": "61(3)",
"journal": "Mycoses",
"keywords": "antifungal agents; invasive fungal infection; itraconazole; neutropenia; posaconazole; real-world comparison",
"medline_ta": "Mycoses",
"mesh_terms": "D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D000072742:Invasive Fungal Infections; D055744:Invasive Pulmonary Aspergillosis; D017964:Itraconazole; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D065129:Pre-Exposure Prophylaxis; D012189:Retrospective Studies; D017211:Treatment Failure; D014230:Triazoles",
"nlm_unique_id": "8805008",
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"pages": "206-212",
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"pmid": "29125660",
"pubdate": "2018-03",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Primary prophylaxis of invasive fungal infections with posaconazole or itraconazole in patients with acute myeloid leukaemia or high-risk myelodysplastic syndromes undergoing intensive cytotoxic chemotherapy: A real-world comparison.",
"title_normalized": "primary prophylaxis of invasive fungal infections with posaconazole or itraconazole in patients with acute myeloid leukaemia or high risk myelodysplastic syndromes undergoing intensive cytotoxic chemotherapy a real world comparison"
} | [
{
"companynumb": "ES-JNJFOC-20180303166",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "We report a 13-year-old female with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome, panhypopituitarism, dyslipidemia, type 2 diabetes mellitus, and nonalcoholic fatty liver disease, who developed rhabdomyolysis and acute kidney injury, two weeks after switching from lovastatin to rosuvastatin. She had been on lovastatin for eight years without any adverse effects.",
"affiliations": "Department of Pediatrics, Division of Endocrinology, Emory University School of Medicine, Atlanta, GA 30322, United States.;Department of Pediatrics, Division of Endocrinology, Emory University School of Medicine, Atlanta, GA 30322, United States.;Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Atlanta, GA 30322, United States.;Department of Pediatrics, Division of Endocrinology, Emory University School of Medicine, Atlanta, GA 30322, United States. Electronic address: tanicia.daley@emory.edu.",
"authors": "Vijayakanthi|Nandini|N|;Felner|Eric I|EI|;Romero|Rene|R|;Daley|Tanicia C|TC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jacl.2021.09.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-4789",
"issue": null,
"journal": "Journal of clinical lipidology",
"keywords": "Pediatric obesity; ROHHAD syndrome; Rhabdomyolysis; Rosuvastatin; Secondary dyslipidemia",
"medline_ta": "J Clin Lipidol",
"mesh_terms": null,
"nlm_unique_id": "101300157",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34600840",
"pubdate": "2021-09-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rhabdomyolysis due to rosuvastatin in a patient with ROHHAD syndrome.",
"title_normalized": "rhabdomyolysis due to rosuvastatin in a patient with rohhad syndrome"
} | [
{
"companynumb": "US-CPL-002603",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ROSUVASTATIN"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "OBJECTIVE\nLenalidomide is an immunomodulatory agent with therapeutic activity in chronic lymphocytic leukemia (CLL). In preclinical models, lenalidomide acted synergistically with rituximab. The CLL Research Consortium initiated a phase II study to evaluate this combination in treatment-naive patients.\n\n\nMETHODS\nLenalidomide was initiated at 2.5 mg/day and was escalated based on treatment tolerability to a maximum of 10 mg/day, for 21 days/cycle, for a maximum of seven cycles. Rituximab was administered at the end of cycle 1 and was continued for seven cycles. Patients received allopurinol and aspirin for prophylaxis.\n\n\nRESULTS\nSixty-nine patients enrolled onto one of two age-specific strata; patients' median age was 56 and 70 years for arms A and B, respectively. Patients in the older-patient stratum more frequently had elevated serum beta-2 microglobulin levels, high-risk Rai stage, and were less likely to complete the maximum planned therapy. Adverse events were similar in the two arms. Nonhematologic toxicity was predominantly at grade 1/2, and neutropenia was the most common hematologic adverse event. The response rate for arm A was 95%, with 20% complete responses (CRs) and 20% nodular partial responses. Of arm B patients, 78% achieved a response, of which 11% were CRs. Median progression-free survival (PFS) was 19 months for the younger cohort and 20 months for the older cohort.\n\n\nCONCLUSIONS\nIntrapatient dose-escalation was safe. The majority of patients reached the maximum lenalidomide dose and experienced a response to a defined seven-cycle course of lenalidomide and rituximab therapy. Despite differences in baseline characteristics and the response rate between the two strata, the PFS did not differ.",
"affiliations": "Danelle F. James, Januario E. Castro, Andrew Greaves, Laura Z. Rassenti, Thomas J. Kipps, Moores Cancer Center, University of California San Diego, La Jolla, CA; Lillian Werner, Jennifer R. Brown, Donna Neuberg, Dana-Farber Cancer Institute, Boston, MA; William G. Wierda, MD Anderson Cancer Center, The University of Texas, Houston, TX; Jacqueline C. Barrientos, Kanti R. Rai, North Shore-Long Island Jewish Health System, New Hyde Park, NY; Amy J. Johnson, The Ohio State University, Columbus, OH.;Danelle F. James, Januario E. Castro, Andrew Greaves, Laura Z. Rassenti, Thomas J. Kipps, Moores Cancer Center, University of California San Diego, La Jolla, CA; Lillian Werner, Jennifer R. Brown, Donna Neuberg, Dana-Farber Cancer Institute, Boston, MA; William G. Wierda, MD Anderson Cancer Center, The University of Texas, Houston, TX; Jacqueline C. Barrientos, Kanti R. Rai, North Shore-Long Island Jewish Health System, New Hyde Park, NY; Amy J. Johnson, The Ohio State University, Columbus, OH.;Danelle F. James, Januario E. Castro, Andrew Greaves, Laura Z. Rassenti, Thomas J. Kipps, Moores Cancer Center, University of California San Diego, La Jolla, CA; Lillian Werner, Jennifer R. Brown, Donna Neuberg, Dana-Farber Cancer Institute, Boston, MA; William G. Wierda, MD Anderson Cancer Center, The University of Texas, Houston, TX; Jacqueline C. Barrientos, Kanti R. Rai, North Shore-Long Island Jewish Health System, New Hyde Park, NY; Amy J. Johnson, The Ohio State University, Columbus, OH.;Danelle F. James, Januario E. Castro, Andrew Greaves, Laura Z. Rassenti, Thomas J. Kipps, Moores Cancer Center, University of California San Diego, La Jolla, CA; Lillian Werner, Jennifer R. Brown, Donna Neuberg, Dana-Farber Cancer Institute, Boston, MA; William G. Wierda, MD Anderson Cancer Center, The University of Texas, Houston, TX; Jacqueline C. Barrientos, Kanti R. Rai, North Shore-Long Island Jewish Health System, New Hyde Park, NY; Amy J. Johnson, The Ohio State University, Columbus, OH.;Danelle F. James, Januario E. Castro, Andrew Greaves, Laura Z. Rassenti, Thomas J. Kipps, Moores Cancer Center, University of California San Diego, La Jolla, CA; Lillian Werner, Jennifer R. Brown, Donna Neuberg, Dana-Farber Cancer Institute, Boston, MA; William G. Wierda, MD Anderson Cancer Center, The University of Texas, Houston, TX; Jacqueline C. Barrientos, Kanti R. Rai, North Shore-Long Island Jewish Health System, New Hyde Park, NY; Amy J. Johnson, The Ohio State University, Columbus, OH.;Danelle F. James, Januario E. Castro, Andrew Greaves, Laura Z. Rassenti, Thomas J. Kipps, Moores Cancer Center, University of California San Diego, La Jolla, CA; Lillian Werner, Jennifer R. Brown, Donna Neuberg, Dana-Farber Cancer Institute, Boston, MA; William G. Wierda, MD Anderson Cancer Center, The University of Texas, Houston, TX; Jacqueline C. Barrientos, Kanti R. Rai, North Shore-Long Island Jewish Health System, New Hyde Park, NY; Amy J. Johnson, The Ohio State University, Columbus, OH.;Danelle F. James, Januario E. Castro, Andrew Greaves, Laura Z. Rassenti, Thomas J. Kipps, Moores Cancer Center, University of California San Diego, La Jolla, CA; Lillian Werner, Jennifer R. Brown, Donna Neuberg, Dana-Farber Cancer Institute, Boston, MA; William G. Wierda, MD Anderson Cancer Center, The University of Texas, Houston, TX; Jacqueline C. Barrientos, Kanti R. Rai, North Shore-Long Island Jewish Health System, New Hyde Park, NY; Amy J. Johnson, The Ohio State University, Columbus, OH.;Danelle F. James, Januario E. Castro, Andrew Greaves, Laura Z. Rassenti, Thomas J. Kipps, Moores Cancer Center, University of California San Diego, La Jolla, CA; Lillian Werner, Jennifer R. Brown, Donna Neuberg, Dana-Farber Cancer Institute, Boston, MA; William G. Wierda, MD Anderson Cancer Center, The University of Texas, Houston, TX; Jacqueline C. Barrientos, Kanti R. Rai, North Shore-Long Island Jewish Health System, New Hyde Park, NY; Amy J. Johnson, The Ohio State University, Columbus, OH.;Danelle F. James, Januario E. Castro, Andrew Greaves, Laura Z. Rassenti, Thomas J. Kipps, Moores Cancer Center, University of California San Diego, La Jolla, CA; Lillian Werner, Jennifer R. Brown, Donna Neuberg, Dana-Farber Cancer Institute, Boston, MA; William G. Wierda, MD Anderson Cancer Center, The University of Texas, Houston, TX; Jacqueline C. Barrientos, Kanti R. Rai, North Shore-Long Island Jewish Health System, New Hyde Park, NY; Amy J. Johnson, The Ohio State University, Columbus, OH.;Danelle F. James, Januario E. Castro, Andrew Greaves, Laura Z. Rassenti, Thomas J. Kipps, Moores Cancer Center, University of California San Diego, La Jolla, CA; Lillian Werner, Jennifer R. Brown, Donna Neuberg, Dana-Farber Cancer Institute, Boston, MA; William G. Wierda, MD Anderson Cancer Center, The University of Texas, Houston, TX; Jacqueline C. Barrientos, Kanti R. Rai, North Shore-Long Island Jewish Health System, New Hyde Park, NY; Amy J. Johnson, The Ohio State University, Columbus, OH.;Danelle F. James, Januario E. Castro, Andrew Greaves, Laura Z. Rassenti, Thomas J. Kipps, Moores Cancer Center, University of California San Diego, La Jolla, CA; Lillian Werner, Jennifer R. Brown, Donna Neuberg, Dana-Farber Cancer Institute, Boston, MA; William G. Wierda, MD Anderson Cancer Center, The University of Texas, Houston, TX; Jacqueline C. Barrientos, Kanti R. Rai, North Shore-Long Island Jewish Health System, New Hyde Park, NY; Amy J. Johnson, The Ohio State University, Columbus, OH.;Danelle F. James, Januario E. Castro, Andrew Greaves, Laura Z. Rassenti, Thomas J. Kipps, Moores Cancer Center, University of California San Diego, La Jolla, CA; Lillian Werner, Jennifer R. Brown, Donna Neuberg, Dana-Farber Cancer Institute, Boston, MA; William G. Wierda, MD Anderson Cancer Center, The University of Texas, Houston, TX; Jacqueline C. Barrientos, Kanti R. Rai, North Shore-Long Island Jewish Health System, New Hyde Park, NY; Amy J. Johnson, The Ohio State University, Columbus, OH. tkipps@ucsd.edu.",
"authors": "James|Danelle F|DF|;Werner|Lillian|L|;Brown|Jennifer R|JR|;Wierda|William G|WG|;Barrientos|Jacqueline C|JC|;Castro|Januario E|JE|;Greaves|Andrew|A|;Johnson|Amy J|AJ|;Rassenti|Laura Z|LZ|;Rai|Kanti R|KR|;Neuberg|Donna|D|;Kipps|Thomas J|TJ|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D011961:Receptors, Fc; D000069283:Rituximab; D013792:Thalidomide; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2013.51.5890",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "32(19)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011961:Receptors, Fc; D012307:Risk Factors; D000069283:Rituximab; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "2067-73",
"pmc": null,
"pmid": "24868031",
"pubdate": "2014-07-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "17995965;20888994;17971612;9552069;18216293;23270003;21220603;20055660;21212432;15329427;21725050;16682719;15588506;18427150;18772452;17361231;11806974;19965642;18334676;21189385;18628480;18577710;15767648;17088571;18551193;11049967",
"title": "Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the chronic lymphocytic leukemia research consortium.",
"title_normalized": "lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia a multicenter clinical translational study from the chronic lymphocytic leukemia research consortium"
} | [
{
"companynumb": "US-CELGENEUS-163-21880-11120371",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null... |
{
"abstract": "Aim The physical health of people with mental health conditions is often suboptimal, and in many cases this may be related to their prescription medicines. One issue is that patients are monitored inconsistently for adverse drug reactions (ADRs). The aim of this study was to explore whether the nurse-led West Wales Adverse Drug Reaction (WWADR) Profile for Mental Health Medicines could improve recognition and management of ADRs in a crisis resolution home treatment service. Method The WWADR Profile was implemented in addition to usual care, in a one-group 'before and after' comparison study (n=20). The study took place from October to November 2013. Results The WWADR Profile identified previously unreported physical health problems for all participants in the study, including two potentially life-threatening conditions: cardiac arrhythmia, chest pain plus breathlessness, and valproate-induced pancreatitis. In total, four participants' medicines were discontinued, three were referred to a consultant psychiatrist, three were referred to GPs, one was referred to an electrocardiogram technician and one was referred to a dentist. Previously overlooked health promotion issues were also recognised. Conclusion The WWADR Profile identified several physical health problems that had been overlooked previously. Therefore, it might be beneficial to use the WWADR Profile in routine mental health practice.",
"affiliations": "Hywel Dda University Health Board, Hafan Derwen, Carmarthen, Wales.;Hywel Dda University Health Board, Hafan Derwen, Carmarthen, Wales.;Swansea University, Department of Nursing, College of Human and Health Sciences, Swansea, Wales.",
"authors": "Jones|Richard|R|;Moyle|Christopher|C|;Jordan|Sue|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.7748/ns.2016.e10447",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-6570",
"issue": "31(14)",
"journal": "Nursing standard (Royal College of Nursing (Great Britain) : 1987)",
"keywords": "West Wales Adverse Drug Reaction Profile; adverse drug reactions; drug monitoring; medicines management; medicines optimisation; mental health",
"medline_ta": "Nurs Stand",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D008991:Monitoring, Physiologic; D009740:Nursing Staff; D006113:United Kingdom",
"nlm_unique_id": "9012906",
"other_id": null,
"pages": "42-53",
"pmc": null,
"pmid": "27902153",
"pubdate": "2016-11-30",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Nurse-led medicines monitoring: a study examining the effects of the West Wales Adverse Drug Reaction Profile.",
"title_normalized": "nurse led medicines monitoring a study examining the effects of the west wales adverse drug reaction profile"
} | [
{
"companynumb": "GB-BION-005783",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": null,
"dru... |
{
"abstract": "Cholangiocarcinoma is an aggressive tumor with poor prognosis. Most of the cases are not available for surgery at the stage of the diagnosis and the best clinical practice chemotherapy results in about 12-month median survival. Several tyrosine kinase inhibitors (TKIs) are currently under investigation as an alternative treatment option for cholangiocarcinoma. Thus, the report of personalized selection of effective inhibitor and case outcome are of clinical interest.\nHere we report a case of aggressive metastatic cholangiocarcinoma (MCC) in 72-year-old man, sequentially treated with two targeted chemotherapies. Initially disease quickly progressed during best clinical practice care (gemcitabine in combination with cisplatin or capecitabine), which was accompanied by significant decrease of life quality. Monotherapy with TKI sorafenib was prescribed to the patient, which resulted in stabilization of tumor growth and elimination of pain. The choice of the inhibitor was made based on high-throughput screening of gene expression in the patient's tumor biopsy, utilized by Oncobox platform to build a personalized rating of potentially effective target therapies. However, time to progression after start of sorafenib administration did not exceed 6 months and the regimen was changed to monotherapy with Pazopanib, another TKI predicted to be effective for this patient according to the same molecular test. It resulted in disease progression according to RECIST with simultaneous elimination of sorafenib side effects such as rash and hand-foot syndrome. After 2 years from the diagnosis of MCC the patient was alive and physically active, which is substantially longer than median survival for standard therapy.\nThis case evidences that sequential personalized prescription of different TKIs may show promising efficacy in terms of survival and quality of life in MCC.",
"affiliations": "1I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991 Russia.;Clinical Center Vitamed, 10, Seslavinskaya St., Moscow, 121309 Russia.;Pathology Department, Morozov Children's City Hospital, 4th Dobryninsky Lane 1/9, Moscow, 119049 Russia.;4State Research Center-Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow, 123098 Russia.;1I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991 Russia.;4State Research Center-Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow, 123098 Russia.;5Stanford University School of Medicine, Stanford, CA 94305 USA.;1I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991 Russia.;D. Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117198 Russia.",
"authors": "Poddubskaya|Elena V|EV|;Baranova|Madina P|MP|;Allina|Daria O|DO|;Smirnov|Philipp Y|PY|;Albert|Eugene A|EA|;Kirilchev|Alexey P|AP|;Aleshin|Alexey A|AA|;Sekacheva|Marina I|MI|;Suntsova|Maria V|MV|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40164-018-0113-x",
"fulltext": "\n==== Front\nExp Hematol OncolExp Hematol OncolExperimental Hematology & Oncology2162-3619BioMed Central London 11310.1186/s40164-018-0113-xCase ReportPersonalized prescription of tyrosine kinase inhibitors in unresectable metastatic cholangiocarcinoma Poddubskaya Elena V. 12Baranova Madina P. 2Allina Daria O. 3Smirnov Philipp Y. 4Albert Eugene A. 1Kirilchev Alexey P. 4Aleshin Alexey A. 5Sekacheva Marina I. 1Suntsova Maria V. suntsova86@mail.ru 61 0000 0001 2288 8774grid.448878.fI.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991 Russia 2 Clinical Center Vitamed, 10, Seslavinskaya St., Moscow, 121309 Russia 3 Pathology Department, Morozov Children’s City Hospital, 4th Dobryninsky Lane 1/9, Moscow, 119049 Russia 4 grid.465277.5State Research Center‐Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow, 123098 Russia 5 0000000419368956grid.168010.eStanford University School of Medicine, Stanford, CA 94305 USA 6 D. Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117198 Russia 6 9 2018 6 9 2018 2018 7 215 4 2018 28 8 2018 © The Author(s) 2018Open 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\nCholangiocarcinoma is an aggressive tumor with poor prognosis. Most of the cases are not available for surgery at the stage of the diagnosis and the best clinical practice chemotherapy results in about 12-month median survival. Several tyrosine kinase inhibitors (TKIs) are currently under investigation as an alternative treatment option for cholangiocarcinoma. Thus, the report of personalized selection of effective inhibitor and case outcome are of clinical interest.\n\nCase presentation\nHere we report a case of aggressive metastatic cholangiocarcinoma (MCC) in 72-year-old man, sequentially treated with two targeted chemotherapies. Initially disease quickly progressed during best clinical practice care (gemcitabine in combination with cisplatin or capecitabine), which was accompanied by significant decrease of life quality. Monotherapy with TKI sorafenib was prescribed to the patient, which resulted in stabilization of tumor growth and elimination of pain. The choice of the inhibitor was made based on high-throughput screening of gene expression in the patient’s tumor biopsy, utilized by Oncobox platform to build a personalized rating of potentially effective target therapies. However, time to progression after start of sorafenib administration did not exceed 6 months and the regimen was changed to monotherapy with Pazopanib, another TKI predicted to be effective for this patient according to the same molecular test. It resulted in disease progression according to RECIST with simultaneous elimination of sorafenib side effects such as rash and hand-foot syndrome. After 2 years from the diagnosis of MCC the patient was alive and physically active, which is substantially longer than median survival for standard therapy.\n\nConclusion\nThis case evidences that sequential personalized prescription of different TKIs may show promising efficacy in terms of survival and quality of life in MCC.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s40164-018-0113-x) contains supplementary material, which is available to authorized users.\n\nissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nCholangiocarcinoma (CCA) is a bile duct cancer that is mainly characterized by its late diagnosis and fatal outcome [1]. CCA accounts about 3% of all gastrointestinal tumors and is second most common liver tumor after hepatocellular carcinoma [2]. Overall 5-year survival rate is lower than 10% [3], while overall 1-year survival of patients at stage 4 is only 5% [4]. Treatment options for CCA include surgery and chemotherapy, but only about 30% of patients are available for surgery [5].\n\nStandard care chemotherapy treatment for CCA is Gemcitabine, which is administered alone or in combination with cytotoxic agents such as Cisplatin. The response rate ranges from 8 to 60%, depending on the cohort of patients [6]. Nevertheless, these patients have a poor prognosis with a median survival of 6–12 months [7]. Thus, there is a need for improvement of general CCA treatment options.\n\nCurrently there are several ongoing clinical trials utilizing different approaches for target therapy in CCA. Chimeric antigen receptor-modified T (CART) cell-based therapy was recently attempted in CCA [8]. Authors reported 8.5- and 4.5-month partial response to CART-EGFR and CART-CD133 therapy respectively. Nevertheless, several associated side effects were discovered, from which epidermal damage was the most prominent. Indeed, so far CART showed limited efficiency in solid tumor and further studies are still required for successful clinical applications [9].\n\nMajority of clinical trials investigate the efficacy of small molecule inhibitors acting at different levels of EGFR signaling pathway, which is known for being upregulated in CCA (summarized in the recent review [10]). Several case reports [11–13] on TKI usage in CCA demonstrated potential benefits from such treatment. However, results of clinical trials so far are controversial. Luo et al. in non-controlled and single arm study showed that Sorafenib in combination with best clinical practice had modest effect for the patients with advanced CCA [14]. At the same time, Sorafenib monotherapy had been shown to be beneficial in a cohort of 15 patients [15], but larger studies demonstrated that Sorafenib as a single agent had rather low activity in cholangiocarcinoma [16, 17]. In turn, Pazopanib in combination with another TKI drug Trametinib showed a trend to increase 4-month progression-free survival as compared with the prespecified null hypothesized 4-month PFS of 25%. However, this trend did not reach statistical significance [18]. Previously reported treatment outcomes described above are summarized in Table 1. Differential efficiency of TKIs between studies and individual patients within a study could be explained by the range of factors from genetic heterogeneity [19] to patient ethnicity [20]. This illustrates that despite the potential benefits for a distinct cohort of CCA patients there are difficulties associated with the correct TKI prescriptions.Table 1 Results of published case reports and clinical trials for TKI usage in CCA\n\nDrug\tNumber of patients\tDose\tDuration of treatment\tOutcome\tSide effects\tRefs.\t\nSorafenib\t2\t400 mg PO bid\t4 months with later switch to oxaliplatin and gemcitabine; 6 month for the time of report\tTransient disease stabilization; decrease of tumor markers CA 125, CA 19-9, CA 27.29\tMaculopapular rash, hair thinning, grade 3 thrombocytopenia (disappeared after 1-week discontinuation), hypertension, facial rush\t[13]\t\nSorafenib\t1\t400 mg PO bid\t2 years for the time of report\tStable disease with time-to-progression 5.7 month; decrease of tumor marker CA 19-9; decrease of bilirubin level and increase of liver synthesis parameters\tMild diarrhea, fatigue and skin toxicity; no dose reduction or interruption were made\t[12]\t\nSorafenib\t1\t400 mg PO bid; 7 days cessation after 1 year and dose reduction to 200 mg\t4 years for the time of report\tStable disease; decrease of bilirubin level\tMild diarrhea, desquamation rush. Grade 1 hand-foot syndrome, mild thrombocytopenia (required 7 days cessation)\t[11]\t\nSorafenib\t44\t400 mg PO bid\t1.8-month median duration\tMedian time to progression 5.6 month; median overall survival 5.7 month; disease control rate at 3 months 15.9%\tMild diarrhea, fatigue, hand-foot syndrome\t[14]\t\nSorafenib\t15\t400 mg PO bid\t3.2-month median duration\tMedian time to progression 3.2 month; median overall survival 5.7 month; disease control rate at 3 months 73.3%\tSkin rush in 5 patients grade 3 hand-foot syndrome in 1 patient\t[15]\t\nSorafenib\t31\t400 mg PO bid\t2-month median duration\tDisease control rate detected according suggested scheme 0%; median overall survival 9 month; median progression free survival 3 month\tGrades 3 and 4 toxicities in 20 patients included: thrombosis/embolism, hypertension, fatigue, bilirubin evaluation, hand-foot syndrome\t[16]\t\nSorafenib\t46\t400 mg PO bid\tFrom 1 to 12 months\tDisease control rate at 3 months 32.6%; median overall survival 4.4 month; median progression free survival 2.3 month\tHand-foot syndrome, skin rush, diarrhea, fatigue and thrombocytopenia\t[17]\t\nPazopanib\nTrametinib\t25\tPazopanib 800 mg qd\nTrametinib 2 mg qd\t3-month median duration\tMedian overall survival 6.4 month; disease control rate detected according suggested scheme 75%; median progression free survival 3.6 month\tHypertension, fatigue, rash, diarrhea, nausea/vomiting, thrombocytopenia\t[18]\t\n\n\nIn this report we describe a case of advanced metastatic CCA subsequently treated with TKI agents Sorafenib and Pazopanib, which resulted in 2-year survival period after initial diagnosis. Inhibitors were selected based on high throughput gene expression and molecular pathway activation analysis of the patient’s tumor biopsy, thus providing a personalized approach.\n\nCase\nThe patient is a 72-year-old man with histologically confirmed moderately differentiated intrahepatic cholangiocarcinoma (Fig. 1). He was diagnosed in October 2015 with the following symptoms: moderate weight loss, pain in the right hypochondrium, loss of appetite and asthenia, with a Karnofsky scale index of 70%. MRI image at the time of diagnosis is shown on Fig. 2a. The tumor was not surgically removed because of advanced stage, multiple intrahepatic nodules and lung metastases.Fig. 1 Hematoxylin and eosin (H&E) staining shows moderately differentiated intrahepatic cholangiocarcinoma (magnification ~ ×200)\n\n\nFig. 2 MRI tumor evaluation during treatment. Tumor area is highlighted on the left panel. Raw images are provided on the right panel. a Tumor evaluation at the stage of the initial CCA diagnosis (October 2015, was done with liver vein contrasting (7.5 ml Gadovist). Sum of diameters of target lesions equals 221 mm; b tumor progression after the best clinical practice care (July 2016). Sum of diameters of target lesions equals 278 mm (26% increase); c tumor growth during Sorafenib treatment (October 2016). Sum of diameters of target lesions equals 314 mm (16% increase); d tumor growth after Sorafenib treatment prior to start of Pazopanib (January 2017). Sum of diameters of target lesions equals 392 mm (35.3% increase). e Tumor progression after Pazopanib treatment (July 2017). Sum of diameters of target lesions equals 471 mm (35.7% increase if counting a as a reference or 20% increase if counting d as a reference)\n\n\n\n\nFour courses of chemotherapy (2 courses Gemcitabine in combination with Capecitabine and subsequent 2 courses Gemcitabine in combination with Cisplatin) were administered till May 2016. The treatment was poorly effective, and the tumor increased in size according to MRI (Fig. 2b); additional metastatic nodules appeared in the left and the right lobes with the spread to the bile duct, holedoch and into the gallbladder. Serum gamma glutamyltranspeptidase (GGT) level, which is associated with poor prognosis and tumor aggressiveness [21, 22], was significantly increased, when compared to pre-treatment levels (Fig. 3). Karnofsky scale index decreased to 60%. As the patient did not respond to the best clinical practice treatment, we decided to switch the medication and considered TKI inhibitors as further treatment option. Taking into account available data on differential response of CCA patients to TKIs we performed advanced molecular analysis of the tumor to support our choice and identify the most effective drug.Fig. 3 Serum gamma glutamyltranspeptidase levels during treatment\n\n\n\n\nWe profiled gene expression in formalin-fixed, paraffin-embedded (FFPE) patient’s tumor biopsy sample, obtained at the time of the first CCA diagnosis. Briefly total RNA was extracted using Ambion’s RecoverAll™ Total Nucleic Acid Isolation. Complete Whole Transcriptome Amplification WTA2 Kit (Sigma) was used for reverse transcription and library amplification. Hybridization was performed according to CustomArray ElectraSense™ Hybridization and Detection protocol. Hybridization efficiency was detected electrochemically using CustomArray ElectraSense™ Detection Kit and ElectraSense™ 4X2K/12K Reader.\n\nWe next used bioinformatical software Oncobox to analyze gene expression data and to identify molecular pathways differentially regulated in the patient’s tumor sample [23]. Based on the abundance of gene transcripts for the molecular targets of anticancer drugs, Oncobox also makes it possible to generate a rating of target drugs potentially effective for the individual patients [24, 25]. Particularly, this analysis revealed that the ERK and Ras molecular signaling pathways were highly activated in the CCA patient’s tumor biopsy (Fig. 4), the predicted rating of the most effective target drugs is shown in Table 2. Regorafenib, a multi-tyrosine kinase inhibitor was on the top position of the rating. However, there were no published studies of Regorafenib efficacy and tolerability in CCA. At the same time, several case reports demonstrated efficiency of TKI target drug Sorafenib for CCA treatment [11–13]. We, therefore, decided to use Sorafenib as the next line therapy and it was prescribed to the patient (800 mg daily) in May 2016. Treatment with Sorafenib coincided with the decrease of serum GGT level. MRI analysis in October 2016 revealed moderate tumor growth, corresponding to disease stabilization (Fig. 2c). However, additional nodules occurred slightly below the xiphoid process in the diaphragm area. Therefore, disease progressed according to RECIST criteria. And, importantly, after Sorafenib treatment, the patient did not complain of pain in the right hypochondrium. Before Sorafenib treatment the patient received Tramadol (100 mg im once a day) and Fentanyl (75 µg/h, Duragesic transdermal tape). After 1 month of treatment with Sorafenib the pain medication was switched to Ketoral (30 mg im twice a day). Considering all the above-mentioned facts it was decided to continue Sorafenib treatment. MRI performed in January 2017 revealed progression of tumor growth and additional nodule in the left lung (Fig. 2d). In addition, the following side effects occurred: redness, swelling, pain on the palms of the hands and soles of the feet. GGT level increased up to 319 U/L in December 2016.Fig. 4 ERK and Ras signaling pathways were hyperactivated in the biopsy CCA tissue. Visualization was provided by Oncobox software. The pathways are shown as an interacting network, where green arrows indicate activation, red arrows—inhibition. Color depth of each node of the network corresponds to the logarithms of the case-to-normal (CNR) expression rate for each node, where “normal” is a geometric average between normal tissue samples, the scale represents extent of up/downregulation. The molecular targets of Sorafenib and Pazopanib are shown by black arrows\n\n\nTable 2 Rating of target drugs provided by Oncobox test\n\nPosition\tDrug\t\n1\tRegorafenib\t\n2\t\nSorafenib\n\t\n3\tSunitinib\t\n4\t\nPazopanib\n\t\n5\tAxitinib\t\n6\tVandetanib\t\n7\tCabozantinib\t\n8\tImatinib\t\n9\tZiv-aflibercept\t\n10\tDasatinib\t\n\n\nThe treatment regimen was next changed to Pazopanib, another TKI drug recommended based on the Oncobox rating. Sunitinib was not chosen because we attempted to eliminate the hand-foot syndrome, which occurred during Sorafenib administration. In the previous studies, Sunitinib treatment of CCA patients induced hand-foot syndrome in 43% of patients [26]. On the other hand, recent clinical trial of Pazopanib in combination with Trametinib in CCA did not report hand-foot syndrome as a side effect [27]. Pazopanib administration (800 mg daily) started since January 2017. The control MRI in July 2017 revealed progression in the lung nodes and 20% increase in sum of diameters of target lesions, which is a borderline between stabilization and progression according to RECIST (Fig. 2e). However, the change of treatment regimen resulted in elimination of Sorafenib side effects and general improvement of life quality. In addition, start of Pazopanib treatment coincided with a start of a trend towards decrease of serum GGT level (Fig. 3). As for October 2017 (2 years after initial diagnosis), the patient was alive and physically active, with Karnofsky scale 80%. Our patient passed away due to the liver failure in November 2017.\n\nDiscussion\nOur case report describes sequential use of TKI inhibitors Sorafenib and Pazopanib, which were selected based on personalized approach, for treating advanced CCA in patient who did not respond to standard therapy. Selected treatment improved patient life quality and survival period even though did not result in a response according to RECIST classification.\n\nAvailable data on TKI usage in CCA patients underline that despite the potential benefit of such treatment not all patients respond equally. Therefore, it remains a clinical challenge to promptly identify potential responders. Selection of CCA patients, who may benefit from TKI treatment may be based on the molecular characteristics of tumor specimens.\n\nTherefore, to support the usage of TKI in the current clinical case and select the most effective inhibitor we performed a molecular profile of patient tumor biopsy. Total RNA was extracted from FFPE tissue sample, obtained at the stage of the diagnosis, and gene expression was measured using microarray hybridization. Gene expression data was next used for calculating pathway activation scores and for building rating of target drugs using bioinformatical software Oncobox.\n\nPerformed analysis demonstrated that Ras and ERK signaling pathways were highly activated in the patient’s pathological tissue (Additional file 1: Table S1). These molecular pathways are implicated in various process linked with tumorigenesis such as cell proliferation, differentiation, survival and apoptosis [28]. Ras pathway activates ERK pathway, but also is tightly connected with stress response, cell motility and cytoskeleton rearrangements [29]. Normally both, ERK and Ras pathways are activated by binding of extracellular growth factors (like EGFR) to their receptor tyrosine kinases (RTKs). TKIs are capable of targeting RTKs, thus inhibiting cell proliferation and survival [30, 31].\n\nBased on the observed molecular phenotype several TKIs were predicted to be effective in the current clinical case (Table 2). Considering both results of the bioinformatical analysis and available literature data on TKI efficiency in CCA, Sorafenib and then Pazopanib were prescribed to our patient. These drugs overlap in blocking FLT1, FLT4, KDR, C-Kit proto-oncogene and platelet derived growth factor receptor beta (PDGFRB). In addition, Pazopanib targets platelet derived growth factor receptor alpha (PDGFRA), while Sorafenib—B-Raf, C-Raf and ret proto-oncogenes, fibroblast growth factor receptor 1 (FGFR1) and FLT3. Both Pazopanib and Sorafenib are approved for treating advanced renal cell carcinoma (RCC); in addition, Sorafenib is approved for treatment of patients with unresectable hepatocellular carcinoma (HCC).\n\nThus, the performed analysis supported choice of treatment and predicted high chances of TKI efficiency for our patient. Even though the best clinical outcome across this case was progressive disease (according to RECIST), TKIs were beneficial for palliative care of metastatic CCA patient due to improvement of clinical parameters such as quality of life and survival. In addition, start of treatment with TKIs coincided with a trend towards decrease of serum GGT level.\n\nThe success of the most clinical trials of TKI in CCA was evaluated based on the time to progression or progression free survival and, therefore, disease progression was considered as an unsuccessful outcome and resulted in termination of treatment. In this case we report life quality improvement and prolonged survival with TKI therapy on the background of disease progression. This may point to the modest antitumor activity of TKIs in some patients, as also suggested by El-Khoueiry et al. [16]. Such activity, even if not capable to trigger the response, could potentially be sufficient for slowing down disease progression and, thus, life quality improvement.\n\nAdditional file\n\nAdditional file 1: Table S1. Additional table.\n\n \n\n\nAuthors’ contributions\nEP, MB, DA, AK, PS collected and interpreted patient data. EP and MB were involved in clinical management. MSu performed molecular analyses. MSu, MSe, AA, EA and EP wrote this manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nData deposition and access\nGene expression data derived from the patient’s tumor tissue were deposited at the Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) under the Accession Number GSE107233.\n\nEthics approval and consent to participate\nThe patient provided consent for gene expression analysis of his sample and oral consent for the publication of this article. Gene expression profiling was approved by Institutional Review Board (IRB) at Clinical Center Vitamed, Moscow, Russia, according to the Declaration of Helsinki principles.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Bergquist A von Seth E Epidemiology of cholangiocarcinoma Best Pract Res Clin Gastroenterol 2015 29 2 221 232 10.1016/j.bpg.2015.02.003 25966423 \n2. Rizvi S Gores GJ Pathogenesis, diagnosis, and management of cholangiocarcinoma Gastroenterology 2013 145 6 1215 1229 10.1053/j.gastro.2013.10.013 24140396 \n3. Everhart JE Ruhl CE Burden of digestive diseases in the United States part III: liver, biliary tract, and pancreas Gastroenterology 2009 136 4 1134 1144 10.1053/j.gastro.2009.02.038 19245868 \n4. Yusoff AR Survival analysis of cholangiocarcinoma: a 10-year experience in Malaysia World J Gastroenterol 2012 18 5 458 465 10.3748/wjg.v18.i5.458 22346252 \n5. Khan SA Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update Gut 2012 61 12 1657 1669 10.1136/gutjnl-2011-301748 22895392 \n6. Thongprasert S The role of chemotherapy in cholangiocarcinoma Ann Oncol 2005 16 Suppl 2 93 96 10.1093/annonc/mdi712 \n7. Valle J Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer N Engl J Med 2010 362 14 1273 1281 10.1056/NEJMoa0908721 20375404 \n8. Feng KC Cocktail treatment with EGFR-specific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma J Hematol Oncol 2017 10 1 4 10.1186/s13045-016-0378-7 28057014 \n9. Castellarin M Driving cars to the clinic for solid tumors Gene Ther 2018 25 165 175 10.1038/s41434-018-0007-x 29880908 \n10. Ahn DH Bekaii-Saab T Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications J Gastrointest Oncol 2017 8 2 293 301 10.21037/jgo.2016.10.01 28480068 \n11. Chakunta HR Cholangiocarcinoma: treatment with sorafenib extended life expectancy to greater than 4 years J Gastrointest Oncol 2013 4 4 E30 E32 24294517 \n12. Pinter M Sorafenib in unresectable intrahepatic cholangiocellular carcinoma: a case report Wien Klin Wochenschr 2011 123 1–2 61 64 10.1007/s00508-010-1522-y 21240686 \n13. LaRocca RV Effective palliation of advanced cholangiocarcinoma with sorafenib: a two-patient case report J Gastrointest Cancer 2007 38 2–4 154 156 10.1007/s12029-008-9028-9 19089671 \n14. Luo X Effectiveness and safety of sorafenib in the treatment of unresectable and advanced intrahepatic cholangiocarcinoma: a pilot study Oncotarget 2017 8 10 17246 17257 10.18632/oncotarget.12825 27783997 \n15. Pan TT A single-center experience of sorafenib monotherapy in patients with advanced intrahepatic cholangiocarcinoma Oncol Lett 2017 13 5 2957 2964 10.3892/ol.2017.5847 28529557 \n16. El-Khoueiry AB SWOG 0514: a phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma Invest New Drugs 2012 30 4 1646 1651 10.1007/s10637-011-9719-0 21748296 \n17. Bengala C Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial Br J Cancer 2010 102 1 68 72 10.1038/sj.bjc.6605458 19935794 \n18. Shroff RT The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma Br J Cancer 2017 116 11 1402 1407 10.1038/bjc.2017.119 28441383 \n19. Andersen JB Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors Gastroenterology 2012 142 4 1021 1031 10.1053/j.gastro.2011.12.005 22178589 \n20. Guo J Safety of pazopanib and sunitinib in treatment-naive patients with metastatic renal cell carcinoma: asian versus non-Asian subgroup analysis of the COMPARZ trial J Hematol Oncol 2018 11 1 69 10.1186/s13045-018-0617-1 29788981 \n21. Yin X Elevation of serum gamma-glutamyltransferase as a predictor of aggressive tumor behaviors and unfavorable prognosis in patients with intrahepatic cholangiocarcinoma: analysis of a large monocenter study Eur J Gastroenterol Hepatol 2013 25 12 1408 1414 10.1097/MEG.0b013e328364130f 23839159 \n22. Zhang C Serum liver enzymes serve as prognostic factors in patients with intrahepatic cholangiocarcinoma Onco Targets Ther 2017 10 1441 1449 10.2147/OTT.S124161 28331337 \n23. Buzdin AA Oncofinder, a new method for the analysis of intracellular signaling pathway activation using transcriptomic data Front Genet 2014 5 55 10.3389/fgene.2014.00055 24723936 \n24. Artemov A A method for predicting target drug efficiency in cancer based on the analysis of signaling pathway activation Oncotarget 2015 6 30 29347 29356 10.18632/oncotarget.5119 26320181 \n25. Buzdin A Activation of intracellular signaling pathways as a new type of biomarkers for selection of target anticancer drugs J Clin Oncol 2017 35 15_suppl e23142 \n26. Neuzillet C Sunitinib as second-line treatment in patients with advanced intrahepatic cholangiocarcinoma (SUN-CK phase II trial): safety, efficacy, and updated translational results J Clin Oncol 2015 33 3 suppl 343 10.1200/jco.2015.33.3_suppl.343 \n27. Shroff RT Pazopanib (P) and trametinib (T) in advanced cholangiocarcinoma (CC): a phase Ib study J Clin Oncol 2015 33 15 suppl 4072 \n28. Wada T Penninger JM Mitogen-activated protein kinases in apoptosis regulation Oncogene 2004 23 16 2838 2849 10.1038/sj.onc.1207556 15077147 \n29. Simanshu DK Nissley DV McCormick F RAS proteins and their regulators in human disease Cell 2017 170 1 17 33 10.1016/j.cell.2017.06.009 28666118 \n30. Gollob JA Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway Semin Oncol 2006 33 4 392 406 10.1053/j.seminoncol.2006.04.002 16890795 \n31. Sonpavde G Hutson TE Pazopanib: a novel multitargeted tyrosine kinase inhibitor Curr Oncol Rep 2007 9 2 115 119 10.1007/s11912-007-0007-2 17288876\n\n",
"fulltext_license": "CC BY",
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"journal": "Experimental hematology & oncology",
"keywords": null,
"medline_ta": "Exp Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "101590676",
"other_id": null,
"pages": "21",
"pmc": null,
"pmid": "30202637",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "20375404;16890795;28057014;28529557;28331337;24140396;15958484;23839159;19935794;28480068;19089671;29788981;21748296;28441383;24294517;28666118;15077147;25966423;22346252;19245868;22895392;26320181;29880908;17288876;27783997;21240686;24723936;22178589",
"title": "Personalized prescription of tyrosine kinase inhibitors in unresectable metastatic cholangiocarcinoma.",
"title_normalized": "personalized prescription of tyrosine kinase inhibitors in unresectable metastatic cholangiocarcinoma"
} | [
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"abstract": "A fixed drug eruption (FDE) is a toxic skin effect thought to be caused by delayed cell-mediated hypersensitivity to a pharmaceutical agent. We report herein the first known patient with capecitabine-induced FDE that appeared relatively late in the course of adjuvant therapy for rectal cancer. The temporal association with capecitabine use and prompt disappearance after capecitabine discontinuation make this relationship probable. Knowledge about this dermatologic skin effect seen with oral fluoropyrimidines should avoid unnecessary diagnostic workup and provide the necessary patient reassurance.",
"affiliations": null,
"authors": "Del Rosario|Michael|M|;Tsai|Henry|H|;Dasanu|Constantin A|CA|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine",
"country": "United States",
"delete": false,
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"issue": "80(4)",
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"medline_ta": "Conn Med",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D003875:Drug Eruptions; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "0372745",
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"pmid": "27265926",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fixed Drug Eruption Late in the Course of Capecitabine Therapy.",
"title_normalized": "fixed drug eruption late in the course of capecitabine therapy"
} | [
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"abstract": "BACKGROUND\nMethohexital is a short-acting barbiturate used for procedural sedation in the emergency department (ED). As with other sedatives, adverse effects with methohexital include excess sedation and hypotension, but this agent can also lower the seizure threshold. We report a patient who developed a generalized seizure after administration of methohexital.\n\n\nMETHODS\nA 60-year-old man presented to the ED by ambulance with chest pain and shortness of breath. Paramedics had administered adenosine for supraventricular tachycardia without conversion before arrival to the ED. He had no history of seizures. His initial vital signs in the ED included heart rate of 189 beats/min with a supraventricular rhythm, blood pressure 137/108 mm Hg, respiration 22 breaths/min, and oxygen saturation of 98% on room air. It was decided to attempt synchronized electrical cardioversion, and methohexital 1 mg/kg (120 mg) was administered over 2 min for moderate sedation. Within 15 s of methohexital administration, the patient developed a generalized seizure that lasted for 90 s. After seizure termination, he was successfully cardioverted, returned to his previous baseline level of consciousness within 20 min, and discharged without further problems with a follow-up referral to neurology. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Methohexital is a short-acting barbiturate used for moderate sedation. Its adverse effects are unique in that it can lower the seizure threshold in some patients. Alternative agents for sedation should be considered in individuals with possible seizure disorders.",
"affiliations": "Department of Pharmacy, UC San Diego Medical Center, San Diego, California.;Department of Pharmacy, UC San Diego Medical Center, San Diego, California.;Department of Emergency Medicine, UC San Diego Medical Center, San Diego, California.;Department of Emergency Medicine, UC San Diego Medical Center, San Diego, California.;Department of Emergency Medicine, UC San Diego Medical Center, San Diego, California; Division of Medical Toxicology, UC San Diego Medical Center, San Diego, California.",
"authors": "Willeford|Andrew|A|;Trumm|Nicholas|N|;Bisanz|Bryan|B|;Parathasarathy|Vishnu|V|;Clark|Richard F|RF|",
"chemical_list": "D018686:Anesthetics, Intravenous; D006993:Hypnotics and Sedatives; D008723:Methohexital",
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"delete": false,
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"issue": "59(2)",
"journal": "The Journal of emergency medicine",
"keywords": "barbiturates; convulsions; methohexital; seizures; toxicity",
"medline_ta": "J Emerg Med",
"mesh_terms": "D018686:Anesthetics, Intravenous; D016292:Conscious Sedation; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D008723:Methohexital; D008875:Middle Aged; D012640:Seizures",
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"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Methohexital-Induced Seizure in a Patient Undergoing Conscious Sedation.",
"title_normalized": "methohexital induced seizure in a patient undergoing conscious sedation"
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"companynumb": "US-MYLANLABS-2020M1084199",
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"abstract": "A previously healthy, 1-year 7-month-old boy was brought to the emergency department after having unintentionally ingested topical brimonidine antiglaucoma drops. He was pale and lethargic and had brief periods of apnea and bradycardia. Activated charcoal was administered, and supportive measures were initiated, achieving complete resolution of the symptoms 4 hours after admission. Brimonidine poisoning is very rare, and a high index of suspicion is necessary to identify its signs and symptoms in the pediatric emergency department. To our knowledge, only 1 case of brimonidine poisoning after oral ingestion of this topical drug has been previously reported in the literature.",
"affiliations": "Hospital Angeles de las Lomas, Vialidad de la Barranca s/n, México.",
"authors": "Soto-Pérez-de-Celis|Enrique|E|;Skvirsky|David Oldak|DO|;Cisneros|Beatriz Guzmán|BG|",
"chemical_list": "D000316:Adrenergic alpha-Agonists; D011810:Quinoxalines; D002606:Charcoal; D000068438:Brimonidine Tartrate",
"country": "United States",
"delete": false,
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"issue": "23(9)",
"journal": "Pediatric emergency care",
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"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000316:Adrenergic alpha-Agonists; D000068438:Brimonidine Tartrate; D002606:Charcoal; D006801:Humans; D007223:Infant; D008297:Male; D011041:Poisoning; D011810:Quinoxalines",
"nlm_unique_id": "8507560",
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"pubdate": "2007-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Unintentional ingestion of brimonidine antiglaucoma drops: a case report and review of the literature.",
"title_normalized": "unintentional ingestion of brimonidine antiglaucoma drops a case report and review of the literature"
} | [
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"companynumb": "MX-BAUSCH-BL-2020-014279",
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"patient": {
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"actiondrug": "5",
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"activesubstancename": "BRIMONIDINE TARTRATE"
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{
"abstract": "Allergic anaphylactic (type I) reactions to corticosteroid medications are uncommon; however, a number of well-documented cases have been reported. We present a review of the literature, and report on two patients who suffered anaphylaxis after injections of corticosteroids. The first patient, a registered nurse, was finally found to be sensitive to all corticosteroid preparations containing carboxymethylcellulose, as well as the pure carboxymethylcellulose. The second patient had positive skin tests to hydrocortisone, hydrocortisone sodium succinate, methylprednisolone sodium succinate, and suxamethonium. Both patients were tested on two occasions; four normal subjects were tested in parallel, and did not elicit any positive skin reaction. In patients with systemic severe reactions to injectable corticosteroids, we recommend careful and comprehensive skin testing with most available corticosteroids, as well as the components of the injectables.",
"affiliations": "Centre D'Allergie, Hopital Rothschild, Paris, France.",
"authors": "Murrieta-Aguttes|M|M|;Michelen|V|V|;Leynadier|F|F|;Duarte-Risselin|C|C|;Halpern|G M|GM|;Dry|J|J|",
"chemical_list": "D005938:Glucocorticoids; D014222:Triamcinolone Acetonide; C007133:hydrocortisone hemisuccinate; D006854:Hydrocortisone",
"country": "England",
"delete": false,
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"issn_linking": "0277-0903",
"issue": "28(5)",
"journal": "The Journal of asthma : official journal of the Association for the Care of Asthma",
"keywords": null,
"medline_ta": "J Asthma",
"mesh_terms": "D000328:Adult; D004342:Drug Hypersensitivity; D005260:Female; D005938:Glucocorticoids; D006323:Heart Arrest; D006801:Humans; D006854:Hydrocortisone; D006969:Hypersensitivity, Immediate; D008297:Male; D012882:Skin Tests; D014222:Triamcinolone Acetonide; D014581:Urticaria",
"nlm_unique_id": "8106454",
"other_id": null,
"pages": "329-39",
"pmc": null,
"pmid": "1938768",
"pubdate": "1991",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Systemic allergic reactions to corticosteroids.",
"title_normalized": "systemic allergic reactions to corticosteroids"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1052628",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PANCURONIUM"
},
"drugadditional": null,
... |
{
"abstract": "Here, we describe the use of intense pulsed light (IPL) treatment for 13 cases of erythematotelangiectatic rosacea delivered in three sessions. For two-step irradiation, after the whole face had been irradiated using conventional IPL equipment covering a wide area, localized IPL spot irradiation was performed for visibly dilated capillaries. The therapeutic effect was evaluated by image analysis using Image J and scored by 10 dermatologists using two IPL instruments in combination. This therapeutic approach was found to be much more effective than irradiation using a single instrument. Our findings demonstrate that IPL irradiation using the present method can deliver a sufficient therapeutic effect even with a small number of treatment sessions. Although rosacea is difficult to treat, we believe that IPL can be therapeutically useful in such cases.",
"affiliations": "Department of Dermatology, Iwate Medical University School of Medicine, Morioka, Japan.;Department of Dermatology, Iwate Medical University School of Medicine, Morioka, Japan.;Department of Dermatology, Kitakami Saiseikai Hospital, Kitakami, Japan.;Department of Dermatology, Iwate Medical University School of Medicine, Morioka, Japan.",
"authors": "Tsunoda|Kanako|K|http://orcid.org/0000-0002-0207-7402;Akasaka|Kiyomi|K|;Akasaka|Toshihide|T|;Amano|Hiroo|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.14513",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "45(9)",
"journal": "The Journal of dermatology",
"keywords": "facial telangiectasia; intense pulsed light; laser therapy; rosacea; two-step irradiation",
"medline_ta": "J Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D005145:Face; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D062325:Intense Pulsed Light Therapy; D054025:Lasers, Dye; D008297:Male; D008875:Middle Aged; D010781:Photography; D012393:Rosacea; D016896:Treatment Outcome",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "1113-1116",
"pmc": null,
"pmid": "29952023",
"pubdate": "2018-09",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Successful treatment of erythematotelangiectatic rosacea with intense pulsed light: Report of 13 cases.",
"title_normalized": "successful treatment of erythematotelangiectatic rosacea with intense pulsed light report of 13 cases"
} | [
{
"companynumb": "JP-BAUSCH-BL-2018-036138",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE"
},
"dr... |
{
"abstract": "Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological malignancy derived from precursors of plasmacytoid dendritic cells. The majority of patients initially respond to multi-agent chemotherapy, though most relapse within a year and the prognosis is very poor. We report a 67-year-old man with erythema on the right chest and a nasopharyngeal mass. Histological examination revealed a mass of tumor cells expressing CD4, CD56, and CD123, but neither CD3 nor CD20. He was diagnosed with BPDCN. Bone marrow involvement was not seen at diagnosis. He achieved complete remission (CR) with CHOP-like chemotherapy. After 1 year, he relapsed with a cutaneous tumor on the head, a nasopharyngeal tumor, and massive bone marrow involvement. Relapsed BPDCN is generally resistant to chemotherapy and the prognosis is dismal. However, he was successfully treated with biweekly CHOP therapy and achieved a second CR lasting 16 months.",
"affiliations": "Department of Hematology-Oncology, Chiba Cancer Center.",
"authors": "Ono|Keiko|K|;Ise|Mikiko|M|;Ikebe|Dai|D|;Sato|Akiyasu|A|;Wang|Xiaofei|X|;Sugawara|Takeaki|T|;Tsujimura|Hideki|H|;Itami|Makiko|M|;Kumagai|Kyoya|K|",
"chemical_list": "D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.58.150",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "58(2)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001853:Bone Marrow; D003520:Cyclophosphamide; D003713:Dendritic Cells; D004317:Doxorubicin; D019337:Hematologic Neoplasms; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D011239:Prednisolone; D012878:Skin Neoplasms; D014750:Vincristine",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "150-154",
"pmc": null,
"pmid": "28321093",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment with biweekly CHOP for bone marrow relapse of blastic plasmacytoid dendritic cell neoplasm.",
"title_normalized": "successful treatment with biweekly chop for bone marrow relapse of blastic plasmacytoid dendritic cell neoplasm"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1053556",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThere is no consensus on whether restarting TNF inhibitors (TNFis) after treatment of an active tuberculosis (TB) infection caused by previous TNFi exposure is safe. In this study we sought to determine the safety of resuming TNFis in patients following TB treatment.\n\n\nMETHODS\nThe medical records of all patients (n = 683) that received TNFi treatment at a single rheumatology clinic between June 2003 and December 2012 were retrospectively reviewed. Among them, data from patients who developed active TB infection were collected and patient outcomes were evaluated for those who resumed TNFis after TB treatment.\n\n\nRESULTS\nOf 683 patients, 13 patients developed an active TB infection during TNFi treatment (4 on etanercept, 4 on adalimumab and 5 on infliximab). The median duration of TNFi treatment before TB infection was 20 months. TNFi treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment. Four patients reinitiated with the same TNFi, whereas two patients started with another TNFi. During a mean follow-up of 30.6 months, all six patients successfully completed TB treatment with no TB infection relapses.\n\n\nCONCLUSIONS\nOur results suggest that resuming TNFi therapy in patients following adequate TB treatment is safe, even before completion of TB treatment.",
"affiliations": "Division of Rheumatology and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.;Division of Rheumatology and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. bestmd2000@amc.seoul.kr.;Division of Rheumatology and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.;Division of Rheumatology and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.;Division of Rheumatology and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.;Division of Rheumatology and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.;Division of Rheumatology and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.",
"authors": "Kim|You Jae|YJ|;Kim|Yong-Gil|YG|;Shim|Tae Sun|TS|;Koo|Bon San|BS|;Hong|Seokchan|S|;Lee|Chang-Keun|CK|;Yoo|Bin|B|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept",
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/keu041",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": "53(8)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "Mycobacterium tuberculosis; inhibitor; rheumatic disease; safety; tuberculosis; tumour necrosis factor",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015535:Arthritis, Psoriatic; D001172:Arthritis, Rheumatoid; D001528:Behcet Syndrome; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor; D019233:Retreatment; D012189:Retrospective Studies; D014376:Tuberculosis; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "1477-81",
"pmc": null,
"pmid": "24681840",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety of resuming tumour necrosis factor inhibitors in patients who developed tuberculosis as a complication of previous TNF inhibitors.",
"title_normalized": "safety of resuming tumour necrosis factor inhibitors in patients who developed tuberculosis as a complication of previous tnf inhibitors"
} | [
{
"companynumb": "KR-JNJFOC-20140716267",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Follicular dendritic cell sarcoma is a rare malignancy arising from follicular dendritic cells, which form a meshwork within lymphoid follicles. Traditional treatment of metastatic disease with CHOP chemotherapy, the most commonly used regimen for lymphoid malignancies, has met with limited success. I report herein two cases of follicular dendritic cell sarcoma metastatic to the liver treated with the combination of gemcitabine and docetaxel showing unprecedented response in this disease. These observations coupled with recent evidence of a mesenchymal origin of follicular dendritic cells support the premise that this malignancy should be treated similar to other adult soft tissue sarcomas.",
"affiliations": "Division of Hematology & Oncology, University of Alabama at Birmingham, 2145 Bonner Way, Birmingham, AL 35243, USA.",
"authors": "Conry|Robert M|RM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/2045-3329-4-6",
"fulltext": "\n==== Front\nClin Sarcoma ResClin Sarcoma ResClinical Sarcoma Research2045-3329BioMed Central 2045-3329-4-62500973810.1186/2045-3329-4-6Case ReportResponse of follicular dendritic cell sarcoma to gemcitabine and docetaxel: report of two cases and literature review Conry Robert M 1rconry@uabmc.edu1 Division of Hematology & Oncology, University of Alabama at Birmingham, 2145 Bonner Way, Birmingham, AL 35243, USA2014 28 6 2014 4 6 6 16 4 2014 25 6 2014 Copyright © 2014 Conry; licensee BioMed Central Ltd.2014Conry; 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/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Follicular dendritic cell sarcoma is a rare malignancy arising from follicular dendritic cells, which form a meshwork within lymphoid follicles. Traditional treatment of metastatic disease with CHOP chemotherapy, the most commonly used regimen for lymphoid malignancies, has met with limited success. I report herein two cases of follicular dendritic cell sarcoma metastatic to the liver treated with the combination of gemcitabine and docetaxel showing unprecedented response in this disease. These observations coupled with recent evidence of a mesenchymal origin of follicular dendritic cells support the premise that this malignancy should be treated similar to other adult soft tissue sarcomas.\n\nFollicular dendritic cellSarcomaGemcitabineDocetaxelChemotherapyMetastatic\n==== Body\nBackground\nFollicular dendritic cell sarcoma (FDCS) is a rare malignancy arising from follicular dendritic cells which form an arborizing meshwork within lymphoid follicles and are involved in antigen capture, retention and presentation to B cells. Follicular dendritic cells (FDCs) also protect against autoimmunity by expediting removal of potentially self-reactive debris from negatively selected, apoptotic B lymphocytes in germinal centers [1]. The hyaline vascular variant of Castleman’s disease, angiofollicular lymph node hyperplasia, involves a premalignant proliferation of FDCs with dysplasia. Approximately 20% of cases of FDCS are associated with this entity with sequential pathological changes from Castleman’s disease to FDCS documented at individual sites in several reported cases [2,3]. Multicentric Castleman’s disease is usually responsive to CHOP chemotherapy or single agent rituximab despite the fact that FDCs are CD20 negative. The likely mechanism involves depletion of follicular B lymphocytes with secondary reduction of lymphotoxin and other mediator release essential for FDC development. Evidence suggests that Epstein-Barr virus plays a causative role in a rare subset of FDCS affecting the liver and spleen [4].\n\nFDCS affects males and females equally with a median age at diagnosis of 47 years, with a wide range from 14 to 77 years [3]. Approximately 60% of cases arise in lymph nodes, most commonly cervical or mediastinal. Some occur in extranodal sites including lung, liver, spleen and GI tract [5]. FDCSs typically present as a large mass with mean diameter ranging from 7 to 10 centimeters. Systemic symptoms are uncommon. Pathologically, FDCSs are well-circumscribed with spindle to ovoid cells arranged in a fascicular, whorled or storiform pattern, typically with infiltration by scattered small lymphocytes. Ultrastructural examination reveals complex cytoplasmic processes and features resembling fibroblasts [6]. Immunohistochemistry is required to make the diagnosis. FDCSs are usually reactive for FDC markers CD21, CD23, and CD35 [5]. Tumor cells also typically express vimentin, a soft tissue sarcoma marker.\n\nSurgical excision is the treatment of choice for localized FDCS with radiation therapy also used in approximately a third of cases. Local recurrences are reported in 30-40% of cases and metastases also develop in approximately 30% of patients. CHOP chemotherapy has been the most frequently reported systemic therapy with transient, partial responses observed in some patients [7]. Complete responses to CHOP are rare, and the benefits of this regimen may derive primarily from doxorubicin, one of the most broadly active agents against sarcoma in general.\n\nThe regimen of gemcitabine and docetaxel is broadly active against soft tissue sarcomas with relatively good tolerability [8]. Gemcitabine 900 mg/m2 is administered days 1 and 8 with docetaxel 100 mg/m2 administered day 8 of a 21 day cycle with neulasta, G-CSF, given day 9. Response rates are improved using a fixed dose rate infusion of gemcitabine at 10 mg per m2 per minute [9], although cytopenias are somewhat more pronounced. Although objective responses occur in 50% of leiomyosarcomas, the overall response rate is approximately 20% in previously treated soft tissue sarcomas in general [8]. A multicenter phase II trial compared gemcitabine with or without docetaxel and the combination produced superior objective response rate, progression-free survival and overall survival [10]. Although RECIST responses occured in only 16% of patients receiving the combination, median progression-free survival was 6.2 months [10]. I report hereafter two cases of FDCS metastatic to the liver with objective response to gemcitabine and docetaxel.\n\nCase report\nPatient 1 was a 51-year-old Caucasian male who underwent wide excision of a FDCS of the duodenal wall with negative margins. This was a spindle cell malignancy with immunohistochemistry positive for CD21, CD23 and vimentin and negative for CD20, CD34, CD35, CD117 (c-kit), DOG 1 and smooth muscle actin. EGFR expression was negative by immunohistochemistry and mutation analysis was wild type. One year after surgery, he was diagnosed with multiple liver metastases confirmed by biopsy and received six cycles of CHOP chemotherapy at another medical center with partial response. However, four months after completing CHOP he had marked worsening of hepatic metastases with numerous lesions affecting all hepatic segments up to 7 cm diameter. Prior to transfer of care to our center, he went untreated for two additional months during which time liver metastases coalesced with the largest becoming 15 cm in diameter, but the lungs remained clear. He had moderate right upper quadrant pain and fullness, but surprisingly no constitutional symptoms such as fatigue, anorexia or weight loss. Due to limited tissue availability, only two genes were sequenced to determine potential clinical trial eligibility, and both BRAF and PI3KCA were wild type as has been reported in FDCS. He received gemcitabine by fixed dose rate infusion and docetaxel since he had already approached his lifetime limit of doxorubicin. After three cycles, he achieved a RECIST 1.1 partial response with the largest hepatic metastasis decreasing from 15 to 9.5 cm diameter, the second largest decreasing from 10.3 to 7.0 cm and symptomatic improvement. After six cycles, the hepatic metastases continued to respond with the largest mass decreasing to 6.4 cm and the second largest to 5.9 cm. Docetaxel was discontinued after six cycles due to lower extremity edema and bilateral pleural effusions, which subsequently resolved. Gemcitabine was continued for a total of 12 cycles with the largest hepatic mass decreasing to 5 cm and the second largest to 4.7 cm. Performance status and quality of life remained excellent throughout treatment, and a RECIST 1.1 partial response is continuing at the time of this report.\n\nPatient 2 was a 36-year-old African-American female who presented with Coombs positive autoimmune hemolytic anemia unresponsive to steroids successfully treated with splenectomy. One year later, she developed generalized abdominal pain with a 9 cm left periaortic, mesenteric mass with open biopsy revealing FDCS with brisk mitoses (25 per 10 hpf). Immunohistochemistry was positive for CD21, CD23, EGFR, vimentin and dim CD35, but negative for CD20, CD34, CD117 (c-kit) and DOG 1. Insufficient tissue was available for gene sequencing. Bone marrow biopsy and aspirate were mildly hypercellular, but otherwise unremarkable with normal karyotype. Her hemoglobin was stably low at 10.5 with normal MCV and a persistently positive direct Coombs test for IgG. Retrospectively, her autoimmune hemolysis requiring splenectomy appears likely related to subclinical FDCS, particularly since FDCs are known to share antigens with erythrocytes, including CD35. Over two months the primary tumor became 30 percent larger and was treated with radiation. Six months after completing radiation therapy, the primary mass had decreased from 8.8 to 6.6 cm with increased central necrosis, but multiple new hepatic metastases had developed up to 3.3 cm with lungs remaining clear. Liver biopsy confirmed metastatic FDCS, and she received fixed dose rate gemcitabine and docetaxel as initial systemic therapy. After six cycles, she achieved a RECIST 1.1 partial response with the largest liver metastasis decreasing from 3.3 cm to 1.8 cm and the second largest decreasing from 2.4 cm to 0.9 cm. After nine cycles of gemcitabine and docetaxel, the largest metastasis further decreased to 1.5 cm and the second largest remained stable at 0.9 cm. The radiated periaortic primary gradually decreased in diameter and developed calcifications. Chemotherapy was discontinued after nine cycles due to plateauing response and fatigue. At the time of this report, she has a continuing RECIST 1.1 partial response two months after discontinuing gemcitabine and docetaxel.\n\nDiscussion\nThe historic rationale for using CHOP chemotherapy, the most commonly used regimen to treat intermediate grade lymphoma, as systemic therapy for FDCS involved several early observations linking FDCS with B lymphocytes. For example, FDCSs most often arise within lymph node follicles, 20% of cases occur within a background of follicular lymph node hyperplasia, i.e. Castleman’s disease, rare cases are associated with Epstein Barr virus infection, and origin of FDCs from lymphoid precursors was postulated. However, response of Castleman’s disease to CHOP likely involves depletion of B lymphocytes with resultant reduction in paracrine release of FDC growth factors rather than direct cytotoxicity to FDCs. Furthermore, recent work has shown FDC precursors to be of vascular stromal rather than lymphoid origin. FDCs can emerge anywhere in the body during chronic inflammation and participate in the organization of new B cell follicles in non-lymphoid tissues suggesting the existence of a ubiquitous progenitor. Recently discovered FDC precursors are sessile cells originating from vascular stroma found throughout the body in vascular walls and expressing platelet-derived growth factor receptor beta [6]. Thus, FDCs are of mesenchymal origin [11]. FDCSs have complex karyotypes associated with structural abnormalities and loss of multiple chromosomes as seen in the majority of adult sarcomas [12], and the clinical behavior of these tumors is more akin to that of low to intermediate grade soft tissue sarcomas rather than lymphoid malignancies.\n\nThis is the first report of objective response of this rare sarcoma to combination chemotherapy with gemcitabine and docetaxel. These agents are generally well tolerated and applicable to patients across a broad range of age and comorbidity. Response of FDCS to this commonly used sarcoma regimen further supports the mesenchymal nature of this malignancy and suggests a role for other agents like pazopanib approved for soft tissue sarcoma therapy.\n\nEpidermal growth factor receptor (EGFR) expression has been reported in normal FDCs, dysplastic FDCs associated with hyaline vascular Castleman’s disease and 16 of 16 cases of FDCS [11]. Yet, no EGFR mutations or gene amplifications were observed. Absence of somatic mutations of KRAS, NRAS, BRAF and PI3KCA in FDCS suggests EGFR inhibition as another potential treatment strategy [11].\n\nConclusion\nDurable objective response to gemcitabine and docetaxel was observed in two patients with follicular dendritic cell sarcoma metastatic to the liver. This observation supports the notion that FDCS should be treated similar to other adult soft tissue sarcomas rather than lymphoid malignancies. These are to my knowledge the only reported cases of FDCS treated with the combination of gemcitabine and docetaxel. This combination could represent a therapeutic alternative for follicular dendritic cell sarcoma.\n\nConsent\nWritten informed consent was obtained from the patients for publication of this Case Report.\n\nCompeting interests\nThe author declare that they have no competing interests.\n==== Refs\nAguzzi A Krautler NJ Characterizing follicular dendritic cells: a progress report Eur J Immunol 2010 40 2134 2138 10.1002/eji.201040765 20853499 \nChan AC Chan KW Chan JK Au WY Ho WK Ng WM Development of follicular dendritic cell sarcoma in hyaline-vascular Castleman’s disease of the nasopharynx: tracing its evolution by sequential biopsies Histopathology 2001 38 510 518 10.1046/j.1365-2559.2001.01134.x 11422494 \nHwang SO Lee TH Bae SH Cho HD Choi KH Park SH Kim CH Kim SJ Transformation of Castleman’s disease into follicular dendritic cell sarcoma, presenting as an asymptomatic intra-abdominal mass Korean J Gastroenterol 2013 62 131 134 10.4166/kjg.2013.62.2.131 23981949 \nPan ST Cheng CY Lee NS Liang PI Chuang SS Follicular dendritic cell sarcoma of the inflammatory pseudotumor-like variant presenting as a colonic polyp Korean J Pathol 2014 48 140 145 10.4132/KoreanJPathol.2014.48.2.140 24868227 \nShinagare AB Ramaiya NH Jagannathan JP Hornick JL Swanson RS Primary follicular dendritic cell sarcoma of liver treated with cyclophosphamide, doxorubicin, vincristine, and prednisone regimen and surgery J Clin Oncol 2011 29 e849 e851 10.1200/JCO.2011.37.1906 22042944 \nKrautler NJ Kana V Kranich J Tian Y Perera D Lemm D Schwarz P Armulik A Browning JL Tallquist M Buch T Oliveira-Martins JB Zhu C Hermann M Wagner U Brink R Heikenwalder M Aguzzi A Follicular dendritic cells emerge from ubiquitous perivascular precursors Cell 2012 150 194 206 10.1016/j.cell.2012.05.032 22770220 \nKhalid T Folman R Symptoms in cancer patients and an unusual tumor: Case 3. Follicular dendritic cell sarcoma J Clin Oncol 2005 23 9425 9426 10.1200/JCO.2004.00.9365 16361643 \nBay JO Ray-Coquard I Fayette J Leyvraz S Cherix S Piperno-Neumann S Chevreau C Isambert N Brain E Emile G Le Cesne A Cioffi A Kwiatkowski F Coindre JM Bui NB Peyrade F Penel N Blay JY Groupe Sarcome Français Docetaxel and gemcitabine combination in 133 advanced soft-tissue sarcomas: a retrospective analysis Int J Cancer 2006 119 706 711 10.1002/ijc.21867 16496406 \nPatel SR Gandhi V Jenkins J Papadopolous N Burgess MA Plager C Plunkett W Benjamin RS Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation J Clin Oncol 2001 19 3483 3489 11481354 \nMaki RG Wathen JK Patel SR Priebat DA Okuno SH Samuels B Fanucchi M Harmon DC Schuetze SM Reinke D Thall PF Benjamin RS Baker LH Hensley ML Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002[corrected] J Clin Oncol 2007 25 2755 2763 10.1200/JCO.2006.10.4117 17602081 \nVermi W Giurisato E Lonardi S Balzarini P Rossi E Medicina D Bosisio D Sozzani S Pellegrini W Doglioni C Marchetti A Rossi G Pileri S Facchetti F Ligand-dependent activation of EGFR in follicular dendritic cells sarcoma is sustained by local production of cognate ligands Clin Cancer Res 2013 19 5027 5038 10.1158/1078-0432.CCR-13-1275 23888072 \nPerry AM Nelson M Sanger WG Bridge JA Greiner TC Cytogenetic abnormalities in follicular dendritic cell sarcoma: report of two cases and literature review In Vivo 2013 27 211 214 23422480\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-3329",
"issue": "4()",
"journal": "Clinical sarcoma research",
"keywords": "Chemotherapy; Docetaxel; Follicular dendritic cell; Gemcitabine; Metastatic; Sarcoma",
"medline_ta": "Clin Sarcoma Res",
"mesh_terms": null,
"nlm_unique_id": "101577890",
"other_id": null,
"pages": "6",
"pmc": null,
"pmid": "25009738",
"pubdate": "2014",
"publication_types": "D002363:Case Reports",
"references": "22770220;16496406;23422480;22042944;16361643;11481354;23888072;11422494;24868227;23981949;20853499;17602081",
"title": "Response of follicular dendritic cell sarcoma to gemcitabine and docetaxel: report of two cases and literature review.",
"title_normalized": "response of follicular dendritic cell sarcoma to gemcitabine and docetaxel report of two cases and literature review"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/15/0054182",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
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... |
{
"abstract": "To evaluate the efficacy of golimumab on severe and frequent recurrent anterior uveitis in patients with HLA-B27-positive ankylosing spondylitis. In this study, 15 eyes of 12 HLA-B27-positive AS patients with resistant anterior uveitis who received 50 mg of subcutaneous golimumab (Gol) per month due to frequent uveitis recurrences were analyzed retrospectively between May 2013 and October 2015. Assessment criteria were uveitis activity, the number of recurrence of uveitis, visual acuity, systemic corticosteroid, or other drug requirement for maintenance of remission of AU. Twelve patients (15 eyes) with HLA-B27-positive ankylosing spondylitis and anterior uveitis have been treated with golimumab 50 mg/month. Remission of uveitis was observed in 12 eyes out of 15. Malign hypertension developed in one subject after the second dose of golimumab therefore the treatment was stopped and this subject was excluded from the study. Median follow-up time was 11 months (interquartile range: 8-18). No uveitic reaction was seen except in the patient who stopped treatment. No topical or systemic steroid necessity was needed except in two cases with oral 4 mg systemic maintenance. Visual acuity was significantly increased (p = 0.002). Golimumab may be a new and effective choice for maintaining remission and the prevention of recurrences of severe, resistant anterior uveitis in patients with HLA-B27-positive ankylosing spondylitis.",
"affiliations": "Department of Ophthalmology, Medical Faculty, Bulent Ecevit University, Zonguldak, Turkey.;Department of Ophthalmology, Medeniyet University School Of Medicine, Istanbul Medeniyet Üniversitesi Tıp Fakültesi. Göztepe Eğitim Ve Araştırma Hastanesi. Doktor Erkin Caddesi. Kadıköy, Istanbul, Turkey. h.ugurcelik@gmail.com.;Division of Rheumatology, Department of Internal Medicine, Medical Faculty, Bulent Ecevit University, Zonguldak, Turkey.;Division of Rheumatology, Department of Internal Medicine, Ankara Research and Education Hospital, Ankara, Turkey.;Physical Medicine and Rehabilitation, Medical Faculty, Bulent Ecevit University, Zonguldak, Turkey.;Department of Internal Medicine, Medical Faculty, Bulent Ecevit University, Zonguldak, Turkey.;Department of Physiology, Medical Faculty, Bulent Ecevit University, Zonguldak, Turkey.;Division of Rheumatology, Department of Internal Medicine, Medical Faculty, Hitit University, Çorum, Turkey.",
"authors": "Yazgan|Serpil|S|;Celik|Ugur|U|;Işık|Metin|M|;Yeşil|Nesibe Karahan|NK|;Baki|Ali Erdem|AE|;Şahin|Hatice|H|;Gencer|Ercan|E|;Doğan|İsmail|İ|",
"chemical_list": "D000911:Antibodies, Monoclonal; D015796:HLA-B27 Antigen; D007155:Immunologic Factors; D000079424:Tumor Necrosis Factor Inhibitors; C529000:golimumab",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10792-016-0239-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5701",
"issue": "37(1)",
"journal": "International ophthalmology",
"keywords": "Anterior Uveitis; Golimumab; HLA-B27-positive ankylosing spondylitis",
"medline_ta": "Int Ophthalmol",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000911:Antibodies, Monoclonal; D005260:Female; D015796:HLA-B27 Antigen; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012189:Retrospective Studies; D013167:Spondylitis, Ankylosing; D000079424:Tumor Necrosis Factor Inhibitors; D014606:Uveitis, Anterior; D014792:Visual Acuity",
"nlm_unique_id": "7904294",
"other_id": null,
"pages": "139-145",
"pmc": null,
"pmid": "27154720",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": "1561395;22012970;15529379;11026996;16196117;25214011;14656639;21236513;23999006;23352252;12118164;26164736;1561400;16901960;16932659;19284323;24143896;18662932;23916070;24976689;10555027;20643395;7667647;20544353",
"title": "Efficacy of golimumab on recurrent uveitis in HLA-B27-positive ankylosing spondylitis.",
"title_normalized": "efficacy of golimumab on recurrent uveitis in hla b27 positive ankylosing spondylitis"
} | [
{
"companynumb": "TR-JNJFOC-20170310100",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GOLIMUMAB"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nThe aims of this study were to assess (1) the magnitude and temporality of decreased urinary citrate excretion in patients just starting topiramate and (2) the effect of alkali replacement on topiramate-induced hypocitraturia.\n\n\nMETHODS\nStudy 1 was a prospective, non-intervention study in which patients starting topiramate for headache remediation provided pre- and post-topiramate 24 h urine collections for measurement of urine citrate. Study 2 was a clinical comparative effectiveness study in which patients reporting to our stone clinic for kidney stones and who were treated with topiramate were prescribed alkali therapy. Pre- and post-alkali 24 h urinary citrate excretion was compared.\n\n\nRESULTS\nData for 12 and 22 patients (studies 1 and 2 respectively) were evaluated. After starting topiramate, urinary citrate excretion dropped significantly by 30 days (P = 0.016) and 62% of patients had hypocitraturia (citrate <320 mg day(-1) ). At 60 days, urine citrate was even lower than at baseline (P = 0.0032) and 86% of patients had developed hypocitraturia. After starting alkali, urine citrate increased in stone-forming patients on topiramate (198 ± 120 to 408 ± 274 mg day(-1) ; P = 0.042 for difference). 85% of patients were hypocitraturic on topiramate alone vs. 40% after adding alkali. The increase in urinary citrate was greater in patients provided ≥ 90 mEq potassium citrate.\n\n\nCONCLUSIONS\nOur study is the first to provide clinical evidence that alkali therapy can raise urinary citrate excretion in patients who form kidney stones while being treated with topiramate. Clinicians should consider alkali therapy for reducing the kidney stone risk of patients benefitting from topiramate treatment for migraine headaches or other conditions.",
"affiliations": "Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI.;Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.;Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.",
"authors": "Jhagroo|R Allan|RA|;Wertheim|Margaret L|ML|;Penniston|Kristina L|KL|",
"chemical_list": "D000468:Alkalies; D000077236:Topiramate; D019343:Citric Acid; D005632:Fructose; D019357:Potassium Citrate",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.12751",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "81(1)",
"journal": "British journal of clinical pharmacology",
"keywords": "alkali replacement; citrate; headache; nephrolithiasis; topiramate; urolithiasis",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D000468:Alkalies; D019343:Citric Acid; D005260:Female; D005632:Fructose; D006801:Humans; D007669:Kidney Calculi; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders; D019357:Potassium Citrate; D011446:Prospective Studies; D000077236:Topiramate",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "131-6",
"pmc": null,
"pmid": "26297809",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article",
"references": "24338699;23592242;22158731;20888032;23470015;24219102;19302942;26098405;17396168;25280288;16417067;26297809;16985842;21165738",
"title": "Alkali replacement raises urinary citrate excretion in patients with topiramate-induced hypocitraturia.",
"title_normalized": "alkali replacement raises urinary citrate excretion in patients with topiramate induced hypocitraturia"
} | [
{
"companynumb": "US-JNJFOC-20160103291",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "Hemophagocytic syndrome (HS) is a syndromic complex that is categorized in the group of histiocytic disorders associated with macrophages. A 39-year-old male patient was admitted to the outpatient clinic with complaint of left flank pain. A 1 cm kidney stone was found in the upper pole of left kidney at radiologic imaging. The patient underwent retrograde intrarenal surgery (RIRS) with no peroperative complication. High fever and increasing of acute-phase reactants were observed at postoperative first day. Besides resistant fever, pancytopenia developed despite the appropriate antibiotherapy. The urine and blood cultures were sterile. After multidisciplinary consultation, bone marrow sampling was performed. Microscopic examination of the bone marrow material revealed that the macrophage cells phagocyted the erythrocytes, which was compatible with HS. Unfortunately despite the appropriate medical HS treatment, the patient died due to multiorgan failure at the 21st day of RIRS. HS is a significantly rare complication after RIRS, which was presented initially with postoperative fever. HS should be kept in mind if the patient had resistant fever and pancytopenia despite the appropriate antibiotherapy.",
"affiliations": "Urology Department and Faculty of Medicine, Tekirdağ Namık Kemal University, Tekirdağ, Turkey.;Urology Department and Faculty of Medicine, Tekirdağ Namık Kemal University, Tekirdağ, Turkey.;Urology Department and Faculty of Medicine, Tekirdağ Namık Kemal University, Tekirdağ, Turkey.;Urology Department and Faculty of Medicine, Tekirdağ Namık Kemal University, Tekirdağ, Turkey.;Hematology Department, Faculty of Medicine, Tekirdağ Namık Kemal University, Tekirdağ, Turkey.",
"authors": "Akgül|Murat|M|;Yazıcı|Cenk|C|;Ateş|Hüseyin|H|;Altın|Enes|E|;Turgut|Burhan|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/cren.2020.0066",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2379-9889",
"issue": "6(4)",
"journal": "Journal of endourology case reports",
"keywords": "complication; hemophagocytic syndrome; retrograde intrarenal surgery",
"medline_ta": "J Endourol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101684114",
"other_id": null,
"pages": "339-342",
"pmc": null,
"pmid": "33457669",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A Rare Retrograde Intrarenal Surgery Complication: Hemophagocytic Syndrome.",
"title_normalized": "a rare retrograde intrarenal surgery complication hemophagocytic syndrome"
} | [
{
"companynumb": "TR-TEVA-2021-TR-1882309",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Opioid-associated ototoxicity is a known complication of opioid exposure, although the mechanism remains unclear. While historically most closely linked to heroin and oxycodone, evolving reports suggest that it may be a class effect of opioids. However, the evidence is limited to case reports.\n\n\n\nA retrospective review of the New Jersey Poison Center records (ToxiCALL®) identified cases that included both hearing loss and recent opioid exposure between January 1, 1999, and September 21, 2018.\n\n\n\nForty-one cases were identified, mean age 29.4 years, 51% (n = 21) were male. Reported heroin exposures comprised 51% (n = 22), 18 of which were heroin alone. The next most commonly cited opioids were oxycodone (n = 7), methadone, (n = 4), and tramadol (n = 3). Hearing loss was described as tinnitus in 24% of cases, hypoacusis in 37% of cases, deafness in 29% of cases, and mixed tinnitus/hypoacusis in 10% of cases. Only 34% (n = 14) of cases were associated with a potential hypoxic event. Of the cases that documented resolution data, 21% (n = 4 of 19) reported no improvement at time of hospital discharge.\n\n\n\nOpioid-associated ototoxicity appears to be a hypoxia-independent adverse effect since most of the reported cases did not involve a known contributory hypoxic event. It occurs with a wide array of opioids, which supports an opioid receptor-mediated mechanism. The ototoxic effect may be self-limited in many patients.\n\n\n\nOpioid-associated ototoxicity was most commonly associated with heroin exposure and appeared independent of hypoxic events. Further investigation that clarifies the risk factors and long-term outcomes is needed.",
"affiliations": "Rutgers New Jersey Medical School, 140 Bergen Street, Suite G1600, Newark, NJ, 07103, USA. amozeika@njms.rutgers.edu.;New Jersey Poison Information and Education System, Newark, NJ, USA.;New Jersey Poison Information and Education System, Newark, NJ, USA.;New Jersey Poison Information and Education System, Newark, NJ, USA.",
"authors": "Mozeika|Alexander M|AM|0000-0003-4037-7526;Ruck|Bruce E|BE|;Nelson|Lewis S|LS|;Calello|Diane P|DP|",
"chemical_list": "D009292:Narcotic Antagonists",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-020-00785-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "16(4)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": "Hearing; Opioid; Ototoxicity; Poison center; Toxicology",
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D055030:Drug Users; D005260:Female; D034381:Hearing Loss; D006801:Humans; D008297:Male; D008875:Middle Aged; D009292:Narcotic Antagonists; D009515:New Jersey; D009293:Opioid-Related Disorders; D000081015:Ototoxicity; D011039:Poison Control Centers; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "416-422",
"pmc": null,
"pmid": "32468345",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": "23983704;30627386;25278190;19116790;10881270;19128688;11683145;682808;21586255;16817873;12855366;20028962;17525781",
"title": "Opioid-Associated Hearing Loss: A 20-Year Review from the New Jersey Poison Center.",
"title_normalized": "opioid associated hearing loss a 20 year review from the new jersey poison center"
} | [
{
"companynumb": "US-SPECGX-T202001357",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPROPION"
},
"drugadditional": "3",
"dr... |
{
"abstract": "For many, sleep and sex are crucial for physical, emotional, and mental well-being. Poor sleep quality is linked to a myriad of ailments from coronary artery disease to major depressive disorder. Likewise, a decrease in the frequency of sexual activity is associated with a decrease in self-rated health status. Kleine-Levin syndrome (KLS) is a rare sleep disorder that provides a unique lens to examine the intricate interplay between sleep and sex as it is one of the few sleep disorders defined by concomitant sexual dysfunction.\n\n\n\nThis study reviews the literature on links between sleep disorders and sexuality with a focus on women's health followed by a case study of unusual patient with KLS with persistent genital arousal disorder.\n\n\n\nLiterature searches were conducted for English language publications, including foreign language publications with English abstracts with ninety-five articles reviewed. The literature review is followed by a case report.\n\n\n\nWe review the known literature linking sleep and women's sexual health with a focus on insomnia, circadian rhythm sleep disorder, obstructive sleep apnea, restless leg syndrome, sexsomnia, and KLS. We then present a case of KLS-associated persistent genital arousal disorder, which was amenable to treatment with a multimodal approach aimed at symptomatic relief with intravaginal diazepam suppositories, topical clitoral lidocaine, and duloxetine.\n\n\n\nThis case highlights that hypersexuality and persistent arousal cannot effectively be treated in isolation but rather must be contextualized within a patient's broader medical history and diagnoses. Specifically, sleep quality and potential sleep disorders should be assessed for those presenting with sexual health complaints (and vice versa). Zwerling B, Keymeulen S, Krychman ML. Sleep and Sex: A Review of the Interrelationship of Sleep and Sexuality Disorders in the Female Population, Through the Lens of Sleeping Beauty Syndrome. Sex Med Rev 2021;9:221-229.",
"affiliations": "Department of Obstetrics & Gynecology, University of California, Irvine, Orange, CA, USA.;School of Medicine, University of California, Irvine, Orange, CA, USA.;Department of Obstetrics & Gynecology, University of California, Irvine, Orange, CA, USA. Electronic address: mkrychman@icloud.com.",
"authors": "Zwerling|Blake|B|;Keymeulen|Sawa|S|;Krychman|Michael L|ML|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.sxmr.2020.08.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2050-0521",
"issue": "9(2)",
"journal": "Sexual medicine reviews",
"keywords": "Circadian Rhythm; Kleine-Levin Syndrome; Parasomnias; Persistent Genital Arousal Disorder; Restless Legs Syndrome; Sexual Dysfunction; Sleep Apnea; Sleep Disorders; Sleep Initiation and Maintenance Disorders; Women's Health",
"medline_ta": "Sex Med Rev",
"mesh_terms": null,
"nlm_unique_id": "101614773",
"other_id": null,
"pages": "221-229",
"pmc": null,
"pmid": "33023862",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Sleep and Sex: A Review of the Interrelationship of Sleep and Sexuality Disorders in the Female Population, Through the Lens of Sleeping Beauty Syndrome.",
"title_normalized": "sleep and sex a review of the interrelationship of sleep and sexuality disorders in the female population through the lens of sleeping beauty syndrome"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP005233",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional":... |
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